Homocysteinic Acid Causes Oxidative Stress in Lymphocytes by Potentiating Toxic Effect of NMDA

Abstract

Short-term incubation of lymphocytes with homocysteine or its oxidation product homocysteinic acid increased the formation of reactive oxygen species and cell necrosis (in case of homocysteinic acid). Effective concentration of homocysteine and homocysteinic acid (500 microM) significantly surpassed the level observed during hyperhomocysteinemia. The addition of homocysteinic acid in a nontoxic concentration of 100 microM potentiated the toxic effect of NMDA and led to massive cell death. During hyperhomocysteinemia the amount of these metabolites in the blood was much higher than in the brain. Oxidative stress produced by these substances can result from activation of NMDA glutamate receptors that were recently detected on lymphocytes.

Effect of homocysteine and homocysteic acid on glutamate receptors on rat lymphocytes

“…It can be hypothesized that permanent increase in the concentrations of HC and its oxidation product (HCA) provides conditions for oxidative stress and stimulation of immune cells. Our previous studies showed that long-term incubation of lymphocytes with HCA in vitro causes massive cell death [1].…”

“…Long-term incubation of lymphocytes with NMDA and HCA increases ROS content in these cells and their death [1,2]. Published data show that lymphocytes express various subtypes of glutamate receptors [4,10].…”

Physiological Roles of Non-Neuronal NMDA Receptors

“…L-Homocysteic acid (L-HCA), for example, is a derivative of hepatic L-methionine metabolism that has been linked to NMDAR-induced lymphocytic apoptosis [108], NMDAR-mediated glomerulosclerosis [109], and podocyte NMDARs regulating glomerular filtration [87]. Hyperhomocysteinemia also contributes to upregulation of matrix metalloproteinases, disruption of connexin-43, and mitophagy, in part by excessive NMDAR activation in cardiac myocytes, which enhances the incidence of arrhythmia and sudden cardiac death [110].…”

Immunosuppression by N-Methyl-d-Aspartate Receptor Antagonists Is Mediated through Inhibition of Kv1.3 and KCa3.1 Channels in T Cells

“…NMDARs, AMPARs (GluA3 subunit), and metabotropic glutamate receptors (mGluRs) (group 1) were found to be expressed in human peripheral blood lymphocytes and Jurkat T cells and modulate their function (10)(11)(12)(13)(14). For murine CD4 ϩ CD8 ϩ thymocytes in contact with antigenpresenting DCs, inhibition of NMDARs regulated T-cell receptor (TCR)-induced Ca 2ϩ flux and, thereby, the apoptosis of doublepositive cells (9).…”