Aldose Reductase Inhibition by AS-3201 in Sural Nerve From Patients With Diabetic Sensorimotor Polyneuropathy

Abstract

OBJECTIVE -The primary purpose of this investigation was to determine whether AS-3201, a new aldose reductase inhibitor, penetrates the sural nerve and inhibits sorbitol and fructose accumulation in patients with diabetic sensorimotor polyneuropathy (DSP). An additional aim was to determine whether any changes in nerve function would manifest with AS-3201 therapy.RESEARCH DESIGN AND METHODS -Patients with mild to moderate DSP based on nerve conduction studies were randomized into one of three treatment groups in a doubleblind fashion: placebo or AS-3201 at 5 or 20 mg/day. After 12 weeks of administration, the sural nerve was biopsied for measurement of sorbitol, fructose, and AS-3201.RESULTS -At baseline, no important clinical, electrophysiological, or laboratory differences were found between the three groups. The nerve sorbitol concentration of 3.14 ϫ 10 Ϫ2 nmol/mg wet nerve in patients in the placebo group was inhibited by 65 and 84% in patients on AS-3201 at 5 and 20 mg/day, respectively (P Ͻ 0.001). Fructose levels were similarly inhibited. Sensory nerve conduction velocities improved by Ն1 m/s (P Ͻ 0.05).CONCLUSIONS -AS-3201 penetrates the sural nerve and inhibits sorbitol accumulation in patients with DSP. Additional studies are needed to confirm the electrophysiological suggestion that AS-3201 delays progression or leads to regression of DSP. Diabetes Care 27:2369 -2375, 2004D espite advances in the management of diabetes, diabetic sensorimotor polyneuropathy (DSP) continues to be a frequent and potentially serious complication leading to foot ulceration and amputation (1). A fundamental pathophysiologic mechanism in DSP is aberrant activity of the polyol pathway in which hyperglycemia increases aldose reductase enzyme activity (2). This activation in turn results in an increased conversion of glucose to sorbitol, leading to an accumulation of sorbitol and fructose in several organ systems, including erythrocytes, retina, kidneys, and various nerves. Laboratory studies in animals with diabetes have shown that increased nerve sorbitol is associated with nerve damage with decreased conduction velocity as a result of osmotic changes and oxidative stress (3). If the aldose reductase enzyme system could be pharmacologically inhibited with a decrease in nerve sorbitol and fructose levels, then nerve damage could be prevented or even possibly reversed.A number of aldose reductase inhibitors (ARIs) have been developed, but none have achieved clinical success for diverse reasons (4,5). The study failures have provided information on the natural progression of DSP and have led to suggested criteria for clinical development of ARIs (5). In a recent trial, inhibition of nerve sorbitol levels was associated with improved motor nerve conduction velocity (NCV) and an increase in the density of small-diameter sural nerve myelinated fibers (6). These encouraging results support the role of the polyol pathway in the pathogenesis of DSP. Experience has shown that inhibition of human nerve sorbitol levels must be demonstrat...

Ranirestat (AS-3201), a Potent Aldose Reductase Inhibitor, Reduces Sorbitol Levels and Improves Motor Nerve Conduction Velocity in Streptozotocin-Diabetic Rats

“…These findings may account for the different results in clinical trials of diabetic sensorimotor polyneuropathy with these 3 compounds (8). Interestingly, the 12-week clinical study in patients with sensorimotor polyneuropathy showed greater changes in sensory nerve conduction velocity than in motor nerve function, so perhaps longer treatment would show changes corresponding to those in the STZ-rat (8). Repeated oral administration of ranirestat (0.1 -1 mg/ kg) for 21 days improved the decrease in MNCV induced by STZ in diabetic rats (Fig.…”

“…2), a novel, new chemical entity ARI developed in our laboratories, has been shown to have a potentially beneficial effect on diabetic sensorimotor polyneuropathy in humans (8). Although the pharmacodynamics of ranirestat in humans was predicted from preclinical studies in diabetic rats, the pharmacological effects of ranirestat on AR in diabetic animal models have not been reported.…”

C-Peptide Replacement Therapy and Sensory Nerve Function in Type 1 Diabetic Neuropathy

“…This lack of improvement may be related to the short study duration in relation to the initial conduction velocity deficit. In fact, lack of improvement in MCV was reported also for another intervention attempt involving 3 months' treatment duration (30), but with more prolonged treatment a tendency for improved MCV was noted (31). The deterioration rate of nerve functional measures is not linear and differs among types of nerves (32).…”

A Selective Aldose Reductase Inhibitor of a New Structural Class Prevents or Reverses Early Retinal Abnormalities in Experimental Diabetic Retinopathy

“…Currently, there are new ARIs of the spiroimide/hydantoin class that show greater potency than sorbinil and have achieved in diabetic patients a robust inhibition of the polyol pathway in sural nerves (12), as well as improvement in signs and symptoms of sensorimotor polyneuropathy at well-tolerated doses (13,14). Recently, an ARI from an entirely new structural class was described ( Fig.…”