Lipton S A, Kim W K, Choi Y B, Kumar S, D'Emilia D M, Rayudu P V, Arnelle D R, Stamler J S
Laboratory of Cellular and Molecular Neuroscience, Children's Hospital, and Program in Neuroscience, Harvard Medical School, 300 Longwood Avenue, Enders Building, Suite 361, Boston, MA 02115, USA.
Proc Natl Acad Sci U S A. 1997 May 27;94(11):5923-8. doi: 10.1073/pnas.94.11.5923.
Severely elevated levels of total homocysteine (approximately millimolar) in the blood typify the childhood disease homocystinuria, whereas modest levels (tens of micromolar) are commonly found in adults who are at increased risk for vascular disease and stroke. Activation of the coagulation system and adverse effects of homocysteine on the endothelium and vessel wall are believed to underlie disease pathogenesis. Here we show that homocysteine acts as an agonist at the glutamate binding site of the N-methyl-D-aspartate receptor, but also as a partial antagonist of the glycine coagonist site. With physiological levels of glycine, neurotoxic concentrations of homocysteine are on the order of millimolar. However, under pathological conditions in which glycine levels in the nervous system are elevated, such as stroke and head trauma, homocysteine's neurotoxic (agonist) attributes at 10-100 microM levels outweigh its neuroprotective (antagonist) activity. Under these conditions neuronal damage derives from excessive Ca2+ influx and reactive oxygen generation. Accordingly, homocysteine neurotoxicity through overstimulation of N-methyl-D-aspartate receptors may contribute to the pathogenesis of both homocystinuria and modest hyperhomocysteinemia.
血液中总同型半胱氨酸水平严重升高（约毫摩尔级）是儿童疾病同型胱氨酸尿症的典型特征，而适度水平（几十微摩尔）常见于血管疾病和中风风险增加的成年人中。凝血系统的激活以及同型半胱氨酸对内皮和血管壁的不良影响被认为是疾病发病机制的基础。我们在此表明，同型半胱氨酸在N-甲基-D-天冬氨酸受体的谷氨酸结合位点充当激动剂，但同时也作为甘氨酸协同激动剂位点的部分拮抗剂。在生理水平的甘氨酸存在下，毫摩尔级的同型半胱氨酸具有神经毒性。然而，在神经系统中甘氨酸水平升高的病理条件下，如中风和头部创伤，10 - 100微摩尔水平的同型半胱氨酸的神经毒性（激动剂）特性超过其神经保护（拮抗剂）活性。在这些条件下，神经元损伤源于过量的Ca2+内流和活性氧的产生。因此，通过过度刺激N-甲基-D-天冬氨酸受体产生的同型半胱氨酸神经毒性可能导致同型胱氨酸尿症和适度高同型半胱氨酸血症的发病机制。
