NEUROTOXICITY ASSOCIATED WITH DUAL ACTIONS OF HOMOCYSTEINE AT THE N-METHYL-D-ASPARTATE RECEPTOR

Severely elevated levels of total homocysteine (approximately millimol ar) in the blood typify the childhood disease homocystinuria, whereas modest levels (tens of micromolar) are commonly found in adults who ar e at increased risk for vascular disease and stroke, Activation of the coagulation system and adverse effects of homocysteine on the endothe lium and vessel wall are believed to underlie disease pathogenesis. He re we show that homocysteine acts as an agonist at the glutamate bindi ng site of the N-methyl-D-aspartate receptor, but also as a partial an tagonist of the glycine coagonist site. With physiological levels of g lycine, neurotoxic concentrations of homocysteine are on the order of millimolar. However, under pathological conditions in which glycine le vels in the nervous system are elevated, such as stroke and head traum a, homocysteine's neurotoxic (agonist) attributes at 10-100 mu M level s outweigh its neuroprotective (antagonist) activity, Under these cond itions neuronal damage derives from excessive Ca2+ influx and reactive oxygen generation. Accordingly, homocysteine neurotoxicity through ov erstimulation of N-methyl-D-aspartate receptors may contribute to the pathogenesis of both homocystinuria and modest hyperhomocysteinemia.