Tolrestat, an Aldose Reductase Inhibitor, Prevents Nerve Dysfunction in Conscious Diabetic Rats

Abstract

The effect of 4 wk of streptozocin (STZ)-induced diabetes on the transmission time of the auditory-evoked brain stem response (ABR) was examined in conscious male Sprague-Dawley rats. Distal nerve transmission time of the auditory pathway (latency of peak II), which includes conduction along the 8th cranial nerve, increased in diabetic rats (n = 9) relative to nondiabetic rats (n = 17). The difference in peak II latency between diabetic and control rats was significant beginning 2 wk after the induction of diabetes (P less than .05). In contrast, 4 wk of STZ-induced diabetes had no effect on the central transmission time of the auditory pathway (interpeak latency between peaks II and IV). Oral administration of tolrestat, a structurally novel aldose reductase inhibitor (n = 8; 20 mg/kg twice daily 1 wk before and 4 wk after STZ injection), prevented the diabetes-induced increase in distal nerve transmission time. These findings indicate that experimentally induced diabetes can result in a nerve dysfunction as measured by the increased latencies of the early components of the ABR. Furthermore, because tolrestat prevents these changes in the ABR, aldose reductase and the polyol pathway are implicated in this neuropathy.

Interactions of hearing loss and diabetes mellitus in the middle age CBA/CaJ mouse model of presbycusis

“…For central auditory function, STZ-induced diabetes in rats (less then 5 months) showed no effect on ABR interpeak latencies, but increased peripheral (I and II) and central (IV) peak latencies (Notvest and Inserra 1987; Rubini et al 1992). For longer duration of STZ induced diabetes (over 6 months), prolongation of central transmission times (increased late interpeak latencies) were observed in rats (Biessels et al 1999, 2001; Manschot et al 2003).…”

Relationship of cerebrospinal fluid glucose metabolites to MRI deep white matter hyperintensities and treatment resistance in bipolar disorder patients

“…Although polyol pathway activity has not been directly linked to white matter disease in diabetes, sorbitol does accumulate in the CSF of individuals with diabetes (31) and in the cerebral cortex of animals with experimentally induced diabetes (32). Pharmacologic blockade of the pathway improves central nerve conduction in an animal model of diabetes (33). Furthermore, early‐life‐onset white matter disease has been linked to inborn errors of polyol metabolism (34–36).…”