Molecular mechanisms of homocysteine toxicity and possible protection against hyperhomocysteinemia

Homocysteine is a naturally occurring intermediate connecting metabolism of methionine and cysteine and, subsequently glutathione. Its normal level in mammalian blood does not exceed 10 μmol/l, whereas vitamin deficient diet, increased stationary levels of reactive oxygen species, as well as neurodegenerative and cardiovascular diseases are usually accompanied by an increased content of homocysteine in peripheral blood. An increase in homocysteine levels above 50 μmol/l may be a risk factor for recurrent heart attacks and that above 150-200 μmol/l is a cause for ischaemic stroke. Persistent hyperhomocysteinemia with homocysteine levels of 300 μmol/l or higher may induce mental deficiency. Molecular mechanisms of homocysteine toxicity are not fully understood as yet. In the review, novel data are presented which demonstrate that homocysteine and homocysteic acid, a product of its spontaneous oxidation, induce activation of NMDA receptors in the brain neurons accompanied by an increase in the levels of the reactive oxygen species and resulting in induction of apoptotic and Correspondence/Reprint request: Dr. Alexander Boldyrev, M.V. Lomonosov Moscow State University, Dept. Biochemistry, School of Biology, Room 141, Lenin’s Hills, 119992 Moscow, Russia E-mail: [email protected] Alexander Boldyrev 128 (under long-term stimulation) necrotic cell death. Recent findings showed that NMDA receptors are encountered not only in neuronal cells but also in megakaryocytes, red blood cells, lymphocytes, neutrophils, and cardiomyocytes. Thus, the number of target cells of homocysteine is sufficiently increased, thereby underlying the importance of developing new strategies to protect the body from hyperhomocysteinemia. In a model of prenatal hyperhomocysteinemia in rats, we have demonstrated that the neuropeptide carnosine (a natural antioxidant and immune modulator) protects animals against homocysteine toxicity with no change in the blood homocysteine levels. A suggestion was made that carnosine interferes with NMDA receptors preventing their excitotoxicity.