Biegon Anat, Fry Pamela A, Paden Charles M, Alexandrovich Alexander, Tsenter Jeanna, Shohami Esther
Department of Functional Imaging, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
Proc Natl Acad Sci U S A. 2004 Apr 6;101(14):5117-22. doi: 10.1073/pnas.0305741101. Epub 2004 Mar 24.
Traumatic brain injury is a leading cause of mortality and morbidity among young people. For the last couple of decades, it was believed that excess stimulation of brain receptors for the excitatory neurotransmitter glutamate was a major cause of delayed neuronal death after head injury, and several major clinical trials in severely head injured patients used blockers of the glutamate N-methyl-D-aspartate (NMDA) receptor. All of these trials failed to show efficacy. Using a mouse model of traumatic brain injury and quantitative autoradiography of the activity-dependent NMDA receptor antagonist MK801, we show that hyperactivation of glutamate NMDA receptors after injury is short-lived (<1 h) and is followed by a profound and long-lasting (> or =7 days) loss of function. Furthermore, stimulation of NMDA receptors by NMDA 24 and 48 h postinjury produced a significant attenuation of neurological deficits (blocked by coadministration of MK801) and restored cognitive performance 14 days postinjury. These results provide the underlying mechanism for the well known but heretofore unexplained short therapeutic window of glutamate antagonists after brain injury and support a pharmacological intervention with a relatively long (> or =24 h) time window easily attainable for treatment of human accidental head injury.
创伤性脑损伤是年轻人死亡和发病的主要原因。在过去几十年里，人们认为兴奋性神经递质谷氨酸的脑受体过度刺激是头部受伤后神经元延迟死亡的主要原因，并且在重度头部受伤患者中进行的几项主要临床试验使用了谷氨酸N-甲基-D-天冬氨酸（NMDA）受体阻滞剂。所有这些试验均未显示出疗效。利用创伤性脑损伤小鼠模型以及对活性依赖性NMDA受体拮抗剂MK801进行定量放射自显影，我们发现损伤后谷氨酸NMDA受体的过度激活是短暂的（<1小时），随后是功能的严重且持久的（≥7天）丧失。此外，在损伤后24小时和48小时用NMDA刺激NMDA受体会显著减轻神经功能缺损（可通过同时给予MK801来阻断），并在损伤后14天恢复认知功能。这些结果为脑损伤后谷氨酸拮抗剂众所周知但迄今无法解释的短治疗窗提供了潜在机制，并支持一种具有相对较长（≥24小时）时间窗的药物干预方法，这种方法易于实现，可用于治疗人类意外头部损伤。
