Decreased endoneurial fluid electrolytes in normal rat sciatic nerve after aldose reductase inhibition

The role of the enzyme aldose reductase in nerve homeostasis was examined by treating rats with an aldose reductase inhibitor. Female Sprague-Dawley rats were treated with Ponalrestat (25 mg/kg/day) or with excipient alone for 4 to 12 weeks before examining electrophysiologic function, endoneurial fluid electrolyte concentrations, nerve polyol levels, water content and (Na+,K+)-ATPase activity. Sorbitol, the product of glucose metabolism by aldose reductase, was detected in all nerves from control animals, whereas it was below detection limits in 7 of 11 nerves from Ponalrestat-treated rats. Ponalrestat treatment reduced endoneurial fluid sodium and chloride concentrations by 25% and 37%, respectively (both P < 0.001). No differences in nerve water content, conduction velocity, or ATPase activities were detected. These data, and previous studies demonstrating that increased flux through aldose reductase causes the accumulation of endoneurial electrolytes, suggest a role for this enzyme in modulation of the endoneurial microenvironment. However, short-term inhibition of aldose reductase does not appear to affect nerve function. Thus, our findings do not elicit concerns regarding the use of aldose reductase inhibitors in the treatment of clinical diabetic neuropathy.