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.