Sánchez-Pérez Ana M, Montoliu Carmina, Felipo Vicente
Laboratory of Neurobiology, Fundación Valenciana de Investigaciones Biomédicas, Valencia, Spain.
CNS Drug Rev. 2003 Fall;9(3):263-74. doi: 10.1111/j.1527-3458.2003.tb00253.x.
Glutamate neurotoxicity is involved in the pathogenesis of neurodegenerative disorders such as Huntington's, Parkinson's and Alzheimer's diseases. It plays also a major role in the neuronal damage that occurs in brain ischemia and head trauma. Finding molecules that prevent or reverse glutamate neurotoxicity (excitotoxicity) is, therefore, of great interest. Strategies aimed at this end include the screening of libraries of compounds synthesized by combinatorial chemistry to find molecules that prevent neuronal death in vitro and in vivo. A library of trialkylglycines was screened to assess whether they prevent glutamate-induced neuronal death in primary cultures of cerebellar neurons. Two types of trialkylglycines have been found that significantly reduce the incidence of glutamate-induced neuronal death. The first type includes two compounds (referred to as 6-1-2 and 6-1-10) that efficiently prevent glutamate or NMDA-induced neuronal death. They also prevent excitotoxicity in vivo as assessed by using two animal models of excitotoxicity: acute intoxication with ammonia and a model of cerebral ischemia in rats. Trialkylglycines 6-1-2 and 6-1-10 prevent ammonia-induced (NMDA receptor-mediated) death of mice and neuronal degeneration in the model of cerebral ischemia. The trialkylglycines of the second type act as open channel blockers of the NMDA receptor. The first group of trialkylglycines does not block NMDA receptor channels and does not affect the glutamate-nitric oxide-cGMP pathway. Their molecular target has not yet been identified. These two types of trialkylglycines (especially those that do not affect NMDA receptor function) might represent effective drugs for the treatment of neurodegeneration. They are likely to be well tolerated and have fewer side effects than NMDA receptor antagonists.
谷氨酸神经毒性参与了诸如亨廷顿舞蹈症、帕金森氏症和阿尔茨海默病等神经退行性疾病的发病机制。它在脑缺血和头部创伤中发生的神经元损伤中也起主要作用。因此，寻找能够预防或逆转谷氨酸神经毒性（兴奋毒性）的分子具有重大意义。为此目的的策略包括筛选通过组合化学合成的化合物库，以找到在体外和体内预防神经元死亡的分子。对三烷基甘氨酸库进行了筛选，以评估它们是否能预防小脑神经元原代培养物中谷氨酸诱导的神经元死亡。已发现两种类型的三烷基甘氨酸能显著降低谷氨酸诱导的神经元死亡发生率。第一类包括两种化合物（称为6-1-2和6-1-10），它们能有效预防谷氨酸或NMDA诱导的神经元死亡。通过使用两种兴奋毒性动物模型评估，它们还能预防体内的兴奋毒性：氨急性中毒和大鼠脑缺血模型。三烷基甘氨酸6-1-2和6-1-10能预防氨诱导的（NMDA受体介导的）小鼠死亡和脑缺血模型中的神经元变性。第二类三烷基甘氨酸作为NMDA受体的开放通道阻滞剂。第一组三烷基甘氨酸不阻断NMDA受体通道，也不影响谷氨酸-一氧化氮-cGMP途径。它们的分子靶点尚未确定。这两种类型的三烷基甘氨酸（尤其是那些不影响NMDA受体功能的）可能代表治疗神经退行性变的有效药物。它们可能具有良好的耐受性，并且比NMDA受体拮抗剂副作用更少。
