Aldose Reductase Inhibition Improves Nerve Conduction Velocity in Diabetic Patients

Abstract

To assess the potential role of polyol-pathway activity in diabetic neuropathy, we measured the effects of sorbinil--a potent inhibitor of the key polyol-pathway enzyme aldose reductase--on nerve conduction velocity in 39 stable diabetics in a randomized, double-blind, cross-over trial. During nine weeks of treatment with sorbinil (250 mg per day), nerve conduction velocity was greater than during a nine-week placebo period for all three nerves tested: the peroneal motor nerve (mean increase [+/- S.E.M.], 0.70 +/- 0.24 m per second, P less than 0.008), the median motor nerve (mean increase, 0.66 +/- 0.27, P less than 0.005), and the median sensory nerve (mean increase, 1.16 +/- 0.50, P less than 0.035). Conduction velocity for all three nerves declined significantly within three weeks after cessation of the drug. These effects of sorbinil were not related to glycemic control, which was constant during the study. Although the effect of sorbinil in improving nerve conduction velocity in diabetics was small, the findings suggest that polyol-pathway activity contributes to slowed nerve conduction in diabetics. The clinical applicability of these observations remains to be determined, but they encourage further exploration of this approach to the treatment or prevention of diabetic neuropathy.

Pharmacological Profiles of a Novel Aldose Reductase Inhibitor, SPR-210, and Its Effects on Streptozotocin-Induced Diabetic Rats

“…Table 6. Recovery effect of SPR-210 on the peak latency of oscillatory potential on electroretinogram (ERG) in diabetic rats DISCUSSION AR inhibitors including the hydantoin type, e.g., sor binil, have been reported to show a high AR inhibition activity and a significant improvement in diabetic neuro pathy (29), but show a lasting high concentration in the plasma; and adverse effects, such as skin rash, were also observed in clinical trials (30,31). Based on these reports, we selected a 1,4-benzothiazin acetic acid compound from the various AR inhibitor prototypes (carboxylic acid derivatives) and finally chose SPR-210 as one of our candi date AR inhibitors among approximately 200 benzo thiazin derivatives with an acetic acid moiety synthesized in our laboratories.…”

Phosphorylation of c-Jun N-terminal kinase (JNK) in sensory neurones of diabetic rats, with possible effects on nerve conduction and neuropathic pain: prevention with an aldose reductase inhibitor

“…Since the earliest demonstration that aldose reductase inhibitors prevented slowing of motor nerve conduction velocity (MNCV) in rats with experimental diabetes [3], it has become a welldefined end-point for the evaluation of this class of drug. Conduction changes have also been the most responsive component of neuropathic diabetic defects in the clinic [4,5]. In spite of this, there is no proven link between exaggerated flux through the sorbitol pathway and the molecular basis of the conduction velocity deficit or of the other features of neuropathy.…”

A defect in sodium-dependent amino acid uptake in diabetic rabbit peripheral nerve. Correction by an aldose reductase inhibitor or myo-inositol administration.

“…Aldose reductase inhibitors improve nerve conduction in nonneuropathic diabetic patients (9) and ameliorate the sorbitol accumulation (10, I 1) and structural fiber abnormalities (10) in the peripheral nerves of neuropathic diabetic subjects. MI administration also appears to marginally improve nerve conduction in highly selected diabetic neuropathic patients (12)(13)(14)(15), but not in more heterogeneous populations of diabetic subjects (16,17).…”