Why is homocysteine toxic for the nervous and immune systems?

Hyperhomocysteinemia is a risk factor for a number of neurodegenerative and cardiovascular diseases. We have shown that homocysteine induces excitotoxic effects in cells expressing glutamate receptors of the NMDA class. These receptors were found not only in neurons but also in immune-competent cells, neutrophils, red blood cells, cardiomyocytes, and osteoblasts.

Pinealon protects the rat offspring from prenatal hyperhomocysteinemia.

The offspring of rats with experimental hyperhomocysteinemia caused by alimentary loading with dietary methionine within pregnancy has been studied. Using pinealon (Glu-Asp-Arg) under these conditions was found to result in the offspring cognitive function being improved significantly and their cerebellum neurons becoming more resistant to oxidative stress. This may be proved by the fact that the administration of pinealon to pregnant rats loaded with methionine improved their offspring spatial orientation and learning ability and decreased both reactive oxygen species accumulation and the number of necrotic cells in the population of the neurons isolated from the cerebellum of the offspring developed under the prenatal hyperhomocysteinemia.

NMDA receptors are expressed in lymphocytes activated both in vitro and in vivo.

There is increasing evidence showing that the interplay between neuronal and immune systems may be regulated by neuromediators. However, little is known about the involvement of glutamatergic system in such neuro-immune relations. In the present study, we have shown that some intact lymphocytes express N-methyl-D: -aspartate activated receptors (NMDA receptors), an important constituent of glutamatergic system.

The excitotoxic effect of NMDA on human lymphocyte immune function.

N-Methyl-d-aspartate (NMDA)-activated glutamate receptors are expressed in lymphocytes, but their roles have not yet been defined. We show that incubation of human peripheral blood lymphocytes with NMDA resulted in increased intracellular calcium and reactive oxygen species (ROS) levels through effects on NMDA-activated glutamate receptors. In terms of ROS production, T cells were most affected, followed by NK cells, whereas B cell ROS levels were not increased.

Rodent lymphocytes express functionally active glutamate receptors.

RT-PCR demonstrated that ionotropic (iGluR NR1) and metabotropic (mGluR Group III) glutamate receptors are expressed in rodent lymphocytes. Flow cytometry showed that activation of iGluR NR1 by N-methyl-D-aspartate (NMDA) increased intracellular free calcium and reactive oxygen species (ROS) levels and activated caspase-3. The latter effect was attenuated by the NMDA antagonist, 5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801), by the antioxidant N-acetylcysteine and by cyclosporin A.