Neuroprotective effect of epalrestat mediated through oxidative stress markers, cytokines and TAU protein levels in diabetic rats

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Aims:Type-2 diabetes mellitus (DM) is associated with cognitive impairment. Increasing evidence establishes that neuro-inflammatory and oxidative stress condition plays a main role in the development of neurodegeneration. Epalrestat, an aldose reductase inhibitor is commonly prescribed for the treatment of diabetic peripheral neuropathy. Its beneficial effects for antioxidant, anti-inflammatory potential and being rhodanine structure containing compound suggests possible role for treatment of DM associated with cognitive dysfunction.Main methods:In the present study, we evaluated the effect of epalrestat (54, 27, 13.5mg/kg, p.o.) and donepezil (1mg/kg, p.o.) on Tau protein levels, oxidative stress and inflammatory markers in high fat diet (HFD) and Streptozotocin (STZ; 35mg/kg, i.p.) induced cognitive impairment in diabetic rats.Key findings:The epalrestat - 54, 27mg/kg p.o. and donepezil treatment significantly increased CAT (p<0.001, p<0.01, p<0.001) and GSH (p<0.001, p<0.01, p<0.001) activities respectively as compared to diabetic control rats. In addition, similar dose of epalrestat treatment indicated considerably lowered TAU protein levels (p<0.001, p<0.05) while no significant effect was noted with donepezil. These treatments significantly decreased gene expression of TNF-α (1.6, 1.6, 1.7 fold change) and IL-6 (2.5, 1.9, 1.7 fold change). Histopathological examination indicated that epalrestat could attenuate apoptosis of neurons, vacuolations and clumped processes, disorganization and thinning of all the layers.Significance:Our findings suggest that diabetic rats treated with epalrestat could ameliorate the cognition deficits and might act as a beneficial agent for prevention and treatment of cognitive impairment in diabetes.

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