Ethanol is one of the most frequently used drugs in the world. Its abuse leads to major health problems for many Americans and results in chronic drinkers having higher morbidity and mortality rates. Distal polyneuropathy is a common neurological disorder among chronic alcoholics. But, despite its frequent occurrence, very little is known about the cause of this progressive disorder. The predominant pathogenesis is an axonal degeneration by a dying back process which preferentially affects distal portions of large, long axons. We postulate that the axonal transport system may be the site of vulnerability inducing the peripheral neuropathy associated with chronic alcoholism in man. Acetaldehyde, an ethanol metabolite, may act as a neurotoxin by forming adducts with proteins essential for the axonal transport process or for the production of ATP. Further, since aging has also been found to alter axonal transport, the aging process may augment the development of peripheral neuropathy by increasing the sensitivity of axons to chemical damage. This hypothesis will be tested in acute in vitro studies with nerve preparations from young and aged rats by examining the toxicity of ethanol and acetaldehyde. Then, the experiment will be repeated with nerves from rats which have been fed a nutritionally complete liquid diet containing 6.7% ethanol for 2 months in order to determine if the prior chronic ethanol exposure increases the susceptibility of the axonal transport system. We will then determine whether protein-acetaldehyde adducts form in peripheral nerves in vitro, the nature of these adducts, and whether adducts form in peripheral nerves in vivo when the blood acetaldehyde concentration is increased by disulfiram and ethanol treatment The proposed studies may lead to a better understanding of the pathogenesis and relations of alcoholic neuropathy and the aging process. Besides providing the basis for improved detection and control of degenerative changes in the peripheral nerves, these studies may lead to new insights in basic neurobiology.
