Sa. Lipton et al., NEUROTOXICITY ASSOCIATED WITH DUAL ACTIONS OF HOMOCYSTEINE AT THE N-METHYL-D-ASPARTATE RECEPTOR, Proceedings of the National Academy of Sciences of the United Statesof America, 94(11), 1997, pp. 5923-5928
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.