Abstract
Aldose reductase (AR), a rate-limiting enzyme in the polyol pathway, mediates the conversion of several substrates, including glucose and galactose. In rodents, galactosemia induced by galactose feeding has been shown to develop peripheral nerve lesions resembling diabetic peripheral neuropathy. However, the mechanisms by which AR-mediated responses elicited Schwan cell lesions under galactosemic conditions remain unresolved. To investigate this, we examined the mechanism of high-galactose-induced damage mediated by AR using AR inhibitors such as ranirestat and epalrestat. The exposure of IMS32 Schwann cells under high-galactose conditions led to galactitol accumulation, the increased production of reactive oxygen species (ROS), endoplasmic reticulum (ER) stress, impaired mitochondrial morphology and membrane potential, decreased glycolysis, and aberrant glycosylation. Under these experimental conditions, ranirestat inhibited intracellular galactitol in a dose-dependent manner, whereas epalrestat failed to inhibit it. Interestingly, even at low concentrations where epalrestat did not inhibit AR activity, it prevented increased ROS production, ER stress, decreased glycolysis, and aberrant RCA120-binding glycosylation; however, no effect of ranirestat on the glycosylation was observed. Epalrestat and ranirestat did not recover mitochondrial morphology. These findings suggest that ER stress is induced by aberrant glycosylation under galactosemic conditions and that epalrestat may be effective in maintaining proper glycosylation in Schwann cells in these conditions.