Marino Michael J, Valenti Ornella, Conn P Jeffrey
Department of Neuroscience, Merck Research Laboratories, West Point, Pennsylvania 19486-0004, USA.
Drugs Aging. 2003;20(5):377-97. doi: 10.2165/00002512-200320050-00006.
Parkinson's disease is a debilitating neurodegenerative movement disorder that is the result of a degeneration of dopaminergic neurons in the substantia nigra pars compacta. The resulting loss of striatal dopaminergic tone is believed to underlie a series of changes in the circuitry of the basal ganglia that ultimately lead to severe motor disturbances due to excessive basal ganglia outflow. Glutamate plays a central role in the disruption of normal basal ganglia function, and it has been hypothesised that agents acting to restore normal glutamatergic function may provide therapeutic interventions that bypass the severe motor side effects associated with current dopamine replacement strategies. Analysis of the effects of glutamate receptor ligands in the basal ganglia circuit suggests that both ionotropic and metabotropic glutamate receptors could have antiparkinsonian actions. In particular, NMDA receptor antagonists that selectively target the NR2B subunit and antagonists of the metabotropic glutamate receptor mGluR5 appear to hold promise and deserve future attention.
帕金森病是一种使人衰弱的神经退行性运动障碍，它是黑质致密部多巴胺能神经元变性的结果。纹状体多巴胺能张力的丧失被认为是基底神经节回路一系列变化的基础，这些变化最终由于基底神经节过度流出而导致严重的运动障碍。谷氨酸在正常基底神经节功能的破坏中起核心作用，并且据推测，作用于恢复正常谷氨酸能功能的药物可能提供治疗干预措施，从而规避与当前多巴胺替代策略相关的严重运动副作用。对基底神经节回路中谷氨酸受体配体作用的分析表明，离子型和代谢型谷氨酸受体都可能具有抗帕金森病作用。特别是，选择性靶向NR2B亚基的NMDA受体拮抗剂和代谢型谷氨酸受体mGluR5的拮抗剂似乎很有前景，值得未来关注。
