Abstract
The mechanisms of alcohol-related peripheral neuropathy (ALPN) are poorly understood. We hypothesize that, like alcohol-related liver and brain degeneration, ALPN may be mediated by combined effects of insulin/IGF resistance and oxidative stress. Adult male Long Evans rats were chronically pair-fed with diets containing 0% or 37% ethanol (caloric), and subjected to nerve conduction studies. Chronic ethanol feeding slowed nerve conduction in the tibial (p = 0.0021) motor nerve, and not plantar sensory nerve, but it did not affect amplitude. Histological studies of the sciatic nerve revealed reduced nerve fiber diameters with increased regenerative sprouts, and denervation myopathy in ethanol-fed rats. qRT-PCR analysis demonstrated reduced mRNA levels of insulin, IGF-1, and IGF-2 polypeptides, IGF-1 receptor, and IRS2, and ELISAs revealed reduced immunoreactivity for insulin and IGF-1 receptors, IRS-1, IRS-4, myelin-associated glycoprotein, and tau in sciatic nerves of ethanol-fed rats (all p < 0.05 or better). The findings suggest that ALPN is characterized by (1) slowed conduction velocity with demyelination, and a small component of axonal degeneration; (2) impaired trophic factor signaling due to insulin and IGF resistance; and (3) degeneration of myelin and axonal cytoskeletal proteins. Therefore, ALPN is likely mediated by molecular and signal transduction abnormalities similar to those identified in alcoholic liver and brain degeneration.
Highlights
Alcohol-related polyneuropathy (ALPN) is a chronic and potentially debilitating disease that can be associated with sensory, motor, and autonomic nerve dysfunctions
The control and ethanol-fed rats gained weight continuously throughout the study, and the ethanol-fed rats weighed less than control, the differences in mean weight were not statistically significant (Table 1)
We examined whether the ethanol-associated abnormalities in peripheral nerve function and insulin/insulin-like growth factor (IGF) signaling mechanisms were associated with reductions in myelin associated glycoprotein-1 (MAG-1) and tau immunoreactivity, as indices of Schwann cell and neuronal integrity, respectively
Summary
Alcohol-related polyneuropathy (ALPN) is a chronic and potentially debilitating disease that can be associated with sensory, motor, and autonomic nerve dysfunctions. Significant ALPN occurs more frequently than appreciated, with rates as high as 66% among severe alcoholics [2,3,4,5,6,7]. Regarding the pathogenesis of ALPN, considerable attention has been paid to the contributions of malnutrition, thiamine deficiency, because thiamine deficiency often complicates alcohol-related diseases, and thiamine deficiency alone can cause peripheral neuropathy [8,9,10,11]. Attention should be focused on how alcohol toxicity either alone or in combination with thiamine deficiency, promotes ALPN
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