Homocysteine as a neurotoxin in chronic alcoholism.
There is evidence from in vitro and in vivo studies that homocysteine induces neuronal damage and cell loss by both excitotoxicity and different apoptotic processes. Clinical evidence suggest a strong relationship between higher plasma homocysteine levels and brain atrophy in healthy elderly subjects as well as in elderly at risk of and with Alzheimer's disease. Chronic alcoholism leads to elevated plasma homocysteine levels, as shown by clinical investigations and animal experiments. In addition, an association between brain atrophy and increased levels of homocysteine in chronic alcoholism was shown. This may have important implications for the pathogenesis of alcoholism-associated brain atrophy. Furthermore, taking into account that high plasma homocysteine levels are helpful in the prediction of alcohol withdrawal seizures, early anticonvulsive therapy could prevent this severe complication. Homocysteine plays a role in a shared biochemical cascade involving overstimulation of N-methyl-D-aspartate (NMDA) receptors, oxidative stress, activation of caspases, DNA damage, endoplasmic reticulum and mitochondrial dysfunction. These mechanisms are believed to be important in the pathogenesis of both excitotoxicity and apoptotic neurotoxicity. Prospective intervention studies may show whether the incidence of complications of alcohol withdrawal or alcoholism-associated disorders can be reduced by therapeutic measures with early lowering of elevated homocysteine levels (e.g. folate administration). The most important pathophysiological and pathobiochemical features of glutamatergic neurotransmission and of ethanol-induced hyperhomocysteinaemia are reviewed in relation to their excitotoxic and apoptotic potential.
Bleich
Stefan
S
Department of Psychiatry and Psychotherapy, Friedrich-Alexander University of Erlangen-Nuremberg, Schwabachanlage 6-10, Erlangen 91054, Germany. srtefan.bleich@psych.imed.uni-erlangen.de
Degner
Detlef
D
Sperling
Wolfgang
W
Bönsch
Dominikus
D
Thürauf
Norbert
N
Kornhuber
Johannes
J
D000437:Alcoholism / Q000150:complications / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002492:Central Nervous System Depressants / Q000009:adverse effects; D000431:Ethanol / Q000009:adverse effects; D006710:Homocysteine / Q000378:metabolism / Q000502:physiology* / Q000633:toxicity*; D006801:Humans; D020138:Hyperhomocysteinemia / Q000209:etiology / Q000378:metabolism; D009498:Neurotoxins / Q000633:toxicity*; D017470:Receptors, Glutamate / Q000502:physiology
D002492:Central Nervous System Depressants; D009498:Neurotoxins; D017470:Receptors, Glutamate; D006710:Homocysteine; D000431:Ethanol