Neuroprotective Effect of Epalrestat on Hydrogen Peroxide-Induced Neurodegeneration in SH-SY5Y Cellular Model

J Microbiol Biotechnol. 2021 Jun 28;31(6):867-874. doi: 10.4014/jmb.2101.01002.


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 100 μM and above. At 50 μM concentration, EPS showed better antioxidant activity against H2O2 (100 μM)-induced cytotoxicity, ROS formation and mitochondrial membrane damage in retinoic acid-differentiated SH-SY5Y cell line. Furthermore, our study revealed that 50 μM of EPS concentration reduced the glycogen synthase kinase-3 β (GSK3-β) expression and total tau protein level in H2O2 (100 μM)-treated cells. Findings from this study confirms the therapeutic efficacy of EPS on regulating Alzheimer's 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 is our view that an optimal concentration of EPS therapy could decrease AD pathology by reducing tau phosphorylation through regulating the expression level of GSK3-β.

Keywords: Epalrestat; SH-SY5Y cell line; Tau pathology; hydrogen peroxide; neuroprotection; oxidative stress.

MeSH terms

  • Cell Differentiation / drug effects
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • DNA Damage / drug effects
  • Glycogen Synthase Kinase 3 beta / metabolism
  • Humans
  • Hydrogen Peroxide / adverse effects*
  • Membrane Potential, Mitochondrial / drug effects
  • Neurons / drug effects*
  • Neurons / metabolism
  • Neurons / pathology
  • Neuroprotective Agents / pharmacology*
  • Oxidative Stress / drug effects
  • Reactive Oxygen Species / metabolism
  • Rhodanine / analogs & derivatives*
  • Rhodanine / pharmacology
  • Thiazolidines / pharmacology*
  • Tretinoin / pharmacology
  • tau Proteins / metabolism


  • Neuroprotective Agents
  • Reactive Oxygen Species
  • Thiazolidines
  • tau Proteins
  • epalrestat
  • Tretinoin
  • Rhodanine
  • Hydrogen Peroxide
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta