Regeneration and Repair of Myelinated Fibers in Sural-Nerve Biopsy Specimens from Patients with Diabetic Neuropathy Treated with Sorbinil

Abstract

There is reason to believe that diabetic neuropathy may be related to the accumulation of sorbitol in nerve tissue through an aldose reductase pathway from glucose. Short-term treatment with aldose reductase inhibitors improves nerve conduction in subjects with diabetes, but the effects of long-term treatment on the neuropathologic changes of diabetic neuropathy are unknown. To determine whether more prolonged aldose reductase inhibition reverses the underlying lesions that accompany symptomatic diabetic peripheral polyneuropathy, we performed a randomized, placebo-controlled, double-blind trial of the investigational aldose reductase inhibitor sorbinil (250 mg per day). Sural-nerve biopsy specimens obtained at base line and after one year from 16 diabetic patients with neuropathy were analyzed morphometrically in detail and compared with selected electrophysiologic and clinical indexes. In contrast to patients who received placebo, the 10 sorbinil-treated patients had a decrease of 41.8 +/- 8.0 percent in nerve sorbitol content (P less than 0.01) and a 3.8-fold increase in the percentage of regenerating myelinated nerve fibers (P less than 0.001), reflected by a 33 percent increase in the number of myelinated fibers per unit of cross-sectional area of nerve (P = 0.04). They also had quantitative improvement in terms of the degree of paranodal demyelination, segmental demyelination, and myelin wrinkling. The increase in the number of fibers was accompanied by electrophysiologic and clinical evidence of improved nerve function. We conclude that sorbinil, as a metabolic intervention targeted against a specific biochemical consequence of hyperglycemia, can improve the neuropathologic lesions of diabetic neuropathy.

The Aldo-Keto Reductase Superfamily and its Role in Drug Metabolism and Detoxification

“…With the rationale that excessive flux of glucose via this enzyme contributes to diabetic injury, several AKR1B-specific inhibitors have been synthesized. Initial small-scale clinical trials showed that inhibition of this enzyme could ameliorate symptomatic somatic and autonomic neuropathies (Jaspan et al, 1983), improve joint mobility (Eaton et al, 1985) and could prevent or delay fiber degeneration in neuropathy (Dyck et al, 1988) and partially correct nerve conduction defects in diabetics (Sima et al, 1988). Later, large-scale clinical trials, however, failed to demonstrate clear benefit and were marred with non-specific sensitivity reactions or off-target effects.…”

Molecular mechanisms of Diabetic Retinopathy, general preventive strategies and novel therapeutic targets

“…A double-blind study in patients with diabetic neuropathy by Sima et al [115] gave exciting evidence of the efficacy of sorbinil, an aldose reductase inhibitor, against morphological signs of degeneration accompanied by a decrease in the nerve sorbitol level and an increase in the nerve conduction velocity. A similar observation was reported by Greene et al [116] using another aldose reductase inhibitor, FK-366.…”

Acute augmentation of epoxygenated fatty acid levels rapidly reduces pain-related behavior in a rat model of type I diabetes

“…The nerve dysfunction as a consequence of diabetes is debilitating and can lead to lifethreatening autonomic neuropathy, cardiac diseases, and CNS atrophy (3,4). Dying back of distal peripheral nerve fibers because of glucose toxicity and the ensuing spinal sensitization are thought to be the underlying causes of pain (5)(6)(7)(8)(9). Although hyperglycemia is the initiating cause for diabetic neuropathy, aggressive glycemic control is effective in impeding the progression of neuronal loss and pain, but not in reversing neuropathy (10).…”