Fig 5 - uploaded by Alison Berent-Spillson
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GSH is maintained through the -glutamyl cycle & by recycling from GSSG. In the -glutamyl cycle (A), the rate-limiting GSH synthesis intermediate -glutamylcysteine is formed from glutamate + cysteine, and catalyzed by -glutamylcysteine synthetase. With the addition of glycine, GSH synthetase catalyzes formation of GSH. Degradation yields cysteinylglycine and the substrate amino acids, glutamate , glycine, & cysteine. GSH:GSSG recycling (B) is catalyzed by GSH reductase & peroxidase, and requires NADPH + H + .
Source publication
Multiple in vivo and in vitro studies show that excessive release of glutamate, and subsequent activation of ionotropic glutamate receptors (iGluRs) and some metabotropic glutamate receptors (mGluRs) cause neuronal cell death through either necrosis or apoptosis. However, recently alternative evidence has shown that mGluRs have modulatory effects o...
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Citations
... GABA receptor subunits including GABA Aα1 and GABA B , and Glutamic acid decarboxylase (GAD) expression significantly decreased in diabetic rats' cerebral cortex (13). Glutamate is the main excitatory neurotransmitter in the mammalian CNS including LGB (6,14). Glutamate receptors are divided into two groups, including ionotropic and metabotropic receptors (15). ...
Objectives:
Diabetes during gestation is one of the most common pregnancy complications and has adverse effects on offspring, including a negative impact on the offspring's central nervous system (CNS). Diabetes is a metabolic disease associated with visual impairment. Due to the importance of the lateral geniculate body (LGB) in the visual pathway, the present study examined the effect of maternal diabetes on the expression of gamma-aminobutyric acid (GABAAα1 and GABAB1) and metabotropic Glutamate (mGlu2) receptors in the LGB of male neonates of diabetic rats.
Materials and methods:
Diabetes was induced in female adult rats by a single intraperitoneal dose of streptozotocin (STZ) 65 (mg/kg). In the Insulin-treated diabetic rats, diabetes was controlled by subcutaneous NPH-insulin injection daily. After mating and delivery, male offspring were killed by carbon dioxide gas inhalation at P0, P7, and P14 (postnatal days 0, 7, and 14). The expression of GABAAα1, GABAB1, and mGluR2 in the LGB of male neonates was determined using the immunohistochemistry (IHC) method.
Results:
The expression of GABAAα1 and GABAB1 was significantly reduced, whereas the expression of mGluR2 was markedly increased in the diabetic group compared with the control and insulin-treated groups at P0, P7, and P14.
Conclusion:
The results of the present study showed that induction of diabetes altered the expression of GABAAα1, GABAB1, and mGluR2 in the LGB of male neonates born to diabetic rats at P0, P7, and P14. Moreover, insulin treatment could reverse these effects of diabetes.
... The concentration of GSH is regulated by glutathione disulfide (GSSG) during the redox cycle [3,4]. GSH peroxidase converts GSH to GSSG with H2O2, and GSH reductase converts GSSG to GSH with NADPH + H + [5]. In various brain injury conditions, the presynaptic release of zinc activates a reaction with free radicals to oxidize the reduced form of GSH to its dimer form (GSSG). Additionally, zinc interferes with the formation of GSH by inhibiting glutathione reductase (GR), an enzyme that converts the dimer GSSG to the GSH form [6]. ...
Glutathione (GSH) is necessary for maintaining physiological antioxidant function, which is responsible for maintaining free radicals derived from reactive oxygen species at low levels and is associated with improved cognitive performance after brain injury. GSH is produced by the linkage of tripeptides that consist of glutamic acid, cysteine, and glycine. The adequate supplementation of GSH has neuroprotective effects in several brain injuries such as cerebral ischemia, hypoglycemia, and traumatic brain injury. Brain injuries produce an excess of reactive oxygen species through complex biochemical cascades, which exacerbates primary neuronal damage. GSH concentrations are known to be closely correlated with the activities of certain genes such as excitatory amino acid carrier 1 (EAAC1), glutamate transporter-associated protein 3–18 (Gtrap3-18), and zinc transporter 3 (ZnT3). Following brain-injury-induced oxidative stress, EAAC1 function is negatively impacted, which then reduces cysteine absorption and impairs neuronal GSH synthesis. In these circumstances, vesicular zinc is also released into the synaptic cleft and then translocated into postsynaptic neurons. The excessive influx of zinc inhibits glutathione reductase, which inhibits GSH’s antioxidant functions in neurons, resulting in neuronal damage and ultimately in the impairment of cognitive function. Therefore, in this review, we explore the overall relationship between zinc and GSH in terms of oxidative stress and neuronal cell death. Furthermore, we seek to understand how the modulation of zinc can rescue brain-insult-induced neuronal death after ischemia, hypoglycemia, and traumatic brain injury.
... The mGluRs and related GPCRs have also been shown to regulate islet function, in addition to their roles in the CNS and diabetic neuropathy (18). Group I mGluRs (mGluR1,5) belong to the G q/11 family, and group II mGluRs (mGluR2,3) and group III mGluRs (mGluR4, 6,7,8) belong to the G i/o and G s families, respectively. ...
Neurotransmitters are signaling molecules secreted by neurons to coordinate communication and proper function among different sections in the central neural system (CNS) by binding with different receptors. Some neurotransmitters as well as their receptors are found in pancreatic islets and are involved in the regulation of glucose homeostasis. Neurotransmitters can act with their receptors in pancreatic islets to stimulate or inhibit the secretion of insulin (β cell), glucagon (α cell) or somatostatin (δ cell). Neurotransmitter receptors are either G-protein coupled receptors or ligand-gated channels, their effects on blood glucose are mainly decided by the number and location of them in islets. Dysfunction of neurotransmitters receptors in islets is involved in the development of β cell dysfunction and type 2 diabetes (T2D).Therapies targeting different transmitter systems have great potential in the prevention and treatment of T2D and other metabolic diseases.
... Preclinical data indicate that GCPII inhibitors ameliorate DN in animal models. Direct or indirect activation of mGluR2/3 protects against development of DN in animal models [89]. mGluR2/3 agonists prevent glucose-induced neuronal injury in DRG neuronal cultures by increasing glutathione and maintaining mitochondrial function only in the presence of Schwann/SGC cells [83,90,91]. ...
Dysfunction of mitochondria and signaling pathways related to their function can lead to diabetic peripheral neuropathy and understanding these mechanisms is key to developing new therapies. Though the pathophysiology of diabetic neuropathy (DN) is complex, specific pathways that regulate mitochondrial function are potential targets for therapy. Oxidative and nitrosative stress trigger several pathways that induce neuroinflammation associated with the pathophysiology of diabetic neuropathy. Mitochondrial dysfunction in neurons and axons is amplified by aberrant glycemic and hyperlipidemic metabolism resulting in abnormal DNA structure and protein generation. Mitochondrial function can be regulated by transcription factors such as SIRT1, PGC-1α, and TFAM upregulation of these transcription factors improves diabetic neuropathy. Nrf2, which facilitates the expression of several antioxidant proteins via antioxidant response element (ARE) binding sites affects the progression of diabetic neuropathy. Other pathways that modulate injury to the peripheral nerve are TGF-β, AGEs, glyoxalase 1, PKC, and molecular chaperones. Potential mitochondrial related pathways that can be targeted for treatment are discussed.
... [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15] Diabetes can contribute to hearing loss affecting cochlear and neural elements 16,17 through numerous mechanisms, including microangiopathy, mitochondrial dysfunction, advance glycation end products/inflammation, and glutamate excitotoxicity. 7,[18][19][20][21][22][23][24][25] The net result is increased risk for primarily acquired auditory sensory and neural pathology (i.e., sensorineural hearing loss). Increased risk for infection in persons with diabetes (PWD) also should alert the provider to risk for conductive pathologies of the external and middle ear. ...
Diabetes mellitus is a significant risk factor for acquired hearing loss and tinnitus. Persons with diabetes (PWD) may present with hearing loss symptoms earlier in life than those without diabetes. Furthermore, diabetes may exacerbate risk for hearing loss related to noise exposure and ototoxic drugs. The purpose of this article is to provide recommendations for the prevention, screening, evaluation, and management of hearing loss in PWD.
... Small quantities of reactive oxygen species (ROS) that are produced as by-products are detoxified in the nerve by cellular antioxidants such as glutathione, catalase, and superoxide dismutase (Vincent, Kato, McLean, Soules, & Feldman, 2009). In the peripheral nervous system, Schwann cells have a high antioxidant capacity, that exceeds that in peripheral sensory neurons (Vincent et al., 2009) and easily detoxify the accumulating ROS under normal metabolic conditions (Anjaneyulu, Berent-Spillson, & Russell, 2008;Berent-Spillson & Russell, 2007;Chandrasekaran et al., 2017;Cowell & Russell, 2004). While hyperglycemia does affect cultured adult Schwann cells, the concentration of glucose required to achieve significant cellular and Mt injury is very high (150 mM) (Delaney, Russell, Cheng, & Feldman, 2001). ...
... The drug also prevented a reduction in the level of the most distal unmyelinated nerve fibers in the hind limb paw epidermis and dermis. In diabetic neuropathy, release of glutamate is associated with increased oxidative stress and decreased Mt function (Anjaneyulu et al., 2008;Berent-Spillson et al., 2004;Berent-Spillson & Russell, 2007;Spillson & Russell, 2003). The glutamate hypothesis of DPN was interrogated by inducing the glutamate reuptake pathway with an mGluR2/3 agonist to elucidate the mechanism of protection. ...
... This is consistent with previous findings in which exposure to a mGluR2/3 agonist prevents glucose-induced neuronal injury in DRG neuronal cultures, only in the presence of Schwann/SGC cells, by increasing glutathione and maintaining Mt function (Berent-Spillson et al., 2004;Berent Spillson & Russell, 2003. NMDA receptor antagonists are not as protective as mGluR2/3 agonists, suggesting that ionotropic pathways are not involved in this mechanism (Anjaneyulu et al., 2008;Berent-Spillson et al., 2004;Berent-Spillson & Russell, 2007). Results from western blots of Mt transcription factors and OXPHOS proteins suggest that the physiological response to diabetic injury is insufficient to protect DRG neurons. ...
Survival of human peripheral nervous system neurons and associated distal axons is highly dependent on energy. Diabetes invokes a maladaptation in glucose and lipid energy metabolism in adult sensory neurons, axons and Schwann cells. Mitochondrial (Mt) dysfunction has been implicated as an etiological factor in failure of energy homeostasis that results in a low intrinsic aerobic capacity within the neuron. Over time, this energy failure can lead to neuronal and axonal degeneration and results in increased oxidative injury in the neuron and axon. One of the key pathways that is impaired in diabetic peripheral neuropathy (DPN) is the energy sensing pathway comprising the nicotinamide-adenine dinucleotide (NAD+)-dependent Sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor-γ coactivator α (PGC-1α)/Mt transcription factor A (TFAM or mtTFA) signaling pathway. Knockout of PGC-1α exacerbates DPN, whereas overexpression of human TFAM is protective. LY379268, a selective metabolomic glutamate receptor 2/3 (mGluR2/3) receptor agonist, also upregulates the SIRT1/PGC-1α/TFAM signaling pathway and prevents DPN through glutamate recycling in Schwann/satellite glial (SG) cells and by improving dorsal root ganglion (DRG) neuronal Mt function. Furthermore, administration of nicotinamide riboside (NR), a precursor of NAD+, prevents and reverses DPN, in part by increasing NAD+ levels and SIRT1 activity. In summary, we review the role of NAD+, mitochondria and the SIRT1-PGC-1α-TFAM pathway both from the perspective of pathogenesis and therapy in DPN.
... Similar improvement in IENFD was seen in LCR rats treated with LY379268 (B). 37,38 We propose a novel mechanism of protection that involves activation of glutamate recycling pathways to normalize mitochondrial OXPHOS metabolism. ...
... In diabetic neuropathy, release of glutamate is associated with increased oxidative stress and decreased mitochondrial function. 21,38 We interrogated this glutamate hypothesis of DPN by inducing the glutamate reuptake pathway with an mGluR2/3 agonist to elucidate the mechanism of protection. Glutamate is transported to the axon terminals for synaptic release and induces an ionotropic uptake mechanism involving Na + and Ca 2+ ions. ...
Objectives
There is a critical need to develop effective treatments for diabetic neuropathy. This study determined if a selective mGluR2/3 receptor agonist prevented or treated experimental diabetic peripheral neuropathy (DPN) through glutamate recycling and improved mitochondrial function.
Methods
Adult male streptozotocin treated Sprague‐Dawley rats with features of type 1 diabetes mellitus (T1DM) or Low Capacity Running (LCR) rats with insulin resistance or glucose intolerance were treated with 3 or 10 mg/kg/day LY379268. Neuropathy end points included mechanical allodynia, nerve conduction velocities (NCV), and intraepidermal nerve fiber density (IENFD). Markers of oxidative stress, antioxidant response, glutamate recycling pathways, and mitochondrial oxidative phosphorylation (OXPHOS) associated proteins were measured in dorsal root ganglia (DRG).
Results
In diabetic rats, NCV and IENFD were decreased. Diabetic rats treated with an mGluR2/3 agonist did not develop neuropathy despite remaining diabetic. Diabetic DRG showed increased levels of oxidized proteins, decreased levels of glutathione, decreased levels of mitochondrial DNA (mtDNA) and OXPHOS proteins. In addition, there was a 20‐fold increase in levels of glial fibrillary acidic protein (GFAP) and the levels of glutamine synthetase and glutamate transporter proteins were decreased. When treated with a specific mGluR2/3 agonist, levels of glutathione, GFAP and oxidized proteins were normalized and levels of superoxide dismutase 2 (SOD2), SIRT1, PGC‐1α, TFAM, glutamate transporter proteins, and glutamine synthetase were increased in DRG neurons.
Interpretation
Activation of glutamate recycling pathways protects diabetic DRG and this is associated with activation of the SIRT1‐PGC‐1α–TFAM axis and preservation of mitochondrial OXPHOS function.
... Possible mechanisms proposed included microangiopathy, abnormal accumulation of metabolic by-products due to mitochondrial dysfunction (e.g., oxidative stress), glutathione dysregulation, glycation, and protein synthesis dysfunction (Frisina et al. 2006;Liu et al. 2008). Anjaneyulu et al. (2008) suggested glutamate excitotoxicity and in particular compromised metabotropic glutamate receptor function underlying DM neuropathologies. Glutamate excitotoxicity is also a hypothesized mechanism contributing to noise-induced synaptopathy (Kujawa & Liberman 2009). ...
Objectives:
The purpose of this study was to examine the relationship between noise exposure history, type 1 diabetes mellitus (DM), and suprathreshold measures of auditory function.
Design:
A cross-sectional study was conducted; 20 normal-hearing participants without type 1 DM were matched on age and sex to 20 normal-hearing participants with type 1 DM (n=40). Participants, all having normal audiometric thresholds, completed noise history questionnaires and a battery of auditory physiological tests including transient evoked otoacoustic emissions, distortion product otoacoustic emissions, and auditory brainstem responses (ABR) at 80 dB nHL and at 2 different stimulus rates in both ears. Amplitude and latency for waves I and V are presented. Statistical analysis included analysis of variance and multivariate linear regression.
Results:
No statistically significant difference for noise exposure history, otoacoustic emissions (OAE), or ABR findings were found between type 1 DM and matched controls. Males and females showed statistically significant differences for OAE amplitudes and ABR amplitude and latencies. However, no statistically significant relationship was found between noise outcomes and OAE or ABR findings.
Conclusions:
No statistically significant relationship between noise history and our suprathreshold ABR or OAE findings was indicated for individuals with type 1 DM or matched controls. The lack of evidence of noise related neuropathology might be due to inadequate noise exposure or lack of comorbidities in our DM group. Implications of these findings are discussed.
... As previously reported in the metaanalysis of Li et al. [15], the effect of ALC on neuropathic pain was stronger in diabetes than other conditions. One hypothesis is that in diabetes, the effect of glutamate is more pronounced than other neuropathies [29,30] and consequently, ALC works better in this condition. ...
Background/aim
Deficiency of acetyl-L-carnitine (ALC) and L-carnitine (LC) appears to play a role in peripheral diabetic neuropathy, although the evidence in humans is still limited. We conducted a systematic review and meta-analysis investigating the effect of ALC on pain and electromyographic parameters in people with diabetic neuropathy.
Methods
A literature search in major databases, without language restriction, was undertaken. Eligible studies were randomized controlled trials (RCTs) or pre- and post-test studies. The effect of ALC supplementation on pain perception and electromyographic parameters in patients with diabetic neuropathy was compared vs. a control group (RCTs). The effect of ALC/LC on electromyographic parameters were also calculated vs. baseline values. Standardized mean differences (SMD) and 95% confidence intervals (CIs) were used for summarizing outcomes.
Results
Six articles, with a total of 711 diabetic participants, were included. Three RCTs (340 treated with ALC vs. 203 placebo and 115 with methylcobalamine) showed that ALC reduces pain perception (SMD = −0.45; 95% CI: −0.86 to −0.04; P = 0.03; I2 = 85%). Compared to controls, ALC supplementation improved nerve conduction velocity and amplitude response for ulnar nerve (both sensory and motor component). Compared to baseline values, ALC/LC supplementation improved nerve conduction velocity for all the sensory and motor nerves (except ulnar and peroneal) investigated and the amplitude of all nerves. The onset of adverse events was generally limited to minor side effects.
Conclusion
ALC appears to be effective in reducing pain due to diabetic neuropathy compared to active or placebo controls and improving electromyographic parameters in these patients.
... Activation of (mGluRs) subtypes usually regulates many cellular activities in mammalian systems in various experimental models. Activation of (mGluRs) subtypes protected cells against various types of neuronal insults such as traumatic brain injury, stroke, and NMDA excitotoxicity [17]. Interestingly, in recent years, glutamate has been reported to be efficient in preventing neuropathy caused by many cytotoxic drugs in mice, rats, and humans with no or minimal apparent intrinsic toxicity and its low cost and oral availability make it attractive for clinical use as a neuroprotectant [18]. ...
Cisplatin or cis-diamminedichloroplatinum (II) (CDDP) is a cytotoxic chemotherapeutic agent with dose-dependent peripheral neuropathy as a foremost side effect characterised by ataxia, pain, and sensory impairment. Cumulative drug therapy of CDDP is known to produce severe oxidative damage. It mainly targets and accumulates in dorsal root ganglia that in turn cause damage resulting in secondary nerve fibre axonopathy. In the present study, we investigated the neuroprotective effect of the combination of monosodium glutamate (MSG) with three individual antioxidants, that is, resveratrol, alpha-lipoic acid (ALA), and coenzyme Q10 (CoQ10), in cisplatin (2 mg/kg i.p. twice weekly) induced peripheral neuropathy in rats. After 8 weeks of treatment the degree of neuroprotection was determined by measuring behavioral and electrophysiological properties and sciatic nerve lipid peroxidation, as well as glutathione and catalase levels. The results suggested that pretreatment with the combination of MSG (500 mg/kg/day po) with resveratrol (10 mg/kg/day i.p.) or ALA (20 mg/kg/day i.p.) or CoQ10 (10 mg/kg weekly thrice i.p.) exhibited neuroprotective effect. The maximum neuroprotection of MSG was observed in the combination with resveratrol.
