Inhibition of Macrophage Chemotaxis and Peripheral Nerve Regeneration in Normal and Hyperglycemic Rats by the Aldose Reductase Inhibitor Tolrestat

Abstract

This study examined the effect of Tolrestat, an inhibitor of aldose reductase, on the regenerative capacity and macrophage chemotactic property of crush-injured sciatic nerve in normal and galactose-fed rats. Galactose intoxication reduced the incidence of regeneration but did not alter the regeneration distance or the injury-induced increase in vasoactive intestinal polypeptide content of dorsal root ganglia. Tolrestat improved the incidence of regeneration in galactose-fed rats but significantly (P < 0.05) reduced the distance of nerve regeneration in both control and galactose-fed rats. Galactose intoxication enhanced the ability of homogenates of nerve undergoing Wallerian degeneration to attract macrophages, whereas chemotaxis toward nerve homogenates from Tolrestat-treated rats was absent. Tolrestat, but not the structurally dissimilar aldose reductase inbibitors Ponalrestat and Sorbinil, exhibited a reversible, dose-dependent inhibition of macrophage chemotaxis induced by polyinosinic acid. These data suggest that exaggerated sugar metabolism by aldose reductase may restrict the ability of nerve to initiate regeneration but is not responsible for the reduced distance of nerve regeneration or attenuated increase in vasoactive intestinal polypeptide production that occur after crush injury of diabetic rats. Inhibition of macrophage responses to chemotactic signals by Tolrestat may impede regeneration and other reparative mechanisms.