Department of Anatomy, Physiology, and Pharmacology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
Eur J Neurosci. 2019 May;49(9):1157-1170. doi: 10.1111/ejn.14307. Epub 2019 Jan 1.
Traumatic brain injury (TBI) is a leading major cause of morbidity and mortality in youth and individuals under 45 year age. A wide variety of cellular and molecular mechanisms have been identified contributing to the pathogenesis of TBI. A better understanding of the pathophysiology behind TBI is essential for providing more effective treatment. Excitotoxicity as one of the secondary molecular events is a major contributing factor in apoptosis and neuronal death following the initial injury in TBI. Excitotoxicity is the rapid overload and influx of calcium into the cell cytoplasm, activating a series of deleterious signaling cascades causing the cell to undergo apoptosis. Conventional understanding is that the rapid influx of calcium is initiated through glutamate release. However, there are overlooked glutamate-independent mechanisms that cause the rapid calcium influx into the neuronal cytoplasm, evoking or contributing to excitotoxicity. Therefore, the focus of this review will be on the role of the glutamate-independent excitotoxic mechanisms of the mechanosensitive response of NMDA receptors, mechanoporation of the cell membrane, ischemia, and the release of calcium from intracellular stores. In conclusion, the shear and stretch forces during a TBI event may result in the mechanosensitive activation of NMDA receptors which contribute to glutamate-independent excitotoxicity.
创伤性脑损伤 (TBI) 是导致年轻人和 45 岁以下人群发病率和死亡率的主要原因之一。大量的细胞和分子机制已被确定有助于 TBI 的发病机制。更好地了解 TBI 背后的病理生理学对于提供更有效的治疗方法至关重要。兴奋性毒性是继 TBI 初始损伤后细胞凋亡和神经元死亡的主要因素之一，是继发性分子事件之一。兴奋性毒性是指细胞外钙离子迅速进入细胞质，激活一系列有害信号级联反应，导致细胞发生凋亡。传统的认识是，钙的快速内流是通过谷氨酸的释放启动的。然而，还有一些被忽视的谷氨酸非依赖性机制会导致神经元细胞质内的钙快速内流，引发或促进兴奋性毒性。因此，本综述的重点将放在 NMDA 受体的机械敏感性反应、细胞膜的机械穿孔、缺血和细胞内储存钙释放等谷氨酸非依赖性兴奋性毒性机制的作用上。总之，TBI 事件中的剪切力和拉伸力可能导致 NMDA 受体的机械敏感激活，从而导致谷氨酸非依赖性兴奋性毒性。
