Effect of lipoic acid (thioctic acid) on peripheral nerve of experimental diabetic neuropathy

Oxidative stress is present in the diabetic state. Our work in streptozotocin-diabetic rats has focussed on its presence in peripheral nerve. Antioxidant enzymes are reduced in peripheral nerve and are further reduced in diabetic nerves. That lipid peroxidation will cause neuropathy is supported by evidence of the development of neuropathy de novo when normal rat nerve is rendered α-tocopherol deficient and augmentation of the conduction deficit in diabetic nerves subjected to this insult. The mechanism of oxidative stress appears to be primarily due to the processes of nerve ischemia and hyperglycemia auto-oxidation. The indices of oxidative stress include an increase in nerve, dorsal root and sympathetic ganglia lipid hydroperoxides and conjugated dienes. However the most reliable and sensitive index is a reduction in reduced glutathione. Experimental diabetic neuropathy results in myelinopathy of dorsal roots and a vacuolar neuropathy of dorsal root ganglion. The vacuoles are mitochondrial; we posit that lipid peroxidation causes mitochondrial DNA mutations that increase reduced oxygen species, causing further damage to mitochondrial chain and function, resulting in a sensory neuropathy. α-lipoic acid is a potent antioxidant that prevents lipid peroxidation in vitro and in vivo. We evaluated the efficacy of the drug in doses of 20, 50 and 100 mg/kg, administered intraperitoneally to streptozotocin diabetic rats in preventing the biochemical, electrophysiologic and nerve blood flow deficits in peripheral nerve of experimental diabetic neuropathy. α-lipoic acid dose- and time-dependently prevented the deficits in nerve conduction, nerve blood flow and biochemical abnormalities of a reduction in reduced glutathione and lipid peroxidation. The nerve blood flow deficit was 50% (p < 0.001). Supplementation dose-dependently prevented the deficit; at the highest concentration, nerve blood flow was not different to control nerves. Digital nerve conduction underwent a dose-dependent improvement at 1 month (p < 0.05). By 3 months, all treated groups had lost their deficit. The antioxidant drug is potentially efficacious for human diabetic sensory neuropathy.