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Congo red-stained brain sections of rats for visualization of amyloid plaques. The micrographs represent the following groups: (a) D-gal-treated group showing red amyloid plaques (arrow) associated with cerebral amyloid angiopathy (arrow head), (b) D-gal/Met group showing sparse deposition of amyloid plaque (arrow), and (c) D-gal/Saxa group showing multiple amyloid plaques (arrows). (Congo red stain, X20). D-gal, rats treated with D-galactose (150 mg/kg/day, s.c); D-gal/Met, rats treated with D-galactose and metformin; Dgal/Saxa, rats treated with D-galactose and saxagliptin. https://doi.org/10.1371/journal.pone.0183565.g010
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Age-related dementia is one of the most devastating disorders affecting the elderly. Recently, emerging data suggest that impaired insulin signaling is the major contributor in the development of Alzheimer’s dementia (AD), which is the most common type of senile dementia. In the present study, we investigated the potential therapeutic effects of me...
Citations
... DPP-4 inhibitors have been reported to have cytoprotective effects against various types of organ damage, not just glucose regulation [15]. The DPP-4 inhibitor saxagliptin, for example, suppressed increased insulin signaling impairment and oxidative stress in a D-gal-induced aging model [16]. The anti-glycation effects of DPP-4 inhibitors have been well documented. ...
... Pharmacologically, DPP-4 inhibition is associated with a reduction in oxidative stress [34]. DPP-4 inhibitors have been shown to have a protective effect in conditions characterized by impaired insulin signaling and oxidative stress induced by D-gal in aging rats [16]. Additionally, DPP-4 deficiency has been reported to lead to lower levels of AGEs and improved age-related complications [35]. ...
Oral dryness is among the most common conditions experienced by the elderly. As saliva plays a crucial role in maintaining oral health and overall quality of life, the condition is increasingly taking its toll on a rapidly growing aging population. D-galactose (D-gal) stimulates their formation, which in turn cause oxidative stress and accelerate age-related decline in physical function. In this study, we observed a reduction in salivary secretion and amylase levels in aged rats injected with D-gal, confirming salivary gland dysfunction. Treatment with gemigliptin increased DPP-4 inhibition and GLP-1 levels in the salivary glands of aging rats and reduced the expression of AGEs and receptors for advanced glycation end products (RAGE). This effect was caused by the presence of additional reactive oxygen species (ROS) in the salivary glands of the examined rats. Gemigliptin’s cytoprotective effect reduced amylase and mucin accumulation and increased AQP5 expression, which are important indicators of salivary gland function. In sum, gemigliptin was shown to improve D-gal-induced decline in the salivary gland function of aged rats through its anti-glycation and antioxidant activities. Gemigliptin shows promise as a treatment strategy for patients experiencing decreased salivary function associated with their advancing age.
... The combination therapy of metformin and vitamin E showed significant improvements in brain and pancreatic tissue morphology compared to the effects of metformin and vitamin E alone [39]. Metformin has been shown to play a central role in inhibiting the aggregation of amyloid-β through the activation of AMPK [40]. ...
Cardiovascular diseases (CVDs) and neurodegenerative disorders, such as diabetes mellitus and Alzheimer’s disease, share a common pathophysiological link involving insulin resistance (IR), inflammation, and hypertension. Aluminium chloride (AlCl3), a known neurotoxicant, has been associated with neurodegeneration, cognitive impairment, and various organ dysfunctions due to the production of reactive oxygen species (ROS) and oxidative stress. In this study, we aimed to investigate the potential protective effects of metformin and vitamin E against AlCl3-induced neuroinflammation and cardiometabolic disturbances in rat models. Rats were divided into five groups: a normal control group, an AlCl3-treated diseased group without any treatment, and three groups exposed to AlCl3 and subsequently administered with metformin (100 mg/kg/day) alone, vitamin E (150 mg/kg/day) orally alone, or a combination of metformin (100 mg/kg/day) and vitamin E (150 mg/kg/day) for 45 days. We analyzed serum biomarkers and histopathological changes in brain, heart, and pancreatic tissues using H&E and Masson’s trichrome staining and immunohistochemistry (IHC). Electrocardiogram (ECG) patterns were observed for all groups. The AlCl3-treated group showed elevated levels of inflammatory biomarkers, MDA, and disturbances in glycemic and lipid profiles, along with reduced insulin levels. However, treatment with the combination of metformin and vitamin E resulted in significantly reduced glucose, cholesterol, LDL, and TG levels, accompanied by increased insulin and HDL levels compared to the individual treatment groups. Histopathological analyses revealed that combination therapy preserved neuronal structures, muscle cell nuclei, and normal morphology in the brain, heart, and pancreatic tissues. IHC demonstrated reduced amyloid plaques and neurofibrillary tangles in the combination-treated group compared to the AlCl3-treated group. Moreover, the combination group showed a normal ECG pattern, contrasting the altered pattern observed in the AlCl3-treated group. Overall, our findings suggest that metformin and vitamin E, in combination, possess neuroprotective and cardiometabolic effects, alleviating AlCl3-induced neuroinflammation and metabolic disturbances.
... These complications are linked to insulin resistance, excessive glycation and oxidation causing inflammation and apoptosis in neurons, increased platelet aggregation, endothelial dysfunction, as well as impaired fibrinolysis and eventually increase the risk of dementia and stroke. Diabetes additionally decreases the energy and nutrients important for producing cellular proteins, lipids, and nucleic acids leading to cell starvation and death [58][59][60][61][62]. There was a significant improvement of the cognitive function domains (fluency, language, and shape recognition), total score of ACEIII, and TMT A and B among the interventional group, p < 0.01. ...
Aim: Assessing impact of lifestyle modification on Type 2 diabetes mellitus (T2DM) glycemic control and cognitive function. Subjects & methods: Prospective study was conducted on T2DM patients (92 patients as interventional group and 92 patients conventional therapy). Results: After 6 months, significant improvements of HbA1c, oxidant and antioxidant, lipid profile, and cognitive function among only the interventional group (p < 0.05). Using logistic analysis, conventional therapy, DM duration >10 years, lower education, HbA1c baseline >7 were significant predictive risks for uncontrolled DM (AOR 4.2, 2.9, 2.7 and 2.2, respectively). While, conventional therapy, baseline mild cognitive impairment (MCI) and females were significant risks for MCI (AOR 11.5, 10.8 and 4.8, respectively). Conclusion: Lifestyle modification is a very important for glycemic control and cognitive function.
Clinical Trial Registration: NCT04891887 ( ClinicalTrials.gov )
... The hippocampus or cortex tissues were fixed on a paraffin block, and transverse sections of 4-6 µm thickness were sliced using a rotary microtome (Leica, New York, NY, USA). The sections were stained with hematoxylin and eosin (H&E) and Congo red and were examined using a digital microscope (Motic, Richmond, BC, Canada) [51][52][53][54]. The severity of neurodegeneration was evaluated under 400X magnification [25,51]. ...
Recent evidences indicate that there is a substantial increase in worldwide cases of dementia. Alzheimer's disease is the leading cause of dementia and may contribute to 60–70% of cases. Quercetin is a unique bioflavonoid that has numerous therapeutic benefits such as anti-allergy, anti-ulcer, anti-inflammatory, anti-hypertensive, anti-cancer, immuno-modulatory, anti-infective, antioxidant, acetylcholinesterase inhibitory activity, neuroprotective effects, etc. In the present study, we evaluated the neuroprotective effect of orally administered quercetin with memantine in albino Wistar rats after inducing neurotoxicity through AlCl3 (100 mg/kg, p.o.). Chronic administration of AlCl3 resulted in poor retention of memory and significant oxidative damage. Various behavioral parameters, such as locomotor activity, Morris water maze, elevated plus maze, and passive avoidance test, were assessed on days 21 and 42 of the study. The animals were euthanatized following the completion of the last behavioral assessment. Various oxidative stress parameters were assessed to know the extent of oxidative damage to brain tissue. Quercetin with memantine has shown significant improvement in behavioral studies, inhibition of AChE activity, and reduction in oxidative stress parameters. Histopathological studies assessed for cortex and hippocampus using hematoxylin and eosin (H&E), and Congo red stain demonstrated a reduction in amyloid-β plaque formation after treatment of quercetin with memantine. Immunohistochemistry showed that quercetin with memantine treatment also improved the expression of brain-derived neurotrophic factor (BDNF) and inhibited amyloid-β plaque formation. The present study results demonstrated protective effects of treatment of quercetin with memantine in the neurotoxicity linked to aluminum chloride in albino Wistar rats .
... Moreover, there is growing evidence suggesting that DPP-IV inhibitors suppress inflammatory response beyond their glucose-lowering effects [18]. In fact, different research groups have confirmed the additional benefits of clinically approved DPP-IV inhibitors (namely, gosogliptin, saxagliptin, vildagliptin trelagliptin, omarigliptin, and sitagliptin, Fig. 1) in enhancing insulin sensitivity and reducing inflammation [19][20][21][22][23]. These findings are partially explained by effects subsequent to GLP-1 activation including inhibiting the production of inflammatory cytokines and toxic free radicals [17]. ...
Monoglyceride lipase (MGL) is an important enzyme that plays a critical role in lipolysis and release of free fatty acids from triacylglycerides stores. High levels of circulating free fatty acids impair insulin sensitivity and induce inflammation. Several studies have shown that dipeptidyl peptidase-IV (DPP-IV) inhibitors can improve insulin sensitivity and suppress inflammatory response by unknown mechanism. Structural similarities between DPP-IV and MGL prompted us to propose that DPP-IV inhibitors can block MGL. Accordingly, we evaluated 6 known DPP-IV inhibitors as potential MGL blockers using docking experiments and in vitro bioassay. All tested compounds were successfully docked into the catalytic site of MGL. Vildagliptin, sitagliptin, omarigliptin and trelagliptin illustrated significant anti-MGL inhibitory percentages at 10 µM, while gosogliptin and saxagliptin were rather potent MGL inhibitors with IC50 values of 6.9 nM and 136.2 nM, respectively. This is the first time to report potent inhibitory effects of DPP-IV inhibitors against MGL. This finding provide evidence for a new mechanism by which DPP-IV inhibitors improve insulin sensitivity and suppress inflammation response independent of incretin hormones pathway.
Graphical Abstract
... D-Galactose induced cognitive impairment: D-galactose (D-gal) is a natural reducing sugar that is mainly derived from lactose in the milk. Studies have showed that an excess of D-gal leads to abnormal metabolism due to the reduction in Na + , K + , ATPase activity, excessive oxidative stress due to enhanced lipid peroxidation and downregulation of the superoxide dismutase activity [66] , neuronal damage due to advanced glycation [62] and neuroinflammation [63][64][65] and increased senile plaques formation [66] , tau phosphorylation [68] leading to cognitive impairment in rodents [67] . It is known to cause alteration in hippocampal gene expressions [64] . ...
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterised pathologically by the presence of extracellular amyloid plaques and the intracellular neurofibrillary tangles, along with inflammation, and a compromised antioxidant system. Significant insights into the neurobiology to better understand the pathophysiology of AD and to evaluate the possibility of cutting-edge therapy strategies, can be obtained through the selection of a well-designed experimental animal model. From the transgenic to chemical/drug-induced models, none of them represents the complete picture of Alzheimer pathology and incidence of cognitive dysfunction. Researchers did not explain why one model was preferred over another, did not consider how the pathological phenomena were formed (spontaneously, experimentally, or by genetic manipulation), and did not address the traits of the species that affect the results. There is a lack of concordance between preclinical models and clinical trials that could be due to variety of reasons such as incomplete models, choice of animal species, lack of variability, and the validity of the models. To provide greater translation of preclinical AD studies to clinical trials proper designing of the model is essential. This review provides a brief recap ranging from animal doses to their induction mechanism and common limitations of the chemical-induced AD models.
• Animal models may fail to replicate the exact pathology of the disease
• Validity of the model is essential for proper translation of pathology from animal models to human disease
• Appropriate induction doses need to be administered.
... D-galactose contributes to the generation of ROS via reaction with amino acids to form glycation end-products through non-enzymatic glycation with the benefits of low toxicity, slow oxidation process, and no lethal effect. Moreover, oxidative stress from long-term exposure to D-gal can cause inflammation and affect insulin resistance [31]. As the level of insulin resistance increases, the amount of glucose in the bloodstream increases, resulting in more free radical formation in mitochondrial dysfunction [32]. ...
The development of many chronic diseases is associated with an excess of free radicals leading to harmful oxidative stress. Certain probiotic strains have been shown to have antioxidant and anti-aging properties and are an important resource for development of microbial antioxidants. The present study aimed to explore the protection offered by Bifidobacterium animalis strain MSMC83 in a model of oxidative stress induced by D-galactose (D-gal). Male Sprague Dawley rats were randomly allocated to four groups: a control group injected with saline, a group injected subcutaneously with D-galactose, a probiotic group injected with D-galactose and administered B. animalis MSMC83 (109 CFU/mL) via daily oral gavage, and an ascorbic acid group. The probiotics significantly increased the superoxide dismutase, catalase, and glutathione peroxidase and significantly decreased the malondialdehyde in the plasma and livers of D-galactose-treated rats. Moreover, tumor necrosis factor-alpha level in the liver was significantly decreased. Furthermore, the treatment with B. animalis MSMC83 restored the microbiota diversity after D-galactose injection. Therefore, our results supported a beneficial role of B. animalis MSMC83 in alleviating oxidative stress through the increased expression of antioxidant enzymes and reduction of pro-inflammatory cytokines in rats. Our study suggests that B. animalis MSMC83 may be part of a healthy diet to prevent oxidative stress-associated diseases.
... This suggests that estrogen depletion and D-gal ingestion act synergistically to accelerate cholinergic and glutaminergic neurodegeneration, thereby disrupting the metabolism of these neurotransmitters. Indeed, it is known that chronic administration of D-galactose leads to oxidative stress and neuroin ammation resulting in losses of cholinergic and glutaminergic neurons (13). Compared to OVX + D-gal group, the treatment with extra-virgin avocado oil at all tested doses induced an increase of these parameters. ...
Background: Avocado is a tree’s fruit (Persea AmericanaMill.) of the Laucaceae family. It was reported that consumption of avocado improved cognitive performance. No study has yet been carried out regarding the properties of avocado oil supplementation on the occurrence of Alzheimer's disease. The objective of the present study was to evaluate the effects of extra-virgin avocado oil on a model of D-galactose-induced Alzheimer's disease in ovariectomized Wistar rats.
Methods: To accomplish this, 54 female rats were used, of which 42 were ovariectomized (OVX) and 12 underwent white surgery (SHAM). Fourteen days after surgery, the animals were divided into 9 groups of 6 animals each: SHAM+Veh and OVX+Veh groups receiving the vehicle; SHAM + D-gal and OVX+D-gal groups receiving D-galactose and vehicle; OVX+D-gal+E2V and OVX+D-gal+DNPZ groups receiving D-galactose and reference drugs (estradiol valerate and donepezil respectively) and 3 test groups (OVX+D-gal+AO1; OVX+D-gal+AO2 and OVX+D-gal+AO3) receiving D-galactose each and extra-virgin avocado oil at the doses of 0.25, 0.5 and 1 mL/kg respectively. The treatment was carried out during 70 days during which memory disorders were evaluated using the Object Recognition, Y-Maze and MWM tests. Some biochemical parameters regarding memory function were evaluated on hippocampus homogenate 10%. Isolated brain was fixed in 10% formalin for histological analysis.
Results: As results, compared to SHAM+Veh group, deterioration of both non-spatial and spatial memory (short- and long-term) was observed in OVX animals threated with D-galactose. In addition, a significant decrease in relative hippocampal weight (p < 0.001), Ach (p < 0.001), Glu (p < 0.001), GSH (p < 0.001), CAT (p < 0.05), and SOD (p < 0.001) activities, and a significant (p < 0.001) increase in Methylglyoxal, MDA, and NO2-. was noted in OVX+D-gal group. Compared to OVX+D-gal group, the treatment with extra-virgin avocado oil at all tested doses reversed or prevented the negative effects induced by ovariectomy and/or by D-galactose on biochemical and oxidative stress biomarkers. The analysis of hippocampus microarchitecture shows that the extra-virgin avocado oil induced a significant decrease (p < 0.05; p < 0.01; p < 0.001) of neuronal loss in CA1 and CA3 hippocampal region.
Conclusions: Taken together, these results suggest that avocado oil possesses neuroprotective properties and can be consumed or supplemented to prevent the onset of Alzheimer's disease.
... Numerous authors reported significant changes in these brain regions following i.p and s.c. D-gal treatment such as histological markers of Alzheimer's disease, atrophy and loss of neurons, disorganized nerve fibers etc. [26,29,42,60,62,8]. In current experimental setup, preserved cytoarchitecture was observed through the PFC and HIP with no signs of aberrant neuronal morphology. ...
D-galactose (d-gal) is broadly used in animal aging studies as its chronic administration mimics learning and memory impairments related to aging in humans. However, within the few studies that utilize chronic oral d-gal intake, none of them is focused on alteration in synaptic structure and function. We examined the effects of 6-weeks oral d-gal intake (200 mg/kg and 500 mg/kg, dissolved in tap water) on age-related changes, with emphasis on the prefrontal cortex (PFC) and hippocampus (HIP) of adult male Wistar rats. Memory assessment was followed by histological examination of the PFC and HIP (Nissl staining and Iba-1 immunostaining), while in crude synaptosomal fractions the state of oxidative stress and the expression of proteins involved in glutamatergic signaling was determined. Although applied dosages compromised memory, alterations such as impaired sensory-motor function and aberrant morphology were not detected. In the PFC, analysis of microglia revealed reduction of branching pattern following d-gal intake, in parallel with increased oxidative damage of proteins, lipids and disturbed pro-oxidant antioxidant balance. These changes in the PFC were further accompanied with decreased levels of vesicular glutamate transporter 1, syntaxin-1 and NMDA receptor 2B subunit in both treated groups. Simultaneously, the increased hippocampal oxidative damage of lipids was detected. Results indicate successful provocation of age-related changes following oral d-gal intake, and suggest greater sensitivity of the PFC to d-gal treatment than HIP.
... 81 A previous study showed the effect of D-galactose on the upregulation of GFAP in affected brain tissues. 82 ...
Age-related diseases, including dementia, are a major health concern affecting daily human life. Strawberry (Fragaria ananassa Duch.) is the most eaten fruit worldwide due to its exceptional aroma and flavor. However, it's rapid softening and decay limit its shelf-life. Freezing and boiling represent the well-known conservation methods to extend its shelf-life. Therefore, we aimed to discover the phytochemical content differences of fresh and processed strawberries associated with investigating and comparing their neuroprotective effects in a rat model of aging. Female Wistar rats were orally pretreated with fresh, boiled, and frozen F. ananassa methanolic extracts (250 mg kg-1) for 2 weeks, and then these extracts were concomitantly exposed to D-galactose [65 mg kg-1, subcutaneously (S/C)] and AlCl3 (200 mg kg-1, orally) for 6 weeks to develop aging-like symptoms. The results of UPLC/ESI-MS phytochemical profiling revealed 36 secondary metabolites, including phenolics, flavonoids, and their glycoside derivatives. Compared with boiled and frozen extracts, the fresh extract ameliorated the behavioral deficits including anxiety and cognitive dysfunction, upregulated brain HO-1 and Nrf2 levels, and markedly reduced caspase-3 and PPAR-γ levels. Moreover, LDH and miRNA-9, 124 and 132 protein expressions were reduced. The histological architecture of the brain hippocampus was restored and glial fibrillary acidic protein (GFAP) immunoexpression was downregulated. In conclusion, the fresh extract has neuroprotective activity that could have a promising role in ameliorating age-related neurodegeneration.
