Neuroprotective effect of epalrestat on hydrogen peroxide induced neurodegeneration in SH-SY5Y cellular model.

Epalrestat (EPS) is a brain penetrant aldose reductase inhibitor, an approved drug currently used for the treatment of diabetic neuropathy. At near-plasma concentration, EPS induces glutathione biosynthesis, which in turn reduces oxidative stress in the neuronal cells. In this study we found that EPS reduces neurodegeneration by inhibiting reactive oxygen species (ROS) induced oxidative injury, mitochondrial membrane damage, apoptosis and tauopathy. EPS treatment up to 50 µM did not show any toxic effect on SH-SY5Y cell line (Neuroblastoma cells). However we observed toxic effect at a concentration of 100µM and above. At 50µM concentration, EPS showed better antioxidant activity against H2O2 (100µM) induced cytotoxicity, ROS formation and mitochondrial membrane damage in retinoic acid differentiated SH-SY5Y cell line. Furthermore, the study revealed that 50µM of EPS concentration reduced the glycogen synthase kinase-3 β (GSK3-β) expression and total tau protein level in H2O2 (100µM) treated cells. Findings from this study confirms the therapeutic efficacy of EPS on regulating alzheimer disease (AD) by regulating GSK3-β and total tau proteins phosphorylation, which helped to restore the cellular viability. This process could also reduce toxic fibrillary tangle formation and disease progression of AD. Therefore, it was conceived that an optimal concentration of EPS therapy could decrease AD pathology by reducing tau phosphorylation through regulating the expression level of GSK3-β.