Neurotoxicity associated with dual actions of homocysteine at the N-methyl-d-aspartate receptor

摘要: Severely elevated levels of total homocysteine (approximately millimolar) in the blood typify childhood disease homocystinuria, whereas modest (tens micromolar) are commonly found adults who at increased risk for vascular and stroke. Activation coagulation system adverse effects on endothelium vessel wall believed to underlie pathogenesis. Here we show that acts as an agonist glutamate binding site N-methyl-d-aspartate receptor, but also a partial antagonist glycine coagonist site. With physiological glycine, neurotoxic concentrations order millimolar. However, under pathological conditions which nervous elevated, such stroke head trauma, homocysteine’s (agonist) attributes 10–100 μM outweigh its neuroprotective (antagonist) activity. Under these neuronal damage derives from excessive Ca2+ influx reactive oxygen generation. Accordingly, neurotoxicity through overstimulation receptors may contribute pathogenesis both homocystinuria hyperhomocysteinemia.