Epalrestat

Epalrestat is the only aldose-reductase inhibitor approved for diabetic neuropathy in Japan. Using rat Schwann cells, the authors demonstrate that clinically relevant concentrations of Epalrestat 3-5 fold increase intracellular glutathione by transcriptionally up-regulating the rate-limiting enzyme in GSH synthesis, γ-glutamylcysteine synthetase (γ-GCS). This effect is mediated by nuclear translocation and activation of Nrf2, as shown by ELISA and is abolished by Nrf2 siRNA. The elevated GSH confers striking resistance to oxidative insults.
The results identify Epalrestat as an Nrf2 activator that boosts endogenous antioxidant defenses and thus suggest a new clinical utility for this drug beyond glycaemic control for oxidative stress-related disorders such as neuropathy, atherosclerosis and neurodegeneration.

Fig. 1 Epalrestat increases intracellular glutathione levels. (Sato K.; et al. 2014)

Epalrestat, an aldose reductase inhibitor with poor water solubility, was combined with β-cyclodextrin or sulfobutyl ether β-CD (SBE7β-CD) to form inclusion complexes, which were then encapsulated into chitosan (CS) nanoparticles via ionotropic gelation. Six EPL-CD-loaded CS nanoparticle formulations were prepared and optimized. NP6 (EPL-SBE7β-CD, coprecipitation method) showed the smallest size, highest drug entrapment efficiency, and fastest drug release. FTIR, PXRD, DSC, SEM, and TEM confirmed successful complexation, amorphous drug state, and spherical morphology. In-silico docking supported stable interaction between SBE7β-CD and the cross-linker TPP.

Fig. 2 Nanoparticles loaded with Epalrestat-cyclodextrin inclusion complex. (Alvi Z.; et al. 2021)