Homocysteine Excitotoxic Amino Acids And Vascular Disease

Although the underlying mechanisms are not completely defined, there is a very strong association between increased plasma homocysteine and cerebrovascular, coronary artery, and peripheral vascular disease. Recently, in our ongoing studies of the neurotoxicity of antifolates such as methotrexate, we documented marked increases in the cerebrospinal fluid (CSF) content of adenosine and homocysteine and its metabolic products, the so-called excitotoxic amino acids (4). Excitotoxic amino acids activate the NMDA receptor, which may result in a cascade of events that are associated with neuronal/glial cell death (5). These recent findings add to the large body of literature showing that a folate deficiency leads to homocystinemia (6,7). Most recently, decreases in CSF S-adenosylmethione (SAM) and increases in S-adenosylhomocysteine (SAH), resulting in a very abnormal SAM/SAH ratio, has been found in two children who had developed methotrexate leu-koencephalopathy (8).

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