Kwak Shin, Weiss John H
Department of Neurology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, 113-8655 Tokyo, Japan.
Curr Opin Neurobiol. 2006 Jun;16(3):281-7. doi: 10.1016/j.conb.2006.05.004. Epub 2006 May 15.
Compelling evidence supports contributions of glutamate receptor overactivation ('excitotoxicity') to neurodegeneration in both acute conditions, such as stroke, and chronic neurodegenerative conditions, such as amyotrophic lateral sclerosis. However, anti-excitotoxic therapeutic trials, which have generally targeted highly Ca2+ permeable NMDA-type glutamate channels, have to date failed to demonstrate impressive efficacy. Whereas most AMPA type glutamate channels are Ca2+ impermeable, an evolving body of evidence supports the contention that relatively unusual Ca2+ permeable AMPA channels might be crucial contributors to injury in these conditions. These channels are preferentially expressed in discrete neuronal subpopulations, and their numbers appear to be upregulated in amyotrophic lateral sclerosis and stroke. In addition, unlike NMDA channels, Ca2+ permeable AMPA channels are not blocked by Mg2+, but are highly permeable to another potentially harmful endogenous cation, Zn2+. The targeting of these channels might provide efficacious new avenues in the therapy of certain neurological diseases.
有力证据表明，在急性病症（如中风）和慢性神经退行性病症（如肌萎缩侧索硬化症）中，谷氨酸受体过度激活（“兴奋毒性”）均会导致神经退行性变。然而，通常针对高度Ca2+通透的NMDA型谷氨酸通道的抗兴奋毒性治疗试验，至今未能证明有显著疗效。虽然大多数AMPA型谷氨酸通道对Ca2+不通透，但越来越多的证据支持这样一种观点，即相对不常见的Ca2+通透AMPA通道可能是这些病症中损伤的关键因素。这些通道在离散的神经元亚群中优先表达，且其数量在肌萎缩侧索硬化症和中风中似乎上调。此外，与NMDA通道不同，Ca2+通透AMPA通道不会被Mg2+阻断，但对另一种潜在有害的内源性阳离子Zn2+具有高度通透性。针对这些通道可能为某些神经疾病的治疗提供有效的新途径。
