Mattson Mark P
Laboratory of Neurosciences, National Institute on Aging Gerontology Research Center, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA.
Neuromolecular Med. 2003;3(2):65-94. doi: 10.1385/NMM:3:2:65.
Activation of glutamate receptors can trigger the death of neurons and some types of glial cells, particularly when the cells are coincidentally subjected to adverse conditions such as reduced levels of oxygen or glucose, increased levels of oxidative stress, exposure to toxins or other pathogenic agents, or a disease-causing genetic mutation. Such excitotoxic cell death involves excessive calcium influx and release from internal organelles, oxyradical production, and engagement of programmed cell death (apoptosis) cascades. Apoptotic proteins such as p53, Bax, and Par-4 induce mitochondrial membrane permeability changes resulting in the release of cytochrome c and the activation of proteases, such as caspase-3. Events occurring at several subcellular sites, including the plasma membrane, endoplasmic reticulum, mitochondria and nucleus play important roles in excitotoxicity. Excitotoxic cascades are initiated in postsynaptic dendrites and may either cause local degeneration or plasticity of those synapses, or may propagate the signals to the cell body resulting in cell death. Cells possess an array of antiexcitotoxic mechanisms including neurotrophic signaling pathways, intrinsic stress-response pathways, and survival proteins such as protein chaperones, calcium-binding proteins, and inhibitor of apoptosis proteins. Considerable evidence supports roles for excitotoxicity in acute disorders such as epileptic seizures, stroke and traumatic brain and spinal cord injury, as well as in chronic age-related disorders such as Alzheimer's, Parkinson's, and Huntington's disease and amyotrophic lateral sclerosis. A better understanding of the excitotoxic process is not only leading to the development of novel therapeutic approaches for neurodegenerative disorders, but also to unexpected insight into mechanisms of synaptic plasticity.
谷氨酸受体的激活可引发神经元和某些类型神经胶质细胞的死亡，尤其是当这些细胞同时遭受不利条件时，如氧气或葡萄糖水平降低、氧化应激水平升高、接触毒素或其他病原体，或存在致病基因突变。这种兴奋性毒性细胞死亡涉及过量的钙内流和从内部细胞器的释放、氧自由基的产生以及程序性细胞死亡（凋亡）级联反应的参与。诸如p53、Bax和Par-4等凋亡蛋白会诱导线粒体膜通透性改变，导致细胞色素c的释放和蛋白酶（如caspase-3）的激活。发生在包括质膜、内质网、线粒体和细胞核在内的几个亚细胞位点的事件在兴奋性毒性中起重要作用。兴奋性毒性级联反应在突触后树突中启动，可能导致这些突触的局部退化或可塑性改变，或者将信号传播到细胞体导致细胞死亡。细胞拥有一系列抗兴奋性毒性机制，包括神经营养信号通路、内在应激反应通路以及诸如蛋白伴侣、钙结合蛋白和凋亡抑制蛋白等存活蛋白。大量证据支持兴奋性毒性在急性疾病如癫痫发作、中风以及创伤性脑和脊髓损伤中起作用，以及在与年龄相关的慢性疾病如阿尔茨海默病、帕金森病、亨廷顿病和肌萎缩侧索硬化中起作用。对兴奋性毒性过程的更好理解不仅导致了针对神经退行性疾病的新型治疗方法的开发，还带来了对突触可塑性机制的意外见解。
