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Lipoic Acid Improves Nerve Blood Flow, Reduces Oxidative Stress, and Improves Distal Nerve Conduction in Experimental Diabetic Neuropathy
Abstract
To determine whether lipoic acid (LA) will reduce oxidative stress in diabetic peripheral nerves and improve neuropathy.
We used the model of streptozotocin-induced diabetic neuropathy (SDN) and evaluated the efficacy of LA supplementation in improving nerve blood flow (NBF), electrophysiology, and indexes of oxidative stress in peripheral nerves affected by SDN, at 1 month after onset of diabetes and in age-matched control rats. LA, in doses of 20, 50, and 100 mg/kg, was administered intraperitoneally five times per week after onset of diabetes.
NBF in SDN was reduced by 50%; LA did not affect the NBF of normal nerves but improved that of SDN in a dose-dependent manner. After 1 month of treatment, LA-supplemented rats (100 mg/kg) exhibited normal NBF. The most sensitive and reliable indicator of oxidative stress was reduction in reduced glutathione, which was significantly reduced in streptozotocin-induced diabetic and alpha-tocopherol-deficient nerves; it was improved in a dose-dependent manner in LA-supplemented rats. The conduction velocity of the digital nerve was reduced in SDN and was significantly improved by LA.
These studies suggest that LA improves SDN, in significant part by reducing the effects of oxidative stress. The drug may have potential in the treatment of human diabetic neuropathy.
... The levels of several other inflammatory markers such as C-reactive protein, fibrinogen, plasminogen activator inhibitor I, and interleukin 6 have been shown to increase with the onset of diabetes. Monocyte activation has been documented in the presence of high glucose with induction of inflammatory mediators such as PKC and nuclear factor kB promoting oxidative stress [37]. ...
... Clinical and electrophysiological measures identified more severe peripheral neuropathy in these patients; the cumulative metformin dose correlated strongly with the differences. Thus, metformin exposure may be an iatrogenic cause for exacerbation of peripheral neuropathy in patients with type 2 diabetes [37]. Interval screening for cobalamin deficiency and systemic cobalamin therapy should be considered upon initiation of, as well as during metformin therapy to detect potential secondary causes of worsening peripheral neuropathy. ...
... Oxidation of cholesterol to oxysterols in neurons mediates tissue injury [32], whereas plasma lipoproteins, particularly low-density lipoproteins (LDLs), are oxidized by ROS and bind oxidized LDL receptor 1 (LOX1) [33], Tolllike receptor 4 (TLR4) [34] and RAGE [35]. Binding of oxidized LDLs to these receptors activates a series of signaling cascades, including activation of caspase 3 and nuclear DNA degradation, that mediate additional inflammation and ROS accumulation, with continued and progressive nerve injury [36,37]. ...
Diabetic Peripheral Neuropathy- prevalence, occurance, presentation, treatment
... Parenteral lipoic acid was associated with a considerable elevation of insulin-stimulated disposal of glucose (Jacob S, Henriksen EJ, Schiemann AL, Simon I, Clancy DE, Tritschler HJ, Jung WI, Augustin HJ & Dietze GJ., 1995). Nagamatsu et al (1995) from the USA reported an experimental study on streptozotocin induced diabetes which showed that the nerve blood flow in the diabetic animals was reduced by 50%, and it returned to normal after one month of treatment with lipoic acid 100 mg per kilogram. This beneficial effect was associate with evidence of reduction of oxidative stress (Nagamatsu M, Nickander KK, Schmelzer JD, Raya A, Wittrock DA, Tritschler H & Low PA., 1995). ...
... Nagamatsu et al (1995) from the USA reported an experimental study on streptozotocin induced diabetes which showed that the nerve blood flow in the diabetic animals was reduced by 50%, and it returned to normal after one month of treatment with lipoic acid 100 mg per kilogram. This beneficial effect was associate with evidence of reduction of oxidative stress (Nagamatsu M, Nickander KK, Schmelzer JD, Raya A, Wittrock DA, Tritschler H & Low PA., 1995). Ziegler et al (1995) from Germany reported a 3-week double-blind placebo-controlled study which included 328 diabetic patients (Non-insulin-dependent) from several centers who had symptomatic peripheral neuropathy. ...
Dietary health supplements have been increasingly used in the treatment and prevention of chronic disorders. During the previous years, lipoic acid has been reported to have a beneficial effect on diabetes and some of its complications. The aim of this paper is to review the evidence provided by lipoic acid research findings relevant to its use in diabetes. Since, the1950s, there has been an accumulating experimental evidence showing that that lipoic acid, a naturally occurring substance, has a protective effects against the development of diabetes and its complications especially neuropathy. The beneficial use of oral lipoic acid in diabetic neuropathy has been reported mostly from Germany as early as the 1960s.
... ALA is a key compound in some mitochondrial enzyme complexes (pyruvate dehydrogenase and ketogluterate dehydrogenase), which play a central role in oxidative metabolism. ALA can reduce oxidative stress, preventing damage from oxygen-free radicals [26][27][28][29][30][31][32][33][34][35]. Unlike other antioxidants that have full functionality in aqueous or fatty tissues, ALA exerts its antioxidant function in both water and fats. ...
... In recent years, several studies have demonstrated the utility of oxygen-ozone therapy in the treatment of herniated discs as well as the known analgesic potentialities of ALA, while myrrh and the PEA, on the other hand, act as biological modulators, favoring the physiological tissue response [26][27][28][29][30][31][32][33][34][35]. ...
Background:
The aim of our observational study is to compare the therapeutic efficacy of combined treatment of oxygen-ozone therapy and oral treatment with alpha-lipoic acid (ALA) + palmitoylethanolamide (PEA) and myrrh in patients with peripheral neuropathic pain (sciatica) on radicular disc conflict from disc herniation and the results obtained with oxygen-ozone treatment alone.
Methods:
We enrolled 318 patients with the neuroradiological diagnosis of disc herniation performed with computed tomography (CT) or magnetic resonance imaging (MRI) and symptoms characterized by low back pain complicated by sciatica, which we divided into two groups. Group A was composed of 165 patients who were treated only with oxygen-ozone therapy with CT-guided intraforaminal technique, while the remaining 153 (Group B) have undergone combined oral treatment with ALA + PEA and myrrh. Follow-up visits for the evaluation of the clinical outcome of the treatment were conducted after 60 ± 8 days using a modified version of McNab's method.
Results:
At the clinical check-up, 126/165 patients included in Group A had a complete remission of pain (76.4%), while in Group B, 119/153 (77.8%) had a complete remission of pain.
Conclusion:
The results highlight how the treatment associated with ozone therapy and oral administration of alpha-lipoic acid + palmitoylethanolamide and myrrh is preferred over the simple treatment with only ozone in such patients in the phase of greatest acuity of the disease, where the pain appears to be better controlled.
... Тя е универсален антиоксидант, като се счита, че упражнява едновременно директен (улавяне на свободните радикали) и индиректен антиоксидантен ефект (възстановяване на други ендогенни антиоксиданти като витамин А и Е, глутатион) (16). Допълнително предотвратява липидната пероксидация, което води до редукция на окислителния стрес и подобряване на ендотел-зависимата вазодилатация на невралните микросъдове, тяхната трофика и проводимост (17). Бенфотиаминът също спада към патогенетичните терапии за диабетна невропатия, като повишава нивото на вътреклетъчния тиамин и понижава нивата на крайните продукти на гликирането. ...
Introduction: Diabetic neuropathy is a chronic microvascular complication and one of the most common complications of diabetes. Diabetes changes mainly the sensory function, most often symmetrically, which facilitates the development of ulcers and they in turn are a prerequisite for the development of diabetic neuro-osteoarthropathy (Charcot’s foot). Neuropathic pain, which often accompanies diabetic polyneuropathy, is still a challenge for conventional pharmacological therapy. The treatment plan also includes a non-pharmacological method of treatment, such as photobiomodulation, which includes lasers. The Multiwave Locked System (MLS) is a class IV near infrared (NIR) diode laser, characterized by combining and synchronizing two emissions with different wavelengths—λ-808 nm in constant mode and λ-905 nm in pulsed mode. Aim : The aim of this study is to investigate the long-term effect of MLS laser radiation in patients with diabetic sensorimotor polyneuropathy. Materials and Methods : Twenty patients of both sexes, diagnosed with type 2 diabetes and diabetic sensorimotor neuropathy, were treated with MLS laser radiation. The high-energy laser M6 from ASA Laser, Italy was used. The therapeutic technique used was in two stages: scanning of the foot (100–175 cm²) of the two lower limbs with MLS fixed, robotic multidiode device (remote method), and treatment of seven fields, on each lower limb, each with an area of 3.14 cm², with MLS single-diode hand applicator (contact method). The therapeutic course included 9 procedures distributed within 3 working weeks, 1 procedure per day, every other day, a total of 3 procedures per week. A short form of the McGill Pain Questionnaire (SF-MPQ-2) was used as a subjective indicator. Nerve conduction parameters were used for objectifying treatment results, namely: distal latency, amplitude of action potential and conduction velocity in sensory nerve, n. suralis and motor nerve, n. peroneus. Results : There is a significant reduction in pain intensity in both men and women immediately after the end of the therapeutic course. The strength of the pain in women, on the 90th day from the beginning of the treatment, does not retain its value from the end of the treatment course, but remains significantly lower than its initial levels. Nerve conduction parameters showed an increase in the amplitude of the action potential, bilaterally for n. suralis and n. peroneus, as well as an increase in the conduction velocity of n. suralis and n. peroneus on the left, on the 90th day. Conclusion: The high-energy MLS laser has the potential to be an effective therapy for painful diabetic neuropathy, as it is able to modify the pain and electroneurographic parameters of peripheral nerve function with lasting effects.
... Increased oxidative stress caused by free radical formation and defects in antioxidant defense related to hyperglycemia is thought to cause endoneurial hypoxia and nerve dysfunction, which contribute to DPN [61]. Preclinical studies have shown that administration of the antioxidant alpha-lipoic acid reduces neurovascular abnormalities associated with DPN [62][63][64][65]. ...
Diabetic peripheral neuropathy (DPN) is one of the most prevalent chronic complications of diabetes. The lifetime prevalence of DPN is thought to be >50%, and 15%-25% of patients with diabetes experience neuropathic pain, referred to as "painful DPN." Appropriate treatment of painful DPN is important because this pain contributes to a poor quality of life by causing sleep disturbance, anxiety, and depression. The basic principle for the management of painful DPN is to control hyperglycemia and other modifiable risk factors, but these may be insufficient for preventing or improving DPN. Because there is no promising diseasemodifying medication for DPN, the pain itself needs to be managed when treating painful DPN. Drugs for neuropathic pain, such as gabapentinoids, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, alpha-lipoic acid, sodium channel blockers, and topical capsaicin, are used for the management of painful DPN. The U.S. Food and Drug Administration (FDA) has approved pregabalin, duloxetine, tapentadol, and the 8% capsaicin patch as drugs for the treatment of painful DPN. Recently, spinal cord stimulation using electrical stimulation is approved by the FDA for the treatment for painful DPN. This review describes the currently available pharmacological and nonpharmacological treatments for painful DPN.
... Apart from these, the free radical scavengers like α-Tocopherol and lipoic acids are also reported to elevate the blood flow in peripheral nerve and thereby relieving peripheral neuropathy [257]. Gamma linoleic acid (GLA) is an important constituent in phospholipid bilayer of neuronal membrane whose formation is found to be impaired in diabetes [258]. Studies on animals have shown that gamma linoleic acid has the potential to prevent, or in some cases reverse the neuropathy of diabetes by improving the microcirculation of peripheral nerve [259]. ...
Recently, much attention has been paid to chronic neuro-inflammatory condition underlying neuropathic pain. It is generally linked with thermal hyperalgesia and tactile allodynia. It results due to injury or infection in the nervous system. The neuropathic pain spectrum covers a variety of pathophysiological states, mostly involved are ischemic injury viral infections associated neuropathies, chemotherapy-induced peripheral neuropathies, autoimmune disorders, traumatic origin, hereditary neuropathies, inflammatory disorders, and channelopathies. In CNS, angiogenesis is evident in inflammation of neurons and pain in bone cancer. The role of chemokines and cytokines is dualistic; their aggressive secretion produces detrimental effects, leading to neuropathic pain. However, whether the angiogenesis contributes and exists in neuropathic pain remains doubtful. In the present review, we elucidated summary of diverse mechanisms of neuropathic pain associated with angiogenesis. Moreover, an overview of multiple targets that have provided insights on the VEGF signaling, signaling through Tie-1 and Tie-2 receptor, erythropoietin pathway promoting axonal growth are also discussed. Because angio-genesis as a result of these signaling, results in inflammation, we focused on the mechanisms of neuropathic pain. These factors are mainly responsible for the activation of post-traumatic regeneration of the PNS and CNS. Furthermore, we also reviewed synthetic and herbal treatments targeting angiogenesis in neuropathic pain.
... In the streptozocin-induced rat diabetes model, ALA was shown to delay the onset of development of polyneuropathy. 32 In over a dozen clinical trials of diabetic neuropathic pain, ALA has been reported to reduce pain and other neuropathy symptoms with meta-analysis results showing a number needed to treat of 6.3. 18,45 Investigations into neural mechanisms of ALA suggest that it decreases nociceptive sensitivity through inhibition of Ttype calcium (Cav3.2) channels, 26 distinct from that of pregabalin which inhibits N-type calcium channels, 36 suggesting potential for synergy at these different sites of action. ...
Drug therapy for fibromyalgia is limited by incomplete efficacy and dose-limiting adverse effects (AEs). Combining agents with complementary analgesic mechanisms-and differing AE profiles-could provide added benefits. We assessed an alpha-lipoic acid (ALA)-pregabalin combination with a randomized, double-blind, 3-period crossover design. Participants received maximally tolerated doses of ALA, pregabalin, and ALA-pregabalin combination for 6 weeks. The primary outcome was daily pain (0-10); secondary outcomes included Fibromyalgia Impact Questionnaire, SF-36 survey, Medical Outcomes Study Sleep Scale, Beck Depression Inventory (BDI-II), adverse events, and other measures. The primary outcome of daily pain (0-10) during ALA (4.9), pregabalin (4.6), and combination (4.5) was not significantly different (P = 0.54). There were no significant differences between combination and each monotherapy for any secondary outcomes, although combination and pregabalin were both superior to ALA for measures of mood and sleep. Alpha-lipoic acid and pregabalin maximal tolerated doses were similar during combination and monotherapy, and AEs were not frequent with combination therapy. These results do not support any additive benefit of combining ALA with pregabalin for fibromyalgia. The observation of similarly reached maximal tolerated drug doses of these 2 agents (which have differing side-effect profiles) during combination and monotherapy-without increased side effects-provides support for future development of potentially more beneficial combinations with complementary mechanisms and nonoverlapping side effects.
... ALA is an antioxidant that exerts its antioxidant function in both of these tissues. This property gives thioctic acid a broad spectrum of antioxidant action [33][34][35][36]. ...
Background and objective:
Our study compares the clinical outcome of chronic low back pain present for over six months treated with alpha-lipoic acid (ALA) + palmitoylethanolamide (PEA) and myrrh and periradicular infiltrations of oxygen-ozone under CT guide to periradicular steroidal infiltrations in a short (one week), medium (three months) and long-term period (six months).
Methods:
We enrolled 246 patients (Group A) with low back pain treated with periradicular infiltrations of oxygen-ozone under CT guide combined with 800 mg/day of ALA + 600 mg/day of PEA + 200 mg/day of myrrh orally. Group B consisted of 176 patients with low back pain treated with periradicular infiltrations of steroids. Patients were clinically monitored one week after the end of treatment, at three months, and at six months using a modified version of McNab's method.
Results:
In Group A, the one-week clinical follow-up registered a complete remission of painful symptoms in 206 patients (83.7%), and this manifestation remained optimal in 191 patients at the three-month follow-up (77.6%) and in 178 at six months (72.3%). While the results were satisfactory in 28 patients (10.9%) at one week, 32 (13%) in the medium term, and 41 (16.6%) in the long term, non-significant results were found in 12 patients in the control at one week (4.6%), in 23 at three months (9.3%) and in 27 at six months (10.9%). In Group B, at the short-term follow-up we obtained an excellent clinical result in 103 patients (80.5%), while at three months 85 patients reported the persistence of clinical benefit (66.4%) and at six months, 72 (56.2%) reported the same result. The result was rated satisfactory in 11 (8.5%) and poor in 4 (3%). At the three-month follow-up, 23 (18%) reported a satisfactory result, and 20 (15.6%) had a poor result. At six months, 24 (18.8%) reported the persistence of a satisfactory result while for 32 the result was poor (25%).
Conclusion:
The results highlight how the treatment associated with ozone therapy and oral administration of alpha-lipoic acid + palmitoylethanolamide and myrrh can be considered a valid alternative to common therapeutic approaches in the treatment of chronic low back pain.
... Indeed, ALA can be considered as the only treatment that acts on the pathogenesis of the disease while the others-α2δ ligands, tricyclic antidepressants and opioids-are only symptomatic treatments for pain. The mechanism may be related to an improvement in nerve blood flow and distal nerve conduction mediated by the antioxidant action [111,112].A systematic review including 15 articles, examined the effect of ALA 300-600 mg i.v. per day for two to four weeks, on motor nerve conduction velocity (MNCV) and sensory nerve conduction velocity (SNCV). Both these parameters increased after ALA administration even though most of the studies included in this review were of poor methodological quality [113]. ...
Alpha-lipoic acid (ALA) is a natural compound with antioxidant and pro-oxidant properties which has effects on the regulation of insulin sensitivity and insulin secretion. ALA is widely prescribed in patients with diabetic polyneuropathy due to its positive effects on nerve conduction and alleviation of symptoms. It is, moreover, also prescribed in other insulin resistance conditions such as metabolic syndrome (SM), polycystic ovary syndrome (PCOS) and obesity. However, several cases of Insulin Autoimmune Syndrome (IAS) have been reported in subjects taking ALA. The aim of the present review is to describe the main chemical and biological functions of ALA in glucose metabolism, focusing on its antioxidant activity, its role in modulating insulin sensitivity and secretion and in symptomatic peripheral diabetic polyneuropathy. We also provide a potential explanation for increased risk for the development of IAS.
... SOD also maintains redox balance in neurons as well as vascular endothelium. The oxidation of nicotinamide adenine dinucleotide phosphate (NADP + /NADPH) caused by elevated glucose levels reduces SOD activity [75,76], which activates aldose reductase (AR) and protein kinase C, resulting in pain perception. However, because of the antagonistic interaction between NADPH and glutathione disulfide (GSSG)-reductase, less GSH available to protect cells and the sulfhydryl group of cysteine in proteins [58,77]. ...
Background
Diabetes-induced neuropathic pain is manifested as a lowering of nerve transmission rate, increased discomfort, sensual loss, and axonal degradation, and is the most prevalent secondary consequence of diabetes. Diabetes is a devitalizing disease affecting people from diverse groups in both developing and industrialized countries. The inflammation pathway and oxidative stress both contribute considerably to diabetic peripheral neuropathy via the activation of inflammatory cytokines. Hyperglycemia-mediated neural oxidative stress and damage activates a number of metabolic pathways, causing diabetic neuropathy. The current study investigated the neuroprotective potential of methanolic extract of Sphaeranthus indicus Linn (MESI) in ameliorating diabetic neuropathic pain induced by administration of streptozotocin in rats.
Results
Four weeks after intraperitoneal treatment of streptozotocin (STZ), there was a significant decrease in mechano-tactile allodynia and mechanical and thermal hyperalgesia. Furthermore, STZ-induced oxidative stress increases the extent of neural lipid peroxidation (LPO), as evidenced by increased MDA levels, decreases the activities of endogenous antioxidants such as superoxide dismutase (SOD) and glutathione (GSH), and alters sciatic neural histoarchitecture. Chronic administration of methanolic extract of Sphaeranthus indicus Linn (MESI) for 4 weeks significantly and dose-dependently attenuated the decrease in levels of nociceptive thresholds, endogenous antioxidants (SOD and GSH), and increase in LPO. Furthermore, MESI significantly restored sciatic neural histoarchitecture.
Conclusion
The amelioration of streptozotocin-induced diabetic neuropathy by methanolic extract of Sphaeranthus indicus Linn (MESI) could be attributed to its antinociceptive, antioxidant, and neuroprotective properties.
... Lipoic acid, a potential antioxidant, improves diabetic neuropathy by improving blood flow, reducing oxidative stress, and improving distal nerve conduction [48]. A prospective interventional study conducted in 2015-2016 concluded that lipoic acid administration was associated with reduced neuropathic symptoms and improved quality of life in painful diabetic neuropathy patients [49]. ...
Aim:
Neuropathic pain affects 7-10% of the population, with most of the patients receiving inadequate and incomplete treatment. Owing to the high financial burden and the poor quality of life of the patients and their caretakers, there is a dire need to address the challenges in diagnosing and treating chronic neuropathic pain.
Methods:
This literature review was conducted to review novel treatments and related challenges through a systematic search from sources such as PubMed, Google Scholar with the combination of MESH words such as neuropathic pain, management of neuropathic pain. Articles from non-English literature, reports without human subjects, animal studies, and abstracts/posters were excluded. However, human studies and studies published in English were included.
Result:
This review article discusses novel treatment modalities while acknowledging the challenges medical workers face while encountering neuropathic pain. Despite the recent advances in diagnosis and treatment modalities, several challenges still exist. Hence, there is still a need to explore the various treatment modalities, emphasizing the cause and underlying pathophysiology of neuropathic pain.
Conclusion:
We recommend integrated multimodal treatment with the current treatment facility, including various medical disciplines. However, a personalized approach would work the best depending on the 'patient's medical history. Therefore, this article recommends an integrated, cause-specific, cost-effective approach to address this problem of chronic neuropathic pain.
... Alpha-lipoic acid is used in the treatment of diabetic neuropathy, neuropsychiatric diseases, and cardiovascular diseases. Alpha-lipoic acid has been shown to reduce oxidative stress and improve distal nerve conduction by increasing nerve blood flow (7,8). ...
Amaç: Bu çalışma, Bell paralizisi tedavisinde alfa-lipoik asidin etkinliğini House-Brackmann derecelendirme sistemi ve elektromyografi kullanarak değerlendirmeyi amaçlamaktadır.Gereç ve Yöntemler: Bu retrospektif çalışmaya toplam 33 hasta dahil edildi. Hastalar iki gruba ayrıldı. Grup 1, Bell paralizisi tedavisine ek olarak günde 300 mg alfa-lipoik asit alan 18 hastayı içeriyordu. Grup 2, sadece Bell paralizisi tedavisi alan 15 hastayı içeriyordu. Her iki grupta da kabulde, 21. günde ve 3. ayda House-Brackmann derecelendirme skoru kaydedildi. 21. günde yapılan elektromyografi sonuçları da tarandı. Hastalar elektromyografi sonuçlarına göre iyi prognoz (nöropraksi) ve kötü prognoz (aksonotmezis ve nörotmezis) olarak sınıflandırıldı. İki grup House-Brackmann dereceleri ve elektromyografi sonuçlarına göre karşılaştırıldı.Bulgular: Grup 1, 10 kadın ve 8 erkekten, Grup 2 ise 6 kadın ve 9 erkekten oluşuyordu. Bell felcinin sağda veya solda olmasına göre iki grup arasında fark yoktu. Grupların 21. gün ve 3. aydaki House-Brackmann derecelendirme skoru, başvuru sırasında House-Brackmann derecelendirme skorundan anlamlı derecede düşüktü. House-Brackmann derecelerine göre iki grup arasında anlamlı fark yoktu. Gruplar arasında bileşik kas aksiyon potansiyeli oranı ve prognoz açısından fark yoktu.Sonuç: Alfa-lipoik asit çeşitli hastalıklarda sinir rejenerasyonu için kullanılmasına rağmen çalışmamızda Bell paralizisi tedavisine anlamlı bir etki göstermemiştir.
... Inflammation is an oxidative process, and the modulation and suppression of oxidative damage have been investigated for decades. In Europe, ALA has been extensively studied for the treatment of diabetic neuropathy [65][66][67][68][69]. Treatment with ALA decreases oxidative stress and improves endothelial function in patients with metabolic syndrome and animal models with diabetic neuropathy [70,71]. Both in the short-term (600-1800 mg/day) [65,68] and long-term (4 years), ALA treatments improve neuropathy and muscle weakness with no changes in nerve conduction. ...
Peripheral neuropathies constitute a group of disorders affecting the peripheral nervous system. Neuropathies have multiple causes such as infections (i.e., COVID-19), diabetes, and nutritional (low vitamin levels), among others. Many micronutrients, such as vitamins (A, C, D, E, B6, B12, and folate), certain minerals (Fe, Mg, Zn, Se, and Cu), and ω-3 fatty acids have immunomodulatory effects. Therefore, they may play an instrumental role in the treatment of COVID-19 infection. However, many COVID-19 patients can undergo neuropathy. In this context, there is a wealth of information on a variety of first-, second-, and third-line treatment options. This review focuses on the application of nutraceutical strategies in order to improve the symptomatology of neuropathy and neuropathic pain in patients that suffered from COVID-19. Our aim is to provide an alternative vision to traditional medical-pharmacological treatment through nutraceuticals.
... Peripheral neuropathies include not only sensory loss and motor deficits, but also autonomic neuropathy, such as ED. Oxidative stress plays a main role in the pathogenesis of diabetic neuropathy (27). Alpha lipoic acid improves nerve blood flow, reduces oxidative stress and improves distal nerve conduction in a rat model of diabetic neuropathy (28), suggesting promising results in terms of treatment of neuropathic symptoms (29,30). ...
Aim
To evaluate if therapy with a nutraceutical combination of alpha lipoic acid, Vitis vinifera L. and Ginkgo biloba (Blunorm forte ® ) can be helpful and be synergic with Avanafil.
Methods
The trial included 123 males with type 2 diabetic mellitus and with erectile dysfunction (ED), aged ≥18 years. Patients were divided in four different arms: 1 st arm: placebo during the three months of treatment and before sexual act; 2 nd arm: placebo for three months and Avanafil: 1 tablet, 200 mg, 15-30 minutes before sexual act; 3 rd arm: Blunorm forte: 1 tablet, 40 minutes before the meal (breakfast) during the three months and Avanafil: 1 tablet, 200 mg, 15-30 minutes before sexual act; 4 th arm: Blunorm forte: 1 tablet, 40 minutes before the meal (breakfast and dinner) during the three months and placebo 15-30 minutes before sexual act.
Results
A significant reduction of fasting plasma glucose, and homeostasis model assessment-insulin resistance index were recorded both in Avanafil + Blunorm forte and with Blunorm forte. Metalloproteinases-2, and -9 were reduced in the Avanafil + Blunorm forte group. High sensitivity-C-reactive protein was decreased by both Avanafil, and Avanafil + Blunorm forte group. No variations were recorded with the other treatments.
The group treated with Blunorm forte and Avanafil reached a higher International Index of Erectile Function (IIEF) score after 3 months of therapy compared to baseline and placebo and compared to Avanafil and Blunorm forte taken alone.
Conclusion
Blunorm forte ® can be helpful and synergic with Avanafil in increasing sexual performance compared to placebo.
... It has been approved in Germany for the clinical treatment of diabetic neuropathy. Improvement in the nerve blood flow, distal nerve conduction, an increase in endoneurial glucose uptake, and energy metabolism were observed in animals [179][180][181][182]. ...
Diabetic neuropathy is an incapacitating chronic pathological condition that encompasses a large group of diseases and manifestations of nerve damage. It affects approximately 50% of patients with diabetes mellitus. Autonomic, sensory, and motor neurons are affected. Disabilities are severe, along with poor recovery and diverse pathophysiology. Physical exercise and herbal-based therapies have the potential to decrease the disabilities associated with diabetic neuropathy. Aerobic exercises like walking, weight lifting, the use of nutraceuticals and herbal extracts are found to be effective. Literature from the public domain was studied emphasizing various beneficial effects of different exercises, use of herbal and nutraceuticals for their therapeutic action in diabetic neuropathy. Routine exercises and administration of herbal and nutraceuticals, either the extract of plant material containing the active phytoconstituent or isolated phytoconstituent at safe concentration, have been shown to have promising positive action in the treatment of diabetic neuropathy. Exercise has shown promising effects on vascular and neuronal health and has proven to be well effective in the treatment as well as prevention of diabetic neuropathy by various novel mechanisms, including herbal and nutraceuticals therapy is also beneficial for the condition. They primarily show the anti-oxidant effect, secretagogue, anti-inflammatory, analgesic, and neuroprotective action. Severe adverse events are rare with these therapies. The current review investigates the benefits of exercise and nutraceutical therapies in the treatment of diabetic neuropathy.
... The main action of ALA is a 'scavenger effect' on lipophilic-free radicals (55). A series of experimental studies have shown that ALA may improve the local blood flow and increase the speed of nerve conduction in peripheral nerves (57). ...
Diabetic neuropathy (DN) is a frequent complication of diabetes mellitus (DM) with severe consequences as it progresses and influences all human body systems. This review discusses the risk factors for DN, the main characteristics of the clinical forms of DN, the screening methods and the current therapeutic options. Distal symmetric DN is the primary clinical form, and DM patients should be screened for this complication. The most important treatment of DN remains good glucose control, generally defined as HbA1c ≤7%. Symptomatic treatment improves life quality in diabetic patients. Pharmacological agents such as alpha (α)-lipoic acid and benfotiamine have been validated in several studies since they act on specific pathways such as increased oxidative stress (α-lipoic acid exerts antioxidant effects) and the excessive production of advanced glycosylation products (benfotiamine may inhibit their production via the normalization of glucose). Timely diagnosis of DN is significant to avoid several complications, including lower limb amputations and cardiac arrhythmias.
... In experimental DN, α-lipoic acid treatment averted neurovascular irregularities. In diabetic rat models, this treatment also attenuated GSH levels, digital nerve conduction velocity, and nerve blood flow via increasing free radical scavenging activity [137,138]. Probucol is a strong free radical scavenger and an inhibitor of low-density lipoprotein oxidation that normalizes both electrophysiology and nerve blood flow [139]. In a study, Al-Rejaie et al. [140] revealed that naringenin contains antioxidant properties. ...
Diabetic neuropathy (DN) is a common and serious diabetes-associated complication that primarily takes place because of neuronal dysfunction in patients with diabetes. Use of current therapeutic agents in DN treatment is quite challenging because of their severe adverse effects. Therefore, there is an increased need of identifying new safe and effective therapeutic agents. DN complications are associated with poor glycemic control and metabolic imbalances, primarily oxidative stress (OS) and inflammation. Various mediators and signaling pathways such as glutamate pathway, activation of channels, trophic factors, inflammation, OS, advanced glycation end products, and polyol pathway have a significant contribution to the progression and pathogenesis of DN. It has been indicated that polyphenols have the potential to affect DN pathogenesis and could be used as potential alternative therapy. Several polyphenols including kolaviron, resveratrol, naringenin, quercetin, kaempferol, and curcumin have been administered in patients with DN. Furthermore, chlorogenic acid can provide protection against glutamate neurotoxicity via its hydrolysate, caffeoyl acid group, and caffeic acid through regulating the entry of calcium into neurons. Epigallocatechin-3-gallate treatment can protect motor neurons by regulating the glutamate level. It has been demonstrated that these polyphenols can be promising in combating DN-associated damaging pathways. In this article, we have summarized DN-associated metabolic pathways and clinical manifestations. Finally, we have also focused on the roles of polyphenols in the treatment of DN.
... ALA, and its reduced form (dihydrolipoic acid) act as antioxidants by neutralization of reactive oxygen species, inhibition of reactive-oxygen generators, and restoration of damage caused by other oxidants [12]. Furthermore, studies support that ALA increases glutathione levels, and hampers lipid peroxidation [18] & [19]. In our results, the body mass index decreased significantly at the end of the third month. ...
Introduction: Alpha lipoic acid (ALA) is an antioxidant used in the treatment of neuro-inflammation, diabetes and diabetic nephropathy. The current study aiming to gauge the effect of oral ALA on diabetic peripheral neuropathy, glycemic control, LDL-C, and HDL-C. Methods: This is a prospective, interventional study carried out on patients with type 2 diabetes mellitus (DM) who were following at the outpatient internal medicine & diabetes clinics at Benha University Hospital. Treatment with ALA for 3 months was given to patient with diabetic peripheral neuropathy. Data in the form of age, sex, body mass index (BMI), duration & treatment of DM, manifestations of peripheral neuropathy were collected. LDL-C, HDL-C, HbA1c, TSH, ALT, AST were measured before and after intervention. Peripheral neuropathy symptoms, nerve conduction velocities, cardiovascular (CV) tests of autonomic neuropathy, and cross-section area of the posterior tibial nerve were performed before and after treatment intervention. Results: 90 adult diabetic patients were recruited in the study, 42.2% were females and 57.8% were males with a median age of 50–60.3 years (IQR = 52). A statistically significant improvements of neuropathic symptoms, nerve conduction velocity, and cardiovascular autonomic neuropathy were noted after 3 months of administration of ALA (p ˂0.001). However, the cross-section area of the posterior tibial nerve at baseline and after treatment did not change significantly (p value of 0.84). There was a significant improvement in the BMI, HDL-C, LDL-C, HbA1c (p ˂ 0.001). Conclusion: Oral treatment with ALA might cause ameliorations of peripheral neuropathy, HbA1c, and LDL-C & HDL-C levels in diabetic patients. Our result failed to proof effect of ALA on nerve cross-section area. The global data encourage further studies with this medication as an ancillary treatment of DM2.
Clinical trial registration: It was registered in clinical trial website; ClinicalTrials.gov Identifier (NCT number): NCT04322240.
... 4,12 To evaluate the impact of OXA alone or combined with antioxidants upon oxidative parameters, we selected the dose of 50 mg/kg NAC, a-LA and Vit E, which has been reported effective as antioxidant for the three test compounds. 19,56,59 OXA was administrated in alternate days, combined or not with oral antioxidants, for a total of 14 days as outlined in Fig 2A. We analyzed levels of oxidative stress end products, namely TBARS and protein carbonyl groups, and found that OXA increased lipoperoxidation in the liver, heart, kidneys ( Fig 2B) and in the spinal cord (Fig 2D). ...
Chemotherapy-Induced Peripheral Neuropathy (CIPN) is a common, difficult-to-treat, and dose-limiting side effect associated with Oxaliplatin (OXA) treatment. In this study, we evaluated the effect of three antioxidants - namely N-acetylcysteine, α-lipoic acid and vitamin E – upon nociceptive parameters and antitumor efficacy of OXA in a tumor-bearing Swiss mice model. Oral treatment with antioxidants inhibited both mechanical and cold allodynia when concomitantly administrated with OXA (preventive protocol), as well as in animals with previously established CIPN (therapeutic protocol). OXA increased Reactive Oxygen Species (ROS) production and lipoperoxidation, and augmented the content of pro-inflammatory cytokines (IL-1β and TNF-α) and expression of the astrocytic marker Gfap mRNA in the spinal cord. Antioxidants decreased ROS production and lipoperoxidation, and abolished neuroinflammation in OXA-treated animals. Toll-like receptor 4 (Tlr4) and inflammasome enzyme caspase-1/11 knockout mice treated with OXA showed reduced levels of pro-inflammatory cytokines (but not oxidative stress) in the spinal cord, which were associated with resistance to OXA-induced mechanical allodynia. Lastly, antioxidants affected neither antitumor activity nor hematological toxicity of OXA in vivo. The herein presented results are provocative for further evaluation of antioxidants in clinical management of chemotherapy-induced peripheral neuropathy.
Perspectives: This study reports preventive and therapeutic efficacy of orally administrated antioxidants (N-acetylcysteine, α-lipoic-acid and Vitamin-E) for alleviating oxaliplatin-induced peripheral neuropathy in tumor-bearing mice. Antioxidants’ anti-nociceptive effects are associated with inhibition of ROS-dependent neuroinflammation, and occur at no detriment of OXA antitumor activity, therefore indicating a translational potential of these compounds.
... α-lipoic acid is a naturally occurring anti-oxidant compound, which is required as cofactor for various metabolic 7 processes. In an animal model, various biological activities of α-lipoic acid including reduced oxidative stress, enhance the blood flow to nerves and also boost to nerve conduction have been 8 reported. It is obtained from food in variable quantities and is used as a pharmacological agent administered in oxidative-stress associated disorders like neurodegenerative disorders, diabetes, ischemic heart diseases, cataract and in 9,10 mushroom and heavy metal poisoning. ...
Objective: To compare the mean change in total
symptom score (TSS) or neuropathic symptom
score (NSS) in diabetic patients taking α-lipoic
acid and in controls taking usual treatments.
Methodology: This randomized control trial study
comprised of 110 patients who were divided into
equal treatment group and control group. The
mean change in TSS was determined in both
groups. Data analysis was performed by using
SPSS version 20.
Results: Mean age of patients with treatment
group was 46.09±11.86 years and in control group
47.67±10.66 years. Male to female ratio was
1.03:1. The mean change in TSS in treatment
group was 2.38±1.99 and in control group was
0.53±1.32 (p<0.001). The comparison of mean
TSS score was significantly reduced for other
variables (HbA1c, numbness, burning and
paresthesia) in post-treatment group than the
pretreatment group (p <0.001).
Conclusion: The mean change in TSS improved
in diabetic patients taking α-lipoic acid and it
showed significantly better effect and reduced the
diabetic neuropathic pain in treated patients than
controls. (Rawal Med J 202;46:33-36).
... So, this study was designed to evaluate the effect of ALA, at a dose of 25 mg/kg.ip [20] on chronic neuropathic pain produced by CCI of sciatic nerve in rats. ...
Background
Chronic neuropathic pain syndrome is associated with impaired quality of life and is poorly manageable. Alpha lipoic acid (ALA) is a powerful antioxidant and showed its effectiveness on diabetic neuropathy and other acute peripheral nerve injuries but it was not evaluated in the chronic neuropathic pain, chronic constriction injury (CCI) in rat model by using duloxetine (DLX) as standard.
Methodology
The main objective of the study was to expedite ALA effect on chronic peripheral neuropathy induced by CCI of sciatic nerve in rats. In this study, male Wister rats were randomly divided into six groups (n = 8) including, normal saline, sham operated, surgery control, DLX 30mg/kg treated, ALA treated 25mg/kg, and ALA+DLX. The CCI of sciatic nerve was conducted on all animals except normal saline group and studied for 21 days (i.e. 14 days treatment period & 7 days treatment free period) by using different behavioral, biochemical and, histopathology studies.
Results
ALA showed minor but significant decrease of thermal hyperalgesia, cold allodynia, malondialdehyde (MDA), total protein, lipid peroxidation, and nitric oxide levels and significant increase of motor coordination, glutathione level and decreased axonal degeneration significantly. These effects sustained even during treatment free period. ALA enhanced the effect of DLX when given in combination by showing sustained effect. In conclusion, ALA acted as potent antioxidant may be this activity is responsible for the potent neuroprotective effect.
Conclusion
Hence, ALA attenuated the nueroinflammation mediated by chronic peripheral neuropathy. Further studies are warranted with ALA to develop as a clinically relevant therapeutic agent for the treatment of neuropathic pain.
... This present finding was further substantiated by the findings of Vessal et al (2003) who reported that Alpha Lipoic Acid (ALA) serves beneficial effects in decreasing blood glucose concentration, promoting regeneration of the pancreatic islets and increasing insulin release in STZ-diabetic rats. ALA is a potent antioxidant that has effects on fuel metabolism and also acts as an essential cofactor of mitochondrial respiratory enzymes, including the pyruvate dehydrogenase (PDH) complex (Nagamatsu et al., 1995). Several studies suggest alpha-lipoic acid helps lower blood sugar levels. ...
Antioxidant plays an important role in preventing the progression of diabetes mellitus (DM) complications. This study was undertaken to evaluate the hypoglycemic effect of glutathione complex in Alloxan induced diabetic rats. Thirty albino rats (weighing 120-130g) were divided into six groups of five rats each: Group one serves as normal control, group two served as diabetic control while Group three, four and five were diabetic and administered with 2.4mg/kg body weight, 3.6mg/kg body weight and 4.8mg/kg body weight respectively. All treatments were administered orally for 4 weeks on daily basis. Serum glucose level was measured at an interval of three days throughout the period of the experiment. Results obtained showed that administration of Glutathione Complex to diabetic rats caused a significant decrease (p<0.05) in serum glucose level compared to diabetic control. These results suggest that administration of Glutathione Complex to diabetic rats may help reverse the complications of diabetes mellitus.
... It improved nerve blood flow, reduced oxidative stress, and improved distal nerve conduction in an experimental DN rat model. [19] A clinical study examining the effect of ALA on neuropathic symptoms in patients with DN demonstrated that ALA administration was associated with reduced neuropathic symptoms and triglycerides and improved quality of life. [20] Although some clinical trials have been conducted on the anti-obesity effects of ALA, [21][22][23] several studies have shown that ALA has no significant effect on weight reduction. ...
Alpha-lipoic acid (ALA), a sulfur-containing fatty acid ubiquitously present in living organisms, is a cofactor that covalently binds to mitochondrial enzymes, such as pyruvate dehydrogenase (PDH) and oxoglutarate dehydrogenase (OGDH). ALA is not only crucial to the function of major enzymes that provide carbon to the tricarboxylic acid cycle but also has strong antioxidant properties. Indeed, ALA has a variety of properties under physiological and pathological conditions. In particular, ALA has been shown to have a protective effect on the cardiovascular system. The specific mechanisms may involve an anti-oxidative stress role by scavenging reactive oxygen species (an antioxidant property), regulation of aldehyde dehydrogenase-2 (ALDH2), and anti-inflammatory properties. The present review discusses the endogenous disulfide compound ALA, with a focus on its roles in cardioprotection and the underlying mechanisms.
... [35] It has been shown to improve nerve blood flow, reduce oxidative stress, and improve distal nerve conduction in a rat model of diabetic neuropathy. [36] In Ziegler et al's randomised, [37] double-blind, placebo-controlled, multicenter, double-arm, parallel trial, ALA has been shown to be effective for mild to moderate diabetic sensorimotor polyneuropathy (DSPN). ...
Background:
Diabetes mellitus with erectile dysfunction (DMED) is one of the most common causes of disability in diabetic population, and its pathogenesis is related to a variety of factors. Because its pathogenesis is complex and the existing treatment methods have limitations, DMED is difficult to treat in clinical. Recently, some studies have shown that α-lipoic acid (ALA) is associated with DMED, but there is no systematic review and meta-analysis on the relationship between ALA and DMED.
Methods:
We will search each database from the built-in until July 2020. The English literature mainly searches Cochrane Library, PubMed, EMBASE, and Web of Science, while the Chinese literature comes from CNKI, CBM, VIP, and Wangfang database. Simultaneously we will retrieve clinical registration tests and grey literatures. This study only screen the clinical randomized controlled trials (RCTs) about ALA for DMED to assess its efficacy. The 2 researchers worked independently on literature selection, data extraction, and quality assessment. The dichotomous data is represented by relative risk (RR), and the continuous is expressed by mean difference (MD) or standard mean difference (SMD), eventually the data is synthesized using a fixed effect model (FEM) or a random effect model (REM) depending on whether or not heterogeneity exists. Erectile dysfunction (ED) will be diagnosed by the International Index of Erectile Function 5 (IIEF-5) score. Finally, meta-analysis was conducted by RevMan software version 5.3.
Results:
This study will synthesize and provide high quality to evaluate the effectiveness of ALA supplementation for the treatment of DMED.
Conclusion:
This systematic review aims to provide new options for ALA supplementation treatment of DMED in terms of its efficacy and safety.
Prospero registration number:
INPLASY202070130.
... Plant species such as spinach, broccoli and potatoes possess a high concentration of alpha-lipoic acid (Karaarslan et al. 2013). Several reports showed that lipoic acids possess enhanced anti-diabetic property (Nagamatsu et al. 1995;Packer 1994;Reljanovic et al. 1999;Ruhnau et al. 1999). Karkabounas et al. (2018) revealed that daily supplementation of alpha-lipoic acid can reduce the concentration of glucose by elevating insulin secretion from the pancreas in type 2 diabetic patients via randomized double-blind study. ...
The Organosulfur compounds (OSCs) are bioactive compounds or nutraceuticals derived from both plant and animal sources. They contain sulfur atoms that are bound to a cyanate group or a carbon atom in a cyclic or noncyclic configuration. Broccoli, cauliflower, cabbage, brussel sprouts, garlic, onion, meat, eggs, and fish are the most common sources of OSC. Allicin, s-allyl cysteine, sulforaphane, cysteine, sulfonylureas, methionine, and lipoic acid are the most common type of OSC that have been isolated from different plant sources. Different resources contain different types of OSC and these compounds may have different health benefits. Various OSC/nutraceuticals are claimed to have strong antioxidant activity. In addition, anti-platelet, immunomodulatory, fibrinolytic, anti-ageing, anti-inflammatory, anti-microbial, anti-parasitic, anti-hypertensive, anti-hyperlipidemic, anti-atherosclerotic and antiviral activities also have been reported in OSC. These activities are beneficial in the treatment of various pathological conditions including neurodegenerative disorders, cardiovascular diseases, cancer and diabetes. The present chapter discusses the commonly known OSC and their biological activities so that these compounds can be better harnessed for society.
... For example, the Symptomatic Diabetic Neuropathy study (SYDENY 2), which included 181 diabetic patients (type 1 or 2) with symptomatic DPN (TSS >7.5 points), reported that treatment with once-daily oral doses of ALA (600 mg) for 5 weeks reduced pain (TSS: 51% compared to 32% in the placebo group) and significantly improved stabbing and burning pain, scores on the Neuropathy Symptoms and Change (NSC) scale, and patients' global assessments of efficacy [21]. Other studies have reported that improvements in neuropathic symptoms and deficits following treatment with ALA may be related to improvements in nerve blood flow mediated by antioxidant mechanisms [36,37]. This hypothesis was supported by the Irbesartan and Lipoic Acid in Endothelial Dysfunction (ISLAND) study, in which patients with metabolic syndrome received oral treatment with 300 mg of ALA [32]. ...
Background:
This study was a multicenter, parallel-group, double-blind, double-dummy, randomized, noninferiority trial to evaluate the efficacy and safety of γ-linolenic acid (GLA) relative to α-lipoic acid (ALA) over a 12-week treatment period in type 2 diabetes mellitus (T2DM) patients with painful diabetic peripheral neuropathy (DPN).
Methods:
This study included 100 T2DM patients between 20 and 75 years of age who had painful DPN and received either GLA (320 mg/day) and placebo or ALA (600 mg/day) and placebo for 12 weeks. The primary outcome measures were mean changes in pain intensities as measured by the visual analogue scale (VAS) and the total symptom scores (TSS).
Results:
Of the 100 subjects who initially participated in the study, 73 completed the 12-week treatment period. Per-protocol analyses revealed significant decreases in the mean VAS and TSS scores compared to baseline in both groups, but there were no significant differences between the groups. The treatment difference for the VAS (95% confidence interval [CI]) between the two groups was -0.65 (-1.526 to 0.213) and the upper bound of the 95% CI did not exceed the predefined noninferiority margin (δ₁=0.51). For the TSS, the treatment difference was -0.05 (-1.211 to 1.101) but the upper bound of the 95% CI crossed the noninferiority margin (δ₂=0.054). There were no serious adverse events associated with the treatments.
Conclusion:
GLA treatment in patients with painful DPN was noninferior to ALA in terms of reducing pain intensity measured by the VAS over 12 weeks.
... One of these is oxidative stress [2]. A-lipoic acid (ALA) seems to delay or reverse peripheral diabetic neuropathy through its multiple antioxidant properties [3]. Therefore, the aim of our study was to explore the effect of ALA treatment on the sural nerve conduction velocity (SNCV) and amplitude (SNAP) of T2D patients with DN. ...
... Treatment with α-lipoic acid prevents neurovascular abnormalities in experimental DNP. It also attenuates reduced digital NCV, nerve blood flow and GSH levels in diabetic rats by enhancing oxygen free radical scavenging activity [80,81]. On the other hand, probucol, as an LDLoxidation inhibitor, and a powerful free radical scavenger, normalizes both nerve blood flow and electrophysiology [82]. ...
Objectives:
Diabetic neuropathy (DNP) is a widespread and debilitating complication with complex pathophysiology that is caused by neuronal dysfunction in diabetic patients. Conventional therapeutics for DNP are quite challenging due to their serious adverse effects. Hence, there is a need to investigate novel effective and safe options. The novelty of the present study was to provide available therapeutic approaches, emerging molecular mechanisms, signaling pathways and future directions of DNP as well as polyphenols' effect, which accordingly, give new insights for paving the way for novel treatments in DNP.
Evidence acquisition:
A comprehensive review was done in electronic databases including Medline, PubMed, Web of Science, Scopus, national database (Irandoc and SID), and related articles regarding metabolic pathways on the pathogenesis of DNP as well as the polyphenols' effect. The keywords "diabetic neuropathy" and "diabetes mellitus" in the title/abstract and "polyphenol" in the whole text were used. Data were collected from inception until May 2019.
Results:
DNP complications is mostly related to a poor glycemic control and metabolic imbalances mainly inflammation and oxidative stress. Several signaling and molecular pathways play key roles in the pathogenesis and progression of DNP. Among natural entities, polyphenols are suggested as multi-target alternatives affecting most of these pathogenesis mechanisms in DNP.
Conclusion:
The findings revealed novel pathogenicity signaling pathways of DNP and affirmed the auspicious role of polyphenols to tackle these destructive pathways in order to prevent, manage, and treat various diseases. Graphical Abstract .
... У пациентов с СД типа 2 и ДПН дополнительно отмечена стимуляция выработки аденозинтрифосфата мышцами за счет улучшения функционирования митохондрий [10]. Экспериментальные исследования показывают, что АЛК восстанавливает уровень глутатиона, предотвращает перекисное окисление липидов, повышает активность антиоксидантных ферментов (например, супероксиддисмутазы и каталаз в периферических нервах), увеличивает кровоток, утилизацию глюкозы в сочетании с увеличением скорости нервной проводимости [41,42,56]. Кроме того, она корректирует дефицит нейропептидов (например, нейропептид Y и вещества Р) в спинном мозге [25] и подавляет активацию NF-kB в периферических нервах [11]. ...
... Oxidative stress has also been critically implicated in the development of neuropathy [15]. These abnormalities initiate a chronic progressive damage and loss in unmyelinated and myelinated peripheral nerve fibers that culminate in peripheral polyneuropathy [16,17]. ...
Aims
Chronic hyperglycaemia activates the polyol pathway of glucose metabolism thereby stimulating the activation aldose reductase enzyme that in turn initiates a cascade of deleterious events, eventually, leading to nerve damage or neuropathy. Marine macroalgae and their isolated chemical constituents have been found to possess potential antidiabetic activity and have proved beneficial in the treatment of diabetes. In this study the neuroprotective effect of polyphenols isolated from the red macroalga Symphyocladia latiuscula was evaluated in experimental diabetic peripheral neuropathy.
Main methods
The polyphenolic fraction from Symphyocladia latiuscula was isolated. Diabetic peripheral neuropathy (DPN) was induced in animals by intraperitoneal injection of streptozotocin (45 mg/kg, b. w) and maintained for 6 weeks followed by treatment with SLPP or epalrestat. Nerve Conduction Velocity (NCV) and Compound Muscle Action Potential (CMAP) were measured using a non-invasive method followed by muscular grip strength test. Sciatic nerve aldose reductase activity, sorbitol accumulation, Na⁺K⁺-ATPase activity, production of pro-inflammatory cytokines and expression of AR and PKC were assessed.
Key findings
The Symphyocladia latiuscula polyphenols (SLPP) were found to inhibit aldose reductase activity as well as their expression in diabetic animals thereby improving the NCV, CMAP and muscle grip strength. Improvements in the sciatic nerve Na⁺K⁺-ATPase activity and intraneural accumulation of sorbitol, an index of aldose reductase overactivity, were evident with SLPP treatment. The production of pro-inflammatory cytokines (IL-6, IL-1β and TNF-α) and expression of protein kinase C (PKC) were also diminished.
Significance
The data suggest that the polyphenols of Symphyocladia latiuscula have neuroprotective potential against experimental DPN.
... [89][90][91][92][93] Treatment with ALA reduces oxidative stress and proinflammatory markers and improves endothelial function in patients with metabolic syndrome and animal models of diabetic neuropathy. 94,95 Short-term treatment with the intravenous (IV) form, not available in the USA, at a dose of 600 mg/day IV for 3 weeks, has been shown to reduce pain, burning paresthesias, and numbness in diabetic neuropathy. 96 After 5 weeks of oral treatment, patients demonstrated improvement in multiple measures of neuropathy symptoms. ...
Complementary and alternative treatment modalities are commonly utilized by patients for neuropathy and neuropathic pain due to perceived lack of benefit from conventional medical treatment. As the association between metabolic syndrome and neuropathy is increasingly recognized, diet and lifestyle interventions are becoming important components in the management of neuropathy. Progress in the understanding of the gut–immune interaction highlights the role the gut microbiome and inflammation plays in the modulation of neuropathy and neuropathic pain. Evidence for nutritional interventions, exercise, supplements, acupuncture and mindfulness‐based practices in the treatment of neuropathic pain is encouraging. This article will review the available evidence to support the safe use of complementary and alternative treatments for commonly encountered conditions associated with neuropathy and neuropathic pain.
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Introduction. Over the years, the prevalence of metabolic syndrome has increased dramatically in developing countries as a major by-product of industrialization. Many factors, such as the consumption of hypercaloric diets and sedentary lifestyles, favor the spread of this disorder. Undoubtedly, the massive and still growing incidence of metabolic syndrome makes this epidemic a major public health problem. Metabolic syndrome is also a neurological and psychiatric risk factor. In this paper, an exploratory literature review on the subject will be performed. In this paper, we survey the information as to what is known about the metabolic syndrome beyond its classical association with cardiovascular disease and type 2 diabetes mellitus, since the metabolic syndrome also represents a risk factor for nervous tissue and threatens neuronal function. First, we present some essential concepts of the pathophysiology of metabolic syndrome. Second, we explore some neuroprotective approaches in metabolic syndrome related to cerebral hypoxia. Objectives. To update, review in an exploratory manner, and synthesize the literature concerning the neurological impact of metabolic syndrome, beyond its classical association with cardiovascular disease and type 2 diabetes mellitus. Define and review essential concepts of the pathophysiology of metabolic syndrome. To explore neuropreventive and neuroprotective strategies in metabolic syndrome related to therapeutic cerebral hypoxia. Material and methods. An exploratory survey of scientific literature from January 1989-November 2022 was carried out. Selection/inclusion criteria: scientific publications containing exploratory data and information on metabolic syndrome and neurological comorbidity and possible neurotherapeutic approaches. Pathophysiology. The metabolic pathways characteristically impaired in metabolic syndrome lead to hyperglycemia, insulin resistance, inflammation and hypoxia, all closely related to a generalized prooxidative state. Oxidative stress is well known to cause destruction of cellular structures and tissue architecture. Altered redox homeostasis and oxidative stress alter the macromolecular matrix of nuclear genetic material, lipids and proteins, which in turn disrupts biochemical pathways necessary for normal cellular function. Neuroprotection. Different neuroprotective strategies involving lifestyle changes, medications aimed at mitigating the cardinal symptoms of metabolic syndrome, and treatments aimed at reducing oxidative stress are discussed. It is well known that routine physical exercise, particularly aerobic activity, and a complete and balanced diet are key factors in preventing metabolic syndrome. However, pharmacological control of the metabolic syndrome as a whole and related hypertension, dyslipidemia and endothelial injury contribute to the improvement of neuronal health. Conclusion. The development of metabolic syndrome presents as a risk factor for the development and/or exacerbation of neurological alterations. Therapeutic strategies include multidisciplinary approaches aimed at addressing, in a concerted manner, different pathways involved in its pathophysiology
Relevance. In many countries plants have long been used in folk medicine as a source of medicines, as they are well tolerated, gradual development of therapeutic effect and a mild effect on the body. Due to these features such medicines are being safely used in the treatment and prevention of exacerbations of chronic diseases: of cardiovascular system, respiratory system, digestive system, pathologies of the urinary tract, etc., and also as a rehabilitation therapy after past diseases. The purpose of the study is to systematize and generalize the data of world literature concerning the general health-improving and tonic properties study of plants growing in the Republic of Buryatia. Material and methods. In this work used publication materials from the PubMed and е-library databases, search.rsl. The keyword search: restorative, tonic effect, herbal medicines, medicinal plants of Buryatia, biologically active substances, Astragalus membranaceus, Saposhnikovia divaricatа, Scutellaria baicalensis, Sedum roseum, Crataegus sangunea. The survey comprises the data of foreign and national articles, published on the topic during last 20 years. Conclusions. All the plants listed in this review are used for thousands of years in the Tibetan medicine. Based on the analysis of the presented literature data, their range of medicinal use is much wider, then the applications in modern clinical practice. The information reported in this review may be the basis for the development of new herbal medicines, including officinal mixture, with specified pharmacological properties.
Concerning the past few years in terms of health and nature, the globe has witnessed an upsurge in the use of nutraceuticals and nutritional and natural products in therapeutics. The major reason for this step is the conventional pharmacological treatment using synthetic drugs that do not meet the status of health and therapeutic requirements for various pathological conditions. Nutraceuticals promise prominent health and therapeutic benefits with no adverse or side effects, providing extra health benefits besides their action in any defined pathological condition. Nutraceuticals are extensive biological therapies that include herbs, vitamins, fatty acids, prebiotics, and probiotics used to promote and maintain health to prevent and cure pathological conditions, malignant processes, syndromes, and symptoms. Nutraceuticals have multidirectional therapeutic benefits and are claimed to be effective products in aiding human health. The addition of omega-3 for the treatment of mental and mood disorders was found to have safer, more valuable, and better therapeutic results in comparison to the use of synthetic drugs. Omega-3 is available in the regular diet through soybeans, walnuts, codfish, and salmon fish, and its constituents have been found to play a promising role in brain development, including brain aging and neurodegenerative disorders, in the pathology of mental and mood disorders, and treatment of the same. Supplementation with Omega-3 PUFA provides a promising effect in better brain development, treatment, prevention and cure of mental and mood disorders. This review endeavours to display and assert the clinical relevance of omega-3 PUFA in brain development, pathology, and treatment of mental and mood disorders.
Background
The primary objective of the present study was to evaluate the effects of a Nerve Support Formula NeuropAWAY® on diabetic neuropathic pain.
Methods
This double-blind, placebo-controlled, randomized trial was conducted between August 2020 and February 2021. Patients aged ≥40 and ≤65 years with a history of type 2 diabetes (T2D) with a confirmed diagnosis of diabetic neuropathic pain were included in the study. The primary efficacy endpoint was to assess the effect of the 42 days administration of the Nerve Support Formula on the neuropathic pain as assessed by the 11 point Pain Intensity Numeric Rating Scale (PI-NRS). The secondary objectives were to assess the effect on plasma vitamin B12 levels, nerve conduction velocity, blood flow velocity, Brief Pain Inventory, Neuropathy Total Symptom Score, and Insomnia Severity Index.
Results
The enrolled study population (n=59) was randomized in two study groups; the Investigational Product (IP) group - Nerve Support Formula (n=27) and placebo group (n=32). The mean age of these participants was 52.63 and 53.72 for IP and placebo group, respectively. The mean (SD) HbA1c levels for IP and placebo group were 8.37 (0.85) and 8.16 (0.86), respectively. By the end of the study (Day 42) the decrease in PI-NRS scores for the IP group was maximal (↓61.32%) and highly significant (p<0.001) in comparison to the placebo group (↑2.47%). Significant improvements (p<0.05) were also noted in the secondary efficacy variables after 42 days of IP intake.
Conclusion
The formula was found to be significantly effective as compared to placebo in reducing pain and other sensory symptoms related to the diabetic peripheral neuropathy.
Maternal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes developmental and reproductive disorders in pups due to the attenuated luteinizing hormone (LH) production during the perinatal stage; however, the administration of α-lipoic acid (LA) to TCDD-exposed pregnant rats reversed the attenuated LH production. Therefore, reproductive disorders in pups are expected to be ameliorated with LA supplementation. To address this issue, pregnant rats orally received low dose TCDD at gestational day 15 (GD15) and proceeded to parturition. The control received a corn oil vehicle. To examine the preventive effects of LA, supplementation with LA was provided until postnatal day 21. In this study, we demonstrated that maternal administration of LA restored the sexually dimorphic behavior of male and female offspring. TCDD-induced LA insufficiency is likely a direct cause of TCDD reproductive toxicity. In the analysis to clarify the mechanism of the decrease in LA, we found evidence suggesting that TCDD inhibits the synthesis and increases the utilization of S-adenosylmethionine (SAM), a cofactor for LA synthesis, resulting in a decrease in the SAM level. Furthermore, folate metabolism, which is involved in SAM synthesis, is disrupted by TCDD, which may adversely affect infant growth. Maternal supplementation of LA restored SAM to its original level in the fetal hypothalamus; in turn, SAM ameliorated abnormal folate consumption and suppressed aryl hydrocarbon receptor activation induced by TCDD. The study demonstrates that the application of LA could prevent and recover next-generation dioxin reproductive toxicity, which provides the potential to establish effective protective measures against dioxin toxicity.
Dietary health supplements have been increasingly used in the treatment and prevention of chronic disorders. During the previous years, lipoic acid has been reported to have a beneficial effect on diabetes and some of its complications. The aim of this paper is to review the evidence provided by lipoic acid research findings relevant to its use in diabetes. Since, the1950s, there has been accumulating experimental evidence showing that that lipoic acid, a naturally occurring substance, has a protective effect against the development of diabetes and its complications especially neuropathy. The beneficial use of oral lipoic acid in diabetic neuropathy has been reported mostly from Germany as early as the 1960s. Conclusion: There is convincing research evidence suggesting that lipoic acid has a benerficial effects in diabetes, and is particularly useful in the prevention and treatment of diabetic neuropathy. The beneficial effects of lipoic acid in diabetes and diabetic neuropathy are attributed to increasing insulin sensitivity, reduction of hyperglycemia-induced oxidative stress, and lipid peroxidation. Lipoic acid can possibly help in preventing diabetes in susceptible individuals, and the current expert opinion suggests that lipoic acid can be used in patients with patients with impaired glucose tolerance.
Strong evidence implicates oxidative stress as a mediator of diabetes-induced microvascular complications, including distal symmetric polyneuropathy. Dorsal root ganglia neurons are particularly susceptible to glucose-mediated oxidative stress and die by apoptotic mechanisms in animal and cell culture models of diabetes. Key mediators of glucose-induced oxidative injury are superoxide anions and nitric oxide (NO). Superoxides are believed to underlie many of the oxidative changes in hyperglycemic conditions, including increases in aldose reductase and protein kinase C activity. Superoxides can also react with NO, forming peroxynitrite (ONOO ⁻ ), which rapidly causes protein nitration or nitrosylation, lipid peroxidation, deoxyribonucleic acid (DNA) damage, and cell death. ONOO ⁻ formation is dependent on both superoxide and NO concentrations; therefore, cells that constitutively express NO synthase, such as endothelial cells and neurons, may be more vulnerable to ONOO – induced cell death in conditions favoring the production of superoxides. Although NO and ONOO ⁻ can cause endothelial and neuronal cell death in vitro, in animal models of diabetes, reductions in endothelial NO production can inhibit vasodilatation and cause nerve ischemia. Therefore, ideal therapeutic approaches should limit the formation of superoxides and ONOO while preventing reductions in vascular NO. Despite strong evidence that oxidative stress is associated with complications of diabetes, including neuropathy, the results of clinical trials of antioxidants have shown some promise but not established therapeutic efficacy. Clinical studies of several antioxidants, including α-lipoic acid, vitamins C and E, aldose reductase inhibitors, and growth factors, in diabetic neuropathy are discussed.
Dietary health supplements have been increasingly used in the treatment and prevention of chronic disorders. During the previous years, lipoic acid has been reported to have a beneficial effect on diabetes and some of its complications. The aim of this paper is to review the evidence provided by lipoic acid research findings relevant to its use in diabetes. Since, the1950s, there has been accumulating experimental evidence showing that that lipoic acid, a naturally occurring substance, has a protective effect against the development of diabetes and its complications especially neuropathy. The beneficial use of oral lipoic acid in diabetic neuropathy has been reported mostly from Germany as early as the 1960s.
Conclusion: There is convincing research evidence suggesting that lipoic acid has a benerficial effects in diabetes, and is particularly useful in the prevention and treatment of diabetic neuropathy. The beneficial effects of lipoic acid in diabetes and diabetic neuropathy are attributed to increasing insulin sensitivity, reduction of hyperglycemia-induced oxidative stress, and lipid peroxidation. Lipoic acid can possibly help in preventing diabetes in susceptible individuals, and the current expert opinion suggests that lipoic acid can be used in patients with patients with impaired glucose tolerance.
p>Peripheral neuropathy is an insidious complication of diabetes mellitus with notable secondary events, such as vascular dysfunction and plantar ulceration. Traditional doctrine maintains that diabetic ulceration is a direct consequence of concurrent neuropathy and pressure. It was hypothesised that neuropathic ulceration is promoted by capillary occlusion, the resultant hypoxia leading to expeditious cell death. The Golgi enzyme, core 2 transferase, was implicated in this event, given its mediation of intercellular signalling and leukocyte / endothelial adhesion. Hence, an upregulation of this particular facilitator would increase leukocyte / endothelial binding and thereby, effect microcirculatory stasis and post-occlusion ischaemia.
Type II diabetic study groups, with and without neuropathy (n=20), were canvassed and set against aged matched non-diabetic controls (n=5). All participants were subjected to anthropometric testing prior to venous blood sampling for the key marker, core 2 transferase. Additional blood chemistry and clinical testing (VPT and 10g monofilament) was further undertaken to demonstrate possible correlations with core 2 transferase upregulation.
The outcome of this study identified that core 2 transferase was significantly elevated in both diabetic study groups, in comparison to control participants (p<0.001). This trend was further continued, when comparing diabetic neuropathic individuals to both remaining groups (p<0.001). Subsequent linear regression modelling identified three principal correlations with core 2 transferase over-expression: VPT, 10g monofilament and creatinine levels. Using each of the above correlations as independent co-variates, adjusted models identified a very robust Rsq of 0.911 (91% predictability) for VPT and creatinine, as clinical markers for core 2 transferase specificity.
Consequently, these findings positively implicate core 2 transferase activity within a diabetic population and moreover, offer validated clinical tools to facilitate its early detection.</p
Neuropathic pain is experienced due to injury to the nerves, underlying disease conditions or toxicity induced by chemotherapeutics. Multiple factors can contribute to neuropathic pain such as central nervous system (CNS)-related autoimmune and metabolic disorders, nerve injury, multiple sclerosis and diabetes. Hence, development of pharmacological interventions to reduce the drawbacks of existing chemotherapeutics and counter neuropathic pain is an urgent unmet clinical need. Cannabinoid treatment has been reported to be beneficial for several disease conditions including neuropathic pain. Cannabinoids act by inhibiting the release of neurotransmitters from presynaptic nerve endings, modulating the excitation of postsynaptic neurons, activating descending inhibitory pain pathways, reducing neural inflammation and oxidative stress and also correcting autophagy defects. This review provides insights on the various preclinical and clinical therapeutic applications of cannabidiol (CBD), cannabigerol (CBG), and cannabinol (CBN) in various diseases and the ongoing clinical trials for the treatment of chronic and acute pain with cannabinoids. Pharmacological and genetic experimental strategies have well demonstrated the potential neuroprotective effects of cannabinoids and also elaborated their mechanism of action for the therapy of neuropathic pain.
Background
Diabetic nephropathy (DN) is a kidney dysfunction, which occurs due to elevated urine albumin excretion rate and reduced glomerular filtration rate. Studies in animals have shown that alpha-lipoic acid (ALA) supplementation can reduce the development of DN.
Objectives
We performed a systematic review and meta-analysis to examine the effects of ALA supplementation on biological indices (albumin, creatinine etc.) indicative of human DN.
Methods
The searching procedure included the databases PubMed Central, Embase, Cochrane Library (trials) and Web of Science, (protocol registration: INPLASY 202060095).
Results
We found that ALA supplementation decreased urine albumin 24h excretion rate in patients with diabetes [standardized mean difference=-2.27; confidence interval (CI)=(-4.09)–(-0.45); I2=98%; Z=2.44; p=0.01]. A subgroup analysis revealed that the studies examining only ALA, did not differ from those examined ALA in combination with additional medicines (Chi-squared=0.19; p=0.66; I2=0%), while neither ALA nor ALA plus medication had an effect on urine albumin 24h excretion rate (p>0.05). Also, ALA supplementation decreased urine albumin mg/l [mean difference (MD)=-12.95; CI=(-23.88)–(-2.02); I2=44%; Z=2.32; p=0.02] and urine albumin to creatinine ratio [MD=-26.96; CI=(-35.25)–(-18.67); I2=0%; Z=6.37; p<0.01] in patients with diabetes. When the studies that examined ALA plus medication were removed, ALA supplementation had no effect on urine albumin mg/l (p>0.05), but did significantly decrease urine albumin to creatinine ratio [MD=-25.88, CI=(34.40–(-17.36), I2=0%, Z=5.95, p<0.00001].
Conclusion
The available evidence suggests that ALA supplementation does not improve biological indices that reflect DN in humans. Overall, we identified limited evidence and therefore, the outcomes should be considered with caution.
Background: Multiple factors operate in the development of diabetic neuropathy.Sensory neurons are not protected by blood-brain or blood-nerve barrier; also the dorsal rootganglion cells (DRG) have a higher metabolic requirement than the nerve trunks. Oxygen levelat the dorsal root ganglions also appears to be lower. All these physiological characteristicssuggest that DRG may be particularly susceptible to damage in prolonged diabetic conditions.Objectives: To observe the quantitative cellular changes in dorsal root ganglion cells in rats withprolonged experimental diabetes. Study Design: An experimental study. Setting: Departmentof Human Anatomy, Faculty of Medicine, Umm al Qura University, Makkah, Saudi Arabia.Period: Fifteen months to complete. Material and methods: Observations were made on sixcontrol and six streptozotocin-treated male Sprague-Dawley rats after 12 months of diabetes.Cell count was done on silver-stained paraffin sections. DRG cells were arbitrarily groupedas large A-type and small B-type. Statistical examination of the cell count was done using atwo-tailed t-test. Values were considered significant at P ≤ 0.05. Results: In the control groupof animals the mean total number was 15856.33 ± 552.538 while in the diabetic animals itwas 11836.666 ±583.177; the reduction in the number of cells was significant. The number ofA-type and B-type cells and their percentages in the control group and the diabetic group ofanimals were 2753.833±257.683 (17.36%), 13102.5±443.092 (82.63%) and 1202.833±87.082(10.16%), 10633.833±517.900 (89.83%) respectively. The differences in the number of A-typeand B-type of cells when compared between control and diabetic groups of animals werestatistically highly significant. Conclusion: Selective cells damage to DRG cells may be theharbinger of diabetic neuropathy in experimentally induced diabetic rats.
Oxidative stress (OS), resulting from a disrupted balance between reactive oxygen species (ROS) and protective antioxidants, is thought to play an important pathogenetic role in several diseases, including viral infections. Alpha-lipoic acid (LA) is one of the most-studied and used natural compounds, as it is endowed with a well-defined antioxidant and immunomodulatory profile. Owing to these properties, LA has been tested in several chronic immunoinflammatory conditions, such as diabetic neuropathy and metabolic syndrome. In addition, a pharmacological antiviral profile of LA is emerging, that has attracted attention on the possible use of this compound for the cotreatment of several viral infections. Here, we will review the emerging literature on the potential use of LA in viral infections, including COVID-19.
Purpose
To investigate the effect of astragaloside IV (AS-IV) on mitochondrial-dependent apoptosis in the dorsal root ganglion of diabetic peripheral neuropathy (DPN) rats through the SIRT1/p53 pathway.
Methods
Diabetic rat model was induced by high-carbohydrate/high-fat diet and intraperitoneal injection of STZ. Diabetic rats were divided into three groups (n =16 per group): DPN group, AS-IV group (60mg/kg/d) and α-lipoic acid (ALA) group (60mg/kg/d). Weight and blood glucose levels were monitored every 4 weeks for 12 weeks. DPN was evaluated using the Von Frey Filaments Test and nerve conduction velocity. The dorsal root ganglia of rats were isolated and the pathological changes of mitochondria were observed by electron microscopy. The activity of mitochondrial electron transport chain complex, mitochondrial membrane potential, malonaldehyde (MDA) and glutathione (GSH) levels were measured. Neural apoptosis was detected using the Terminal Deoxynucleotidyl Nick-End Labeling (TUNEL) assay kit. The cleaved caspase-3, major proteins in the SIRT1/p53 pathway, including SIRT1, acetyl p53, Drp1, BAX, and BCL-2, were detected using immunohistochemistry and Western blot. Gene expression of major proteins in the SIRT1/p53 pathway was also detected.
Results
After 12 weeks of treatment, AS-IV and ALA did not significantly affect body weight or fasting glucose levels, but reduced mechanical abnormal pain in DPN and improved nerve conduction velocity. AS-IV and ALA increased the level of GSH and decreased the level of MDA. Both AS-IV and ALA can reduce mitochondrial damage, improve mitochondrial electron transport chain complex activity and mitochondrial membrane potential, and reduce the percentages of positive cells with DNA fragmentation and the expression of cleaved caspase-3 protein. AS-IV and ALA up-regulated the expression of SIRT1 and down-regulated the expression of acetyl-p53, Drp1 and the ratio of BAX to BCL-2. Changes in gene expression were similar.
Conclusion
AS-IV can reduce the occurrence of mitochondrial-dependent apoptosis by regulating the SIRT1/p53 pathway. It has a similar therapeutic effect as ALA and is therefore a promising drug for the potential treatment of DPN.
Worldwide, approximately 463 million people are estimated to suffer from a form of diabetes mellitus, with diabetic neuropathy being one of its most common complication. Using streptozotocin to induce diabetes in C57BL/6J mice, we assess the neuroprotective role of alpha thioctic acid and vitamin B complex in diabetic neuropathy. In order to highlight the peripheral nerve changes produced by diabetes, we performed an electroneurographic recording of the animals and compared the amplitude of the compound muscle action potential (CMAP). Treatment with alpha thioctic acid (A), or vitamin B complex (B), or A+B caused a smaller decrease in CMAP amplitude than if these therapies had not been applied. On the other hand, we found that in group A+B a smaller decrease of CMAP amplitude was observed compared to the control group (6 weeks after the onset of diabetes p<0.0001). Also, separate treatment with alpha thioctic acid alone caused a smaller decrease in CMAP amplitude compared to the control group (6 weeks after the onset of diabetes mellitus p<0.0436), but also separate treatment with vitamin B complex alone resulted in a smaller decrease of CMAP amplitude compared to the Control group (6 weeks after the onset of diabetes p<0.0070). The combined therapy with alpha thioctic acid and vitamin B complex has a greater effect in preventing axonal degeneration in diabetic neuropathy than the single therapy only with alpha thioctic acid or only with vitamin B complex.
It has been shown that parameters of oxidative stress are increased in experimental diabetic neuropathy. The glutathione redox system is one of the intracellular scavenger systems for neutralizing free oxygen radicals. In this investigation we studied the effect of glutathione-treatment on the development of diabetic neuropathy in streptozotocin-induced diabetic rats by measuring sensory and motor nerve conduction velocities. The total study period was 10 weeks. Four groups of rats were studied: Group 1 consisted of non-diabetic, age-matched control rats; Group 2, of diabetic rats treated with placebo from week 0 to 10; Group 3, of diabetic rats treated with 200 mg glutathione/kg body weight i.v. two times per week from weeks 0 to 10; and Group 4, of diabetic rats treated with placebo from weeks 0 to 4 and as Group 3 from weeks 4 to 10. The sensory and motor nerve conduction velocity of rats treated prophylactically with glutathione (Group 3) were significantly different from those of rats treated with placebo (Group 2) or with glutathione administered at a later time point (Group 4). Complete restoration of sensory and motor nerve conduction velocity was not reached. There was a significant improvement in motor nerve conduction velocity from weeks 4 to 6 (p less than 0.005), but not in sensory nerve conduction velocity in the delayed treatment group (Group 4). In conclusion, treatment with glutathione, a free radical scavenger, is partially effective in the prevention of diabetic neuropathy in streptozotocin-induced diabetic rats, but is of limited value when the neuropathy is already present.
Thioctic acid (TA) and its reduced form dihydrolipoic acid (DHLA) have recently gained some recognition as useful biological antioxidants. In particular, the ability of DHLA to inhibit lipid peroxidation has been reported. In the present study, the effects of TA and DHLA on reactive oxygen species (ROS) generated in the aqueous phase have been investigated. Xanthine plus xanthine oxidase-generated superoxide radicals (O2-), detected by electron spin resonance spectroscopy (ESR) using DMPO as a spin trap, were eliminated by DHLA but not by TA. The sulfhydryl content of DHLA, measured using Ellman's reagent decreased subsequent to the incubation with xanthine plus xanthine oxidase confirming the interaction between DHLA and O2-. An increase of hydrogen peroxide concentration accompanied the reaction between DHLA and O2-, suggesting the reduction of O2- by DHLA. Competition of O2- with epinephrine allowed us to estimate a second order kinetic constant of the reaction between O2- and DHLA, which was found to be a 3.3 x 10(5) M-1 s-1. On the other hand, the DMPO signal of hydroxyl radicals (HO.) generated by Fenton's reagent were eliminated by both TA and DHLA. Inhibition of the Fenton reaction by TA was confirmed by a chemiluminescence measurement using luminol as a probe for HO.. There was no electron transfer from Fe2+ to TA or from DHLA to Fe3+ detected by measuring the Fe(2+)-phenanthroline complex. DHLA did not potentiate the DMPO signal of HO. indicating no prooxidant activity of DHLA. These results suggest that both TA and DHLA possess antioxidant properties. In particular, DHLA is very effective as shown by its dual capability by eliminating both O2- and HO..
Nervous tissue, central and peripheral, is, as any other, subject to variations in oxygen tension, and to the attack of different xenobiotics; these situations may promote the generation of activated oxygen species of free radical character. Results are presented showing that the content of total glutathione (GSH) in brain is 10-fold that found in the sciatic nerve of the rat (2620 vs. 261 nmol/g wet weight, respectively). The existence of a relatively high superoxide dismutase activity in peripheral nervous tissue, when compared with brain or liver, in combination with the DT-diaphorase activity detected in the sciatic nerve might represent an effective defense mechanism against quinone toxicity, as is also discussed. Nervous tissue, both central and peripheral lack Se-independent GSH peroxidase activity. Finally, the activities of other glutathione-related enzymes studied in the sciatic nerve are very low, when compared with the central nervous tissue, thus suggesting a higher susceptibility of peripheral tissue to oxidative stress damage, since GSH concentration and/or any GSH-related enzymatic activities, e.g. GSH peroxidase or glutathione disulfide reductase, might become limiting.
A rat model of severe nerve ischemia was used to study the effects of ischemia and reperfusion on nerve conduction, blood flow, and the integrity of the blood-nerve barrier. Conduction failure was consistently found in the sciatic-tibial nerve during 1- and 3-hr ischemic periods. Recovery of the compound muscle action potential was prompt and complete upon reperfusion following 1 hr of ischemia. However, after 3 hr of ischemia, recovery in the proximal portion of the sciatic nerve was less than 10%, and conduction block occurred in the distal portion of the nerve. Nerve blood flow was restored to only 55% and 45% of resting values following 1 and 3 hr, respectively, of ischemia and did not recover even after 2 hr of reperfusion. The blood-nerve barrier was not statistically impaired to the passage of [14C]sucrose following 1 hr of ischemia but was significantly impaired after 3 hr of ischemia. The permeability-surface area product was consistently greater following 1 hr of reperfusion than during the immediate reperfusion period. These data indicate that severe ischemia of peripheral nerve results in reperfusion injury, conduction block, and blood-nerve barrier disruption. Microvascular events, which may occur during reperfusion, may be important in amplifying the nerve fiber damage that began during ischemia.
We have assessed the mechanisms involved in the pathogenesis of the insulin resistance associated with impaired glucose tolerance and Type II diabetes mellitus by exploring, by means of the euglycemic glucose-clamp technique, the in vivo dose-response relationship between serum insulin and the overall rate of glucose disposal in 14 control subjects; 8 subjects with impaired glucose tolerance, and 23 subjects with Type II diabetes. Each subject had at least three studies performed on separate days at insulin infusion rates of 40, 120, 240, 1,200, or 1,800 mU/M2 per min. In the subjects with impaired glucose tolerance, the dose-response curve was shifted to the right (half-maximally effective insulin level 240 vs. 135 microunits/ml for controls), but the maximal rate of glucose disposal remained normal. In patients with Type II diabetes mellitus, the dose-response curve was also shifted to the right, but in addition, there was a posal. This pattern was seen both in the 13 nonobese and the 10 obese diabetic subjects. Among these patients, an inverse linear relationship exists (r = -0.72) so that the higher the fasting glucose level, the lower the maximal glucose disposal rate. Basal rates of hepatic glucose output were 74 +/- 4, 82 +/- 7, 139 +/- 24, and 125 +/- 16 mg/M2 per min for the control subjects, subjects with impaired glucose tolerance, nonobese Type II diabetic subjects, and obese Type II diabetic subjects, respectively. Higher serum insulin levels were required to suppress hepatic glucose output in the subjects with impaired glucose tolerance and Type II diabetics, compared with controls, but hepatic glucose output could be totally suppressed in each study group. We conclude that the mechanisms of insulin resistance in patients with impaired glucose tolerance and in patients with Type II noninsulin-dependent diabetes are complex, and result from heterogeneous causes. (a) In the patients with the mildest disorders of carbohydrate homeostasis (patients with impaired glucose tolerance) the insulin resistance can be accounted for solely on the basis of decreased insulin receptors. (b) In patients with fasting hyperglycemia, insulin resistance is due to both decreased insulin receptors and postreceptor defect in the glucose mechanisms. (c) As the hyperglycemia worsens, the postreceptor defect in peripheral glucose disposal emerges and progressively increases. And (d) no postreceptor defect was detected in any of the patient groups when insulin's ability to suppress hepatic glucose output was measured.
The effect of starvation and chronic food restriction on lipid peroxidation during treatment with ethanol was studied. The experiment was carried out on 64 female Wistar rats. The formation of malondialdehyde was determined in postmitochondrial liver fraction (basal level and after stimulation with ascorbate). The concentration of reduced glutathione was measured in the same fraction.In rats fed ad libitum, the consumption of ethanol, given with the drinking water for either 3 or 28 days, promoted a slight, but statistically nonsignificant, activation of lipid peroxidation. In animals not given ethanol, a 3-day fast increased the formation of lipid peroxides after stimulation with ascorbate. However, some tendency toward inhibition of lipid peroxidation was established after consumption of a restricted diet (6-8g standard pellet food daily) for 28 days. The treatments with alcohol for 3 and 28 days were combined respectively with a 3-day fast and a 28-day food restriction. In both a statistically significant increase in lipid peroxides was observed in comparison with the controls, which were fed ad libitum and were not given ethanol.The concentration of reduced glutathione was decreased in all experimental groups, but only with the 3-day treatments did the extent of its depletion correspond to the activation of lipid peroxidation. The results show that both starvation and chronic malnutrition potentiate lipid peroxide formation in rats treated with ethanol.
As a normal attribute of aerobic life, structural damage to organic compounds of a wide variety (DNA, proteins, carbohydrates and lipids) may occur as a consequence of oxidative reactions. Oxidative damage inflicted by reactive oxygen species has been called “oxidative stress”. Biological systems contain powerful enzymatic and nonenzymatic antioxidant systems, and oxidative stress denotes a shift in the prooxidant/antioxidant balance in favor of the former. Diverse biological processes such as inflammation, carcinogenesis, ageing, radiation damage and photobiological effects appear to involve reactive oxygen species. This field of research provides new perspectives in biochemical pharmacology, toxicology, radiation biochemistry as well as pathophysiology.
Relative α-lipoic acid content of diabetic livers was considerably less than that of normal livers as determined by gas chromatography.
It was not possible to detect any dihydrolipoic acid in the livers. Biochemical abnormalities such as hyperglycaemia, ketonemia,
reduction in liver glycogen and impaired incorporation of [2-14C] -acetate into fatty acids in alloxan diabetic rats were brought to near normal levels by the oral or intraperitoneal administration
of dihydrolipoic acid. The effect of α-lipoic acid was comparable to that of dihydrolipoic acid in reducing the blood sugar
levels of diabetic rabbits during a glucose tolerance test.
The results suggest that the mode of action of lipoic acid was through stimulation of pyruvate dehydrogenase.
Lipoic acid has been reported recently to be an effective antioxidant in biological systems. It may act in vivo through reduction to its dithiol form, dihydrolipoic acid. Using a dual Hg/Au electrode, and HPLC with electrochemical detection, a method was developed which allowed simultaneous measurement of lipoic acid and dihydrolipoic acid, at nanomolar levels. (RS)-α-Lipoic acid was added to human cells in tissue culture (Jurkat T-lymphocytes and primary neonatal diploid fibroblasts). Lipoic acid was converted rapidly by the cells to dihydrolipoic acid, which accumulated in the cell pellet. Monitored over a 2-hr interval, dihydrolipoic acid was released, and several-fold more dihydrolipoic acid could be found in the medium than in the pellet.
Most algorithms for the least-squares estimation of non-linear parameters have centered about either of two approaches. On the one hand, the model may be expanded as a Taylor series and corrections to the several parameters calculated at each iteration on the assumption of local linearity. On the other hand, various modifications of the method of steepest-descent have been used. Both methods not infrequently run aground, the Taylor series method because of divergence of the successive iterates, the steepest-descent (or gradient) methods because of agonizingly slow convergence after the first few iterations. In this paper a maximum neighborhood method is developed which, in effect, performs an optimum interpolation between the Taylor series method and the gradient method, the interpolation being based upon the maximum neighborhood in which the truncated Taylor series gives an adequate representation of the nonlinear model. The results are extended to the problem of solving a set of nonlinear algebraic e
The stabilities of the 1:1 complexes of Mn2+, Cu2+, and Zn2+ with lipoate and its chainshortened catabolites, viz., bisnorlipoate and tetranorlipoate, were studied by potentiometric titrations in water containing 50% dioxane (I = 0.1, NaClO4; 25 °C). A comparison of the stabilities of these complexes with those of simple carboxylates reveals that the catabolite complexes formed with Cu2+ and Zn2+ are more stable than expected from only the basicity of the carboxylate groups. This is evidence that chelates involving the disulfide group are formed. The stability of all Mn2+ complexes is determined by the basicity of the carboxylate groups. The same pattern of stability holds for the mixed-ligand complexes formed by Cu2+ or Zn2+, 2,2′-bipyridyl, and lipoate or one of its derivatives. It is evident that the disulfide group of the 1,2-dithiolane moiety can participate in the formation of binary and ternary complexes. The somewhat less-pronounced coordinating properties of the 1,2-dithiolane moiety compared with the tetrahydrothiophene moiety are discussed. It is apparent that the electron density at S(1) and S(2) in the dithiolane moiety of lipoate is not equivalent: S(1) is favored over S(2) in electrophilic reactions; possible biological implications are indicated.
The purpose of this study was to evaluate sweating and cardiovascular autonomic function in patients with distal small fiber neuropathy (DSFN). Sweat testing by the quantitative sudomotor axon reflex test was abnormal in 32 of 40 (80%) patients. The thermoregulatory sweat test was abnormal in 18 of 25 (72%) patients; one or both tests were abnormal in 36 of 40 (90%). Minor heart rate abnormalities were present in 11 of 40 (28%) patients. We conclude that, in patients with DSFN: (a) the sympathetic sudomotor fibers are frequently affected, and that evaluation of sweating is a useful diagnostic test; (b) that the autonomic nerves controlling heart rate are less affected.
The influence of alpha-lipoic acid (CAS 62-46-4) on the amount of intracellular glutathione (GSH) was investigated in vitro and in vivo. Using murine neuroblastoma as well as melanoma cell lines in vitro, a dose-dependent increase of GSH content was observed. Dependent on the source of tumor cells the increase was 30-70% compared to untreated controls. Normal lung tissue of mice also revealed about 50% increase in glutathione upon treatment with lipoic acid. This corresponds with protection from irradiation damage in these in vitro studies. Survival rate of irradiated murine neuroblastoma was increased at doses of 100 micrograms lipoic acid/d from 2% to about 10%. In agreement with the in vitro studies, in vivo experiments with whole body irradiation (5 and 8 Gy) in mice revealed that the number of surviving animals was doubled at a dose of 16 mg lipoic acid/kg. Improvement of cell viability and irradiation protection by the physiological compound lipoic acid runs parallel with an increase of intracellular GSH/GSSG ratio.
Thioctic (lipoic) acid is used as a therapeutic agent in a variety of diseases in which enhanced free radical peroxidation of membrane phospholipids has been shown to be a characteristic feature. It was suggested that the antioxidant properties of thioctic acid and its reduced form, dihydrolipoic acid, are at least in part responsible for the therapeutic potential. The reported results on the antioxidant efficiency of thioctic and dihydrolipoic acids obtained in oxidation models with complex multicomponent initiation systems are controversial. In the present work we used relatively simple oxidation systems to study the antioxidant effects of dihydrolipoic and thioctic acids based on their interactions with: (1) peroxyl radicals which are essential for the initiation of lipid peroxidation, (2) chromanoxyl radicals of vitamin E, and (3) ascorbyl radicals of vitamin C, the two major lipid- and water-soluble antioxidants, respectively. We demonstrated that: (1) dihydrolipoic acid (but not thioctic acid) was an efficient direct scavenger of peroxyl radicals generated in the aqueous phase by the water-soluble azoinitiator 2,2'-azobis(2-amidinopropane)-dihydrochloride, and in liposomes or in microsomal membranes by the lipid-soluble azoinitiator 2,2'-azobis(2,4-dimethylvaleronitrile); (2) both dihydrolipoic acid and thioctic acid did not interact directly with chromanoxyl radicals of vitamin E (or its synthetic homologues) generated in liposomes or in the membranes by three different ways: UV-irradiation, peroxyl radicals of 2,2'-azobis(2,4-dimethylvaleronitrile), or peroxyl radicals of linolenic acid formed by the lipoxygenase-catalyzed oxidation; and (3) dihydrolipoic acid (but not thioctic acid) reduced ascorbyl radicals (and dehydroascorbate) generated in the course of ascorbate oxidation by chromanoxyl radicals. This interaction resulted in ascorbate-mediated dihydrolipoic acid-dependent reduction of the vitamin E chromanoxyl radicals, i.e. vitamin E recycling. We conclude that dihydrolipoic acid may act as a strong direct chain-breaking antioxidant and may enhance the antioxidant potency of other antioxidants (ascorbate and vitamin E) in both the aqueous and the hydrophobic membraneous phases.
It is known that plasma low density lipoproteins (LDL) contain a great amount of vitamin E and that LDL enter cells via the specific receptor-mediated mechanism. In this study, we aimed to investigate the transport of alpha-tocopherol from plasma to tissues in subjects with non-insulin-dependent diabetes mellitus (NIDDM) with poor glycaemic control; and the relationships between alpha-tocopherol and plasma lipid and lipoprotein levels. alpha-Tocopherol determination was carried out by colorimetric assay according to the modified micromethod of Fabianek et al. The mean plasma alpha-tocopherol and (LDL + VLDL)-alpha-tocopherol levels increased significantly in the diabetic group as compared to control (P less than 0.05 and P less than 0.02), whereas the high density lipoprotein (HDL)-alpha-tocopherol level was significantly lower in the diabetic group than that in the controls (P less than 0.05). Correlations between plasma alpha-tocopherol levels showed close positive relationships (r = 0.87, r = 0.75 and r = 0.78, respectively, P less than 0.001). A strong positive correlation was also observed between alpha-tocopherol and the cholesterol content, either in the HDL or in the (LDL + VLDL) fractions (r = 0.75 and r = 0.77; P less than 0.001). These findings indicate that there is a direct positive relationship between lipid and alpha-tocopherol concentrations. The increased level of alpha-tocopherol in the LDL + VLDL fraction and decreased level in HDL in these patients could be attributed to the impairment of the cholesterol uptake of the cells by the receptor mediated mechanism.
N epsilon-(carboxymethyl)lysine, N epsilon-(carboxymethyl)hydroxylysine, and the fluorescent cross-link pentosidine are formed by sequential glycation and oxidation reactions between reducing sugars and proteins. These compounds, termed glycoxidation products, accumulate in tissue collagen with age and at an accelerated rate in diabetes. Although glycoxidation products are present in only trace concentrations, even in diabetic collagen, studies on glycation and oxidation of model proteins in vitro suggest that these products are biomarkers of more extensive underlying glycative and oxidative damage to the protein. Possible sources of oxidative stress and damage to proteins in diabetes include free radicals generated by autoxidation reactions of sugars and sugar adducts to protein and by autoxidation of unsaturated lipids in plasma and membrane proteins. The oxidative stress may be amplified by a continuing cycle of metabolic stress, tissue damage, and cell death, leading to increased free radical production and compromised free radical inhibitory and scavenger systems, which further exacerbate the oxidative stress. Structural characterization of the cross-links and other products accumulating in collagen in diabetes is needed to gain a better understanding of the relationship between oxidative stress and the development of complications in diabetes. Such studies may lead to therapeutic approaches for limiting the damage from glycation and oxidation reactions and for complementing existing therapy for treatment of the complications of diabetes.
We previously reported the presence of endoneurial hypoxia, ischemia, impairment of the blood-nerve barrier, and reduction of norepinephrine and 6-ketoprostaglandin F1 alpha in chronic streptozocin-induced diabetic neuropathy (SDN) and interpreted these findings as suggesting the involvement of oxygen free radicals (OFRs) but did not directly measure indices of OFR activity. In this study, we report on sciatic nerve conjugated dienes, hydroperoxides, norepinephrine, and malondialdehyde in SDN at 1, 4, and 12 mo in male Sprague-Dawley rats. Severe hyperglycemia was present throughout in diabetic rats. Conjugated dienes were consistently increased at all time points, hydroperoxides were consistently reduced, and malondialdehyde was not significantly different in diabetes compared with controls. These findings are consistent with increased OFR activity in experimental diabetes. It is necessary to monitor several indices of OFR activity in a metabolically active tissue such as the peripheral nerve.
1. Transperineurial arterioles connect the extrinsic (epineurial) and the intrinsic (endoneurial) microvasculatures. Our goal was to determine whether the extrinsic system regulated nerve blood flow locally and whether subperineurial and centrifascicular endoneurial nerve blood flows were regulated differentially. 2. The local application of noradrenaline resulted in a dose-dependent reduction of nerve blood flow in subjacent endoneurium. Asymptotes of 78.8 and 76.3% vasoconstriction were recorded for subperineurial and centrifascicular endoneurial nerve blood flow, respectively, indicating near-complete closure of capillaries. 3. Near-identical concentrations required to generate 50% vasoconstriction (EC50) and asymptotes are suggestive of the fact that the two areas are not differentially regulated. 4. Local vasoconstriction cannot be due to a systemic effect of noradrenaline since a significant decrease in nerve blood flow occurs despite undetectable increases in plasma noradrenaline and mean blood pressure, or decrease in contralateral sciatic nerve blood flow. 5. There are small and statistically non-significant reductions of the compound muscle action potential and conduction velocity in the sciatic-tibial nerve following nerve ischaemia. 6. These findings suggest that epineurial arterioles control regional nerve blood flow and are primarily responsible for its regulation in subjacent endoneurial tissue.
We studied the effect of piroxicam, a long acting inhibitor of platelet aggregation, on the evolution of neuropathy in diabetic rats. We treated half of the rats with piroxicam and serially studied sensory and motor nerve conduction during 20 weeks of diabetes. The sensory nerve action potential amplitude was the same in treated and untreated rats before diabetes, and declined steadily as duration of diabetes increased. In treated rats, the amplitude fell more slowly and by 16 weeks and thereafter was significantly higher than in untreated rats. Sensory conduction velocity and motor nerve conduction studies were not affected by piroxicam treatment. The results suggest that piroxicam may slow the rate of progression of neuropathy in diabetic rats, probably by inhibiting platelet aggregation.
Noradrenaline levels in the superior cervical ganglion and sciatic nerve were significantly reduced in chronic streptozotocin-induced diabetes in rats. Sciatic nerve sheath in vitro biosynthesis of 6-keto prostaglandin F1 alpha (6KPGF1 alpha; the stable metabolite of prostacyclin) was significantly reduced but not in acute experimental diabetes. Nerves with reduced 6KPGF1 alpha had an excessive response to arachidonic acid stimulation. We suggest that the reduced endogenous biosynthesis of prostacyclin is due to reduced substrate availability, possibly due to the reduced noradrenaline. The implications of these findings on the pathogenesis of diabetic neuropathy are discussed. Neuropathy was found to involve all fibre populations studied (motor, sensory and sympathetic) and progressed with duration of diabetes.
The chapter discusses that in experimental ischemic neuropathy caused by exsanguination, the reduction in blood flow velocity is the major factor reducing endoneurial oxygen delivery. The chapter also presents that in arterial hypoxemia caused by reduced oxygen content of inspired air, the effects of reduced arterial oxygen tension (arterial hypoxia) are supplemented by effects of reduced blood flow (venous hypoxia) caused by reduction in cardiac output due to cardiac muscle hypoxia. In experimental edematous neuropathy (e.g., galactose neuropathy), the increased intercapillary distance is a major factor in reducing the oxygen supply. The adverse effects of increased intercapillary distance are partially offset, however, by a reduced oxygen consumption rate per unit volume of tissue that results from the effects of edema, because much of the increase in nerve volume is due to accumulation of extracellular fluid that is not metabolically active. Mathematical models of the release of oxygen from hemoglobin and its diffusion from capillaries to surrounding tissue have been applied to skeletal muscle, cardiac muscle and brain.
The effect of graded, physiologic hyperinsulinemia (+5, +15, +30, +70, +200 microU/ml) on oxidative and nonoxidative pathways of glucose and FFA metabolism was examined in nine lean non-insulin dependent diabetic patients (NIDDM) and in eight age- and weight-matched control subjects. Glucose and FFA metabolism were assessed using stepwise insulin clamp in combination with indirect calorimetry and infusion of [3H]3-glucose/[14C]palmitate. The basal rate of hepatic glucose production (HGP) was higher in NIDDM than in control subjects, and suppression of HGP by insulin was impaired at all but the highest insulin concentration. Glucose disposal was reduced in the NIDD patients at the three highest plasma insulin concentrations, and this was accounted for by defects in both glucose oxidation and nonoxidative glucose metabolism. In NIDDs, suppression of plasma FFA by insulin was impaired at all five insulin steps. This was associated with impaired suppression by insulin of plasma FFA turnover, FFA oxidation (measured by [14C]palmitate) and nonoxidative FFA disposal (an estimate of reesterification of FFA). FFA oxidation and net lipid oxidation (measured by indirect calorimetry) correlated positively with the rate of HGP in the basal state and during the insulin clamp. In conclusion, our findings demonstrate that insulin resistance is a general characteristic of glucose and FFA metabolism in NIDDM, and involves both oxidative and nonoxidative pathways. The data also demonstrate that FFA/lipid and glucose metabolism are interrelated in NIDDM, and suggest that an increased rate of FFA/lipid oxidation may contribute to the impaired suppression of HGP and diminished stimulation of glucose oxidation by insulin in these patients.
Peroxidative decomposition of organelle membrane phospholipids with subsequent organelle dysfunction is a postulated mechanism of liver cell injury in parenchymal iron overload. We studied the effects of different alpha-tocopherol concentrations on hepatic mitochondrial lipid peroxidation and oxidative metabolism in rats with chronic dietary iron overload. There was no evidence of mitochondrial lipid peroxidation (conjugated dienes) or alteration in mitochondrial oxidative metabolism in alpha-tocopherol-deficient rats with normal hepatic iron levels. Significant reductions in mitochondrial respiratory control ratios and oxidative phosphorylation ratios were seen in association with increased conjugated dienes in all three groups of iron-loaded rats regardless of the alpha-tocopherol status (deficient, normal or excess); thus, the alpha-tocopherol deficiency associated with dietary iron overload in this experimental model is not responsible for the mitochondrial abnormalities observed. In addition, chronic parenteral administration of alpha-tocopherol to iron-loaded animals, which increased hepatic levels of this substance 3-fold, did not ameliorate the hepatic mitochondrial lipid peroxidation or the defects in mitochondrial oxidative metabolism resulting from iron overload.
Previous studies from our laboratory have demonstrated the presence of complex alterations in the activities of antioxidant enzymes in various tissues of rats with streptozotocin (STZ)-induced diabetes. In the present investigation, it is shown that rats made diabetic with alloxan (ALX), an agent differing from STZ both chemically and in its mechanism of diabetogenesis, show virtually identical tissue antioxidant enzyme changes which, as is the case with STZ, are preventable by insulin treatment. The finding that the patterns of antioxidant enzyme alterations in chemically-induced diabetes are independent of the diabetogenic agent used and the presence of similar abnormalities in tissues of spontaneously diabetic (BB) Wistar rats (particularly when diabetic control is less than optimal) suggest that the changes observed are a characteristic feature of the uncontrolled diabetic state and that these may be responsible for (or predispose to) the development of secondary complications in clinical diabetes. Comparative studies involving red cells of diabetic rats and human diabetics revealed a number of common changes, namely an increase in glutathione reductase activity, a decreased susceptibility to oxidative glutathione depletion (which was related to the presence of hyperglycemia) and an increased production of malondialdehyde (an indirect index of lipid peroxidation) in response to in vitro challenge with hydrogen peroxide. In the diabetic patients, the extent of this increase in susceptibility of red cell lipids to oxidation paralleled the severity of diabetic complications. Our results suggest that increased (or uncontrolled) oxidative activity may play an important role in the pathogenesis of complications associated with the chronic diabetic state.
A rapid and sensitive high-performance liquid chromatographic method for quantitation of picomole levels of glutathione, glutathione disulfide, cysteine, cystine, cysteinylglycine, cysteinylglycine disulfide and cysteine glutathione-mixed disulfide in biological samples is described. The compounds were separated isocratically on a reversed-phase column by ion-pair chromatography. The mobile phase consisted of an aqueous buffer containing 0.1 M monochloroacetic acid and 3.3 mM 1-heptanesulfonic acid (pH 2.60)-methanol-N,N-dimethylformamide (96.5:3.0:0.5). After chromatographic separation, the disulfides were reduced by a potential (-1.0 V) from a battery, with subsequent detection of all thiols by electrochemical oxidation (+0.15 V) with a dual gold-mercury electrode. Thiol and disulfide concentrations were determined in tissue extracts (liver and kidney) and fluids (bile and plasma) from control rats and rats treated with acivicin, an inhibitor of gamma-glutamyltranspeptidase. A marked increase in biliary glutathione concentration was observed in treated animals with a corresponding decrease in cysteine and cysteinylglycine concentrations. The results demonstrate that this method is useful for measuring glutathione and its degradation products in tissues and fluids.
Alterations in endogenous free radical-scavenging defense mechanisms of rat tissues after body weight loss (induced by starvation for 72 h) associated with hypoinsulinemia were investigated. The activities of catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GSH-PX), and glutathione (GSSG) reductase as well as levels of reduced glutathione (GSH) were examined in several tissues and in erythrocytes. A complex pattern of changes was observed. CAT activities were increased in the heart and pancreas and decreased in the liver. SOD levels were decreased in the heart and increased in the kidney and pancreas. GSH-PX activities were increased only in the kidney, and levels of GSH were decreased only in the liver of starved animals. Erythrocytes from starved animals showed no alterations in the levels of major free radical-scavenging enzymes. However, GSSG reductase levels were lower in erythrocytes from starved animals, and this was associated with an increased susceptibility to H2O2-induced GSH depletion. Paradoxically, H2O2-induced malondialdehyde (MDA) production in erythrocytes from starved animals was lower than that in control erythrocytes. Our results suggest that, in studies of experimental diabetes, attention must be given to the influence of body weight loss per se on the biochemical alterations associated with this disease.
We examined the effect of ischemia on nerve conduction in experimental diabetic neuropathy (EDN) and related electrophysiological changes to nerve adenosine triphosphate (ATP), creatine phosphate (CP), and lactate under anoxic conditions. Rats rendered diabetic with streptozotocin had a resistance to ischemic conduction block (RICB). Caudal nerve action potential (NAP) was well maintained for 10 min in controls and for 15 min in EDN, after which time NAP declined in both groups but more rapidly in normal rats. Time to 50% reduction in nerve ATP and CP was 10 and 3 min, respectively, in controls and delayed to 20 and 8 min in EDN. Rate of utilization of high-energy phosphate (approximately P) was linear for 5 min in controls to be followed by a progressive decline. In EDN rate of utilization of approximately P was linear to 15 min to be followed by a more gradual decline than in normal nerves. These findings suggest that the maintenance of nerve transmission in anoxic-ischemic states depends on anaerobic metabolism and that RICB in EDN is due in part to the ability of diabetic nerves to maintain a higher level of anaerobic glycolysis and for a longer time than normal nerves.
In rat diaphragm incubated in vitro thioctic acid increased the utilization of glucose. Time studies showed that, in contrast to the stimulatory effect of insulin on glucose uptake, the action of thioctic acid became apparent only after prolonged incubation. Thioctic acid did not interfere with the action of insulin and its effect was additive to that of insulin.
Using the hydrogen clearance technique, we have measured blood flow in the sciatic nerves of healthy, anaesthetized rats at rest, at various arterial blood pressures, and during respiratory acidosis and hypoxia. The majority of hydrogen clearance curves were bi-exponential. The slower component appears to reflect nerve blood flow more accurately than either the fast component or the composite value obtained from both components. Mean nerve blood flow estimated from the slow component of the seventeen bi-exponential hydrogen clearance curves and from the seven mono-exponential curves was 15.8 +/- 1.1 ml min-1 100 g-1 (+/- S.E. of the mean). The mean value of the fast component of the bi-exponential curves was 118 +/- 6 ml min-1 100 g-1 and that obtained from both components was 25.9 +/- 2.6 ml min-1 100 g-1. Sciatic nerve blood flow was measured over a range of arterial blood pressures of 60-160 mmHG. There is a curvilinear relationship between pressure and flow suggesting that the nerve vascular bed responds passively to changes in perfusion pressure. Respiratory acidosis resulted in no significant change in nerve blood flow. The mean flow was 15.5 +/- 1.9 ml min-1 100 g-1. During hypoxia, nerve blood flow decreased to 7.5 +/- 1.4 ml min-1 100 g-1 as a result of a reduction in arterial blood pressure and an increase in vascular resistance. These findings suggest that normal nerve blood flow is high in relation to metabolic activity, especially when compared with the brain.
Endoneurial hypoxia has been postulated to be important in the pathogenesis of diabetic peripheral neuropathy and may be due to reduced nerve blood flow. Neither blood flow nor oxygen tension have previously been measured in peripheral nerve in diabetic neuropathy. We have therefore measured both nerve blood flow and endoneurial oxygen tension in the sciatic nerves of 8 rats with streptozotocin-induced diabetes for four months, and in 8 age-matched controls. In 7 of the diabetic animals mean nerve blood flow was 8.7 +/- 1.3 ml X min-1 X 100 g-1 which is significantly less than mean nerve blood flow in the controls (13.08 +/- 0.8 ml X min-1 X 100 g-1; P less than 0.01). In one diabetic animal, nerve blood flow was too low to be accurately measured. The reduction in nerve blood flow in diabetic neuropathy is due to an increase in resistance to flow which may be due to microangiopathy and to blood hyperviscosity. Endoneurial oxygen tension was also significantly reduced in experimental diabetic neuropathy in which 60 per cent of the oxygen measurements were less than 25 mmHg, compared with 19 per cent in the controls. Nerve blood flow was also measured in rats with experimental galactose neuropathy in which there is more marked sugar-alcohol accumulation, endoneurial oedema and elevation of endoneurial fluid pressure than in experimental diabetic neuropathy. The results obtained in this neuropathy suggest that the reduction in nerve blood flow which occurs in experimental diabetic neuropathy is due largely to factors other than sugar-alcohol accumulation in nerve. We postulate that endoneurial hypoxia may produce many of the observed morphological and biochemical changes in experimental diabetic neuropathy.
Consider the situation where samples have been obtained randomly from each of five populations A, B, C, D and E. The question arises, 'How should the data be analyzed?'. A common answer to this question is 'Do one-way analysis of variance and, if P < .05, make pairwise comparisons using an appropriate multiple-comparison algorithm'. This is the approach presented in virtually all textbooks, subscribed to by most statisticians, and expected (if not required) by most journals. Conversely, the alternative answer, 'Do 10 two-sample t tests', would typically be considered naive and likely to elicit the response, 'You should consult a statistician'. Perhaps most importantly, medical research is likely to fare poorly among reviewers when the statistical analysis is judged to be naive. Thus the purpose of this
The therapeutic efficacy of thioctic acid was studied in patients with peripheral diabetic neuropathy. In a double-blind study ten diabetics were treated with thioctic acid or a placebo for 21 days. In a second study ten diabetics were also treated with thioctic acid intravenously (i.v.) for 21 days. Before and on the 11th and 21st day of treatment, we examined the clinical neurological state, the vibration sense according to biothesiometry, the nerve conduction velocity, and the degree of diabetic control. In addition the patients were asked about neuropathic complaints. The therapeutic efficacy of oral or i.v. thioctic acid could not be verified by measurements of the nerve conduction velocity or the vibration sensibility. No effect of oral thioctic acid on subjective complaints was observed. However, i.v. treatment with thioctic acid resulted in a distinct improvement of subjective complaints.
Diabetic patients with increased plasma glucose concentrations may develop cerebral symptoms of hypoglycemia when their plasma
glucose is rapidly lowered to normal concentrations. The symptoms may indicate insufficient transport of glucose from blood
to brain. In rats with chronic hyperglycemia the maximum glucose transport capacity of the blood-brain barrier decreased from
400 to 290 micromoles per 100 grams per minute. When plasma glucose was lowered to normal values, the glucose transport rate
into brain was 20 percent below normal. This suggests that repressive changes of the glucose transport mechanism occur in
brain endothelial cells in response to increased plasma glucose.
A high performance liquid chromatographic method with both an ultraviolet spectrometric detector (UVD) and an electrochemical detector (ECD) has been developed for the simultaneous determination of reduced and oxidized ubiquinones in biological materials. This method is based on extraction from animal tissues or mitochondrial fractions with ethanol-n-hexane mixture, followed by quantitation on a reversed-phase column with UVD and ECD. The detection limits by ECD or UVD were 100pg, 2ng, 150pg and 2ng for ubiquinol-9, ubiquinone-9, ubiquinol-10 and ubiquinone-10, respectively. The persentages of reduced ubiquinones (ubiquinols) to total ubiquinones were 41.6, 32.4 and 45.2% for guinea pig heart, rat heart and heart mitochondrial fraction of guinea pig, respectively, with added succinate as a substrate.
A detailed evaluation of the antioxidant and pro-oxidant properties of lipoic acid (LA) and dihydrolipoic acid (DHLA) was performed. Both compounds are powerful scavengers of hypochlorous acid, able to protect alpha 1-antiproteinase against inactivation by HOCl. LA was a powerful scavenger of hydroxyl radicals (OH.) and could inhibit both iron-dependent OH. generation and peroxidation of ox-brain phospholipid liposomes in the presence of FeCl3-ascorbate, presumably by binding iron ions and rendering them redox-inactive. By contrast, DHLA accelerated iron-dependent OH. generation and lipid peroxidation, probably by reducing Fe3+ to Fe2+. LA inhibited this pro-oxidant action of DHLA. However, DHLA did not accelerate DNA degradation by a ferric bleomycin complex and slightly inhibited peroxidation of arachidonic acid by the myoglobin-H2O2 system. Under certain circumstances, DHLA accelerated the loss of activity of alpha-antiproteinase exposed to ionizing radiation under a N2O/O2 atmosphere and also the loss of creatine kinase activity in human plasma exposed to gas-phase cigarette smoke. Neither LA nor DHLA reacted with superoxide radical (O.2-) or H2O2 at significant rates, but both were good scavengers of trichloromethylperoxyl radical (CCl3O2.). We conclude that LA and DHLA have powerful antioxidant properties. However, DHLA can also exert pro-oxidant properties, both by its iron ion-reducing ability and probably by its ability to generate reactive sulphur-containing radicals that can damage certain proteins, such as alpha 1-antiproteinase and creatine kinase.
Nerve blood flow (NBF) is reduced in experimental diabetic neuropathy (EDN), but the mechanism of its reduction is uncertain. We tested the hypothesis that reduced NBF might be due to alterations of nitric oxide synthase (NOS) and endothelin of microvascular endothelial cells of sciatic nerve. We evaluated epineurial arteriolar vasoreactivity in response to superfused test agents. NBF was measured using microelectrode H2 polarography. Vasoconstrictor responses to endothelin-1 (ET-1; 10(-6), 10(-7), 10(-8), 10(-9), 10(-10) M) showed dose-response curves with similar EC50 values, indicating no change in potency. We applied the NOS inhibitor NG-nitro-L-arginine and observed reduced inhibition of NBF in EDN, correctable with insulin treatment and also with infused L-arginine. We conclude that vasoreactivity is disturbed in EDN, and is due to a combination of an impairment of NOS activity with reduced NO and increased endothelin effect (normal receptor sensitivity and increased plasma values) in EDN. Hyperglycemia is likely to be the mechanism of NOS inhibition since insulin treatment reversed this abnormality.
We tested the hypothesis that oxidative stress can cause neuropathy by evaluating the effect of alpha-tocopherol depletion in normal and streptozotocin (STZ) diabetic peripheral nerve (known to be subject to oxidative stress). The end points were nerve electrophysiology and indices of oxidative stress. Studies were done on 6 groups of rats at 1 and 3 months: (1) Controls, normal alpha-tocopherol (Con[N]). (2) Controls, alpha-tocopherol-deficient (Con[-]) (3) Controls, alpha-tocopherol supplemented (Con[+]); (4) Diabetic, normal alpha-tocopherol (STZ[N]); (5) Diabetic, alpha-tocopherol-deficient (STZ[-]) (6) Diabetic, alpha-tocopherol supplemented (STZ[+]). An alpha-tocopherol-deficient diet resulted in a rapid depletion of the vitamin in plasma and sympathetic neurones (superior cervical ganglion), and a slower depletion in sensory neurones (dorsal root ganglion) and nerve. The depletion was associated with a reduction in reduced glutathione and an increase in conjugated dienes and hydroperoxides in normal rats, and resulted in similar changes, or accentuated the abnormalities, in diabetic nerves. Changes were more pronounced at 1 than 3 months and alpha-tocopherol supplementation, for the most part, did not prevent the abnormalities. alpha-Tocopherol depletion induced or worsened nerve conduction abnormalities in both sciatic-tibial and caudal nerves. Sensory fibers were more affected than motor fibers and the changes were more pronounced at 3 than 1 month. These findings support the notion that oxidative stress may cause neuropathy and that it might be mechanistically implicated in experimental diabetic neuropathy (STZ-EDN).
Increased oxygen free radical activity, coupled with reduced protection against oxidative stress, could play a role in the aetiology of neurovascular abnormalities in experimental diabetes mellitus. To test this hypothesis, non-diabetic and streptozotocin-diabetic rats were treated with the anti-oxidant probucol or the pro-oxidant primaquine. One-month diabetes caused 21.4% and 13.6% reduction in sciatic motor and saphenous sensory conduction velocity (p < 0.001). These deficits were prevented by probucol treatment (p < 0.001). After 1-month untreated diabetes, conduction velocity deficits were reversed by a further month of probucol treatment (p < 0.001). For non-diabetic rats, primaquine treatment caused a 12.9% reduction in motor conduction velocity (p < 0.001), which was prevented by probucol treatment (p < 0.001). Primaquine treatment did not affect diabetic rats. Sciatic nerve nutritive endoneurial blood flow, measured using microelectrode polarography and hydrogen clearance, was 48.0% reduced by 2-month diabetes (p < 0.001). This was completely prevented by probucol treatment (p < 0.001). Primaquine treatment did not affect blood flow in diabetic rats. However, in non-diabetic rats it caused a 30.0% reduction (p < 0.01) which was prevented by probucol treatment (p < 0.05). Sciatic endoneurial oxygen tensions were also measured by microelectrode polarography. Mean tension was 38.8% reduced by diabetes (p < 0.001). This was prevented by probucol treatment. Non-diabetic rats given primaquine treatment showed a 21.7% reduction in endoneurial oxygen tension (p < 0.01). The data suggest that vascular-mediated nerve dysfunction in diabetes depends on oxidative stress, and that similar effects in non-diabetic rats may be produced by pro-oxidant treatment. This provides evidence for the potentially important role of oxygen free radical activity in diabetic neuropathy.
We investigated the effects of glucose on specific D-alpha-tocopherol binding to cultured bovine aortic endothelial cells. Our results confirmed that cultured bovine aortic endothelial cells have specific binding sites for D-alpha-tocopherol. These binding sites exhibited time- and temperature-dependent saturation. The specific binding affinity of D-alpha-tocopherol was significantly lower in endothelial cells cultured in high concentrations of glucose (16.8 or 22.4 mM) for > 7 days compared with cells cultured in a physiological glucose concentration (5.6 mM). No significant reduction occurred in D-alpha-tocopherol binding when 11.1 mM mannitol was added to cells cultured in 5.6 mM glucose. The addition of an aldose reductase inhibitor (ICI-128436, Statil) did not significantly affect the high-glucose-induced reduction of D-alpha-tocopherol binding, although it reduced sorbitol levels in the cells compared with those from cells cultured in high concentrations of glucose. Moreover, significantly higher amounts of lipid peroxides were produced in aortic endothelial cells cultured in high concentrations of glucose (16.8 or 22.4 mM) for > 3 days compared with cells cultured in a physiological concentration of glucose. These results indicate that high concentrations of glucose reduce D-alpha-tocopherol binding through mechanisms independent of putative osmotic effects of sorbitol accumulation in the cells. Possible mechanisms include glycation of protein or oxidative damage of cells and/or redox and metabolic imbalances associated with increased flux of glucose via the sorbitol pathway. A glucose-mediated reduction in D-alpha-tocopherol binding could diminish the beneficial effects of D-alpha-tocopherol to vascular endothelial cells and thereby may increase the vascular toxicity of hyperglycemia in diabetes mellitus.
The effect of alloxan-induced diabetes on glutathione peroxidase (GSH-Px) activity in sciatic nerve of mice has been studied. We have found, 7 days after alloxan treatment, a significant decrease in this enzymatic activity in the cytosol of sciatic nerve of diabetic mice, and moreover, that these changes remained unaltered up to 21 days after alloxan injection. No modification in the glutathione content of sciatic nerve of diabetic mice was observed throughout the experiment when compared with controls. The decrease in GSH-Px activity in this tissue shows a good correlation with the increase of blood glucose levels throughout the experiment. It is hypothesized whether a combination of mechanisms could be involved in this decrease of GSH-Px activity and if oxygen radicals might be the common mediators of these processes.
Plasma alpha-tocopherol and retinol, both assayed by an HPLC method, have been evaluated in a group of 60 patients affected by insulin-dependent (type 1) diabetes mellitus, stratified according to the presence of retinopathy and nephropathy diagnosed by an urinary albumin excretion rate ranging between 20 and 200 micrograms/min (microalbuminaria) or > 200 micrograms/min (macroalbuminuria), all of whom were compared with 26 healthy controls strictly matched for age and sex. Plasma lipids and age were positively correlated with plasma retinol and alpha-tocopherol in both diabetic and control subjects. Either plasma retinol or its ratio to cholesterol were significantly and independently reduced in the younger subset of diabetics, as compared to controls, independently from other confounding variables, while plasma alpha-tocopherol was unchanged in diabetic subjects and in healthy controls. Retinopathy was not associated with altered levels of both plasma alpha-tocopherol or retinol. The presence of increased urinary albumin excretion was associated with higher plasma levels of alpha-tocopherol and, only for macroalbuminuria, of retinol. However, after processing the data by a multivariate model, nephropathy was characterized by an increase only in plasma alpha-tocopherol. In conclusion, according to our findings, plasma retinol is significantly decreased in younger insulin-dependent diabetic patients while alpha-tocopherol is significantly altered in diabetic patients with nephropathy.
The susceptibility of mitochondria from liver and kidney of diabetic and normal rats to in vitro oxidative damage was assessed. Mitochondria were isolated from diabetic rats 4 weeks after streptozotocin injection and from age-matched, normal rats. Liver mitochondria from diabetic rats were less susceptible to oxidative damage (induced by Fe3+/adenosine 5'-diphosphate (ADP) xanthine/xanthine oxidase), as assessed by the formation of thiobarbituric acid reacting substances (TBARS) and sulfhydryl loss, than were mitochondria from normal rats. The decreased susceptibility of liver mitochondria from diabetic rats to oxidative damage correlated with a sevenfold increase in mitochondrial alpha-tocopherol levels. Activities of the antioxidant enzymes, glutathione reductase, glutathione peroxidase, and superoxide dismutase, were lower in liver mitochondria from diabetic compared to normal rats. Manipulation of dietary alpha-tocopherol, to counteract the increased intake of alpha-tocopherol due to diabetes-associated polyphagia, failed to lower liver mitochondrial alpha-tocopherol to the levels found in normal rats. Mitochondria from kidney of diabetic rats were equally as susceptible to in vitro oxidative damage as kidney mitochondria from normal rats. They had increased levels of superoxide dismutase and glutathione peroxidase but identical levels of alpha-tocopherol compared to mitochondria from normal rats. Dietary manipulation of alpha-tocopherol had no effect on kidney mitochondrial levels of the nutrient.
We tested the notion that oxidative stress makes an important contribution to the aetiology of diabetic neuropathy. The effect of treatment with a 1% dietary supplement of the anti-oxidant butylated hydroxytoluene was studied during 2 months of streptozotocin-induced diabetes mellitus. In final experiments, sciatic motor and saphenous sensory conduction velocities were measured in vivo, and resistance to hypoxic conduction failure for sciatic trunk was examined in vitro. There were 20% and 12% decreases in motor and sensory conduction velocity, respectively after 2 months of diabetes (p < 0.001). There were completely prevented by butylated hydroxytoluene treatment (p < 0.001). Resistance to hypoxic conduction failure, shown by the time taken for sciatic compound action potential amplitude to decline by 80%, was 55% increased by diabetes, and this was limited to 31% (p < 0.01) by treatment. There were no significant effects of treatment on the 9-10 fold elevation of sciatic nerve sorbitol and fructose levels with diabetes, or on the non-significant 22% reduction in myoinositol content. Butylated hydroxytoluene treatment also did not affect sciatic nerve capillary density. We conclude that oxidative stress makes an important contribution to the aetiology of early experimental diabetic neuropathy. Amelioration of oxidative stress could potentially be a final common mechanism whereby a number of diverse treatments exert a beneficial effect on diabetic nerve function.
From a study of acute heavy-metal toxicity it has been found that dl-α-lipoic acid (a) is effective for the prevention and reversal of arsenic intoxication in mice and dogs; (b) effectively prevents mercury intoxication in mice provided a sufficiently large excess is used; (c) prevents gold intoxication in mice only under very specific conditions; and (d) fails to protect mice against a lethal dose of lead.3-(6-Carboxyhexyl)-1,3-dithiolane was as effective as dl-α-lipoic acid in preventing arsenic intoxication in mice.
Experiments were designed to evaluate the competition between erythrocyte catalase and glutathione peroxidase for their common substrate, H2O2. When extracellular H2O2 concentrations were maintained at an upper limit of 10-6 M, the oxidation of glutathione accounted for the major fraction of H2O2 added to the cells. At higher concentrations, the usual decomposition of H2O2 by catalase became increasingly prominent. When normal (catalase-rich) erythrocytes were exposed to low-level, steady-state H2O2 concentrations for up to 24 hours, progressive oxidation of hemoglobin was followed by progressive osmotic fragility increases leading to eventual lysis in isotonic medium. These changes were preceded by the disappearance of intracellular reduced glutathione. The loss in reduced glutathione could be prevented by the addition of glucose to provide a substrate for reduction of the oxidized form of glutathione. Glutathione peroxidase activity sustained by the generation of reduced nicotinamide adenine dinucleotide phosphate (required by glutathione reductase) protected cells against methemoglobin formation and osmotic fragility changes. Catalase-deficient erythrocytes, viz., duck cells and azide-treated human cells, were similarly protected against the toxic effects of low H2O2 concentrations by sustained glutathione peroxidase activity. It is concluded that under physiologic conditions glutathione peroxidase linked to hexose shunt activity represents the major pathway of H2O2 metabolism in intact erythrocytes.
Fasting increases hepatic H 2 O 2 production in vivo
- I Kerckaert
- C Van Den Branden
- F Roels
Kerckaert I, van den Branden C, Roels F:
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