Programmed mechanisms of status epilepticus-induced neuronal necrosis.
Programmed mechanisms of status epilepticus-induced neuronal necrosis.
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DOI：
10.1002/epi4.12593
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发表时间：
2023-05
期刊：
影响因子：
3
通讯作者：
Fujikawa, Denson G.
中科院分区：
文献类型：
--
作者：
Fujikawa, Denson G.
兴奋性毒性是所有急性神经元损伤的潜在机制，包括脑缺血、癫痫持续状态、创伤性CNS损伤和低血糖。它会导致形态学上的神经元坏死，并触发程序性细胞死亡程序。过多的钙通过NMDA受体操纵的阳离子通道进入激活两种关键酶-钙蛋白酶I和神经元型一氧化氮合酶（nNOS）。钙蛋白酶I是一种胞质酶，易位至线粒体和溶酶体膜，导致细胞色素c、核酸内切酶G和凋亡诱导因子（AIF）从线粒体释放，DNA酶II和组织蛋白酶B和D从溶酶体释放。这些都易位到神经元细胞核，造成DNA损伤，激活聚（ADP）核糖聚合酶-1（PARP-1）形成过量的聚（ADP）核糖（PAR）聚合物，这些聚合物易位到线粒体膜，导致截短的AIF（tAIF）释放。从线粒体和过氧亚硝酸盐释放的自由基，由nNOS催化L-精氨酸生成L-瓜氨酸的一氧化氮（NO）形成，破坏线粒体和溶酶体膜和DNA。最终的结果是神经元的坏死性死亡。另一种程序性坏死途径，坏死性凋亡，通过平行途径发生。由于坏死性凋亡的研究者没有认识到兴奋性毒性通路，因此尚不清楚每种通路在多大程度上导致程序性神经元坏死。我们正在研究每种途径对急性神经元坏死的贡献程度以及这些途径之间的相互作用程度。
Excitotoxicity is the underlying mechanism for all acute neuronal injury, from cerebral ischemia, status epilepticus, traumatic CNS injury, and hypoglycemia. It causes morphological neuronal necrosis, and it triggers a programmed cell death program. Excessive calcium entry through the NMDA‐receptor‐operated cation channel activates two key enzymes—calpain I and neuronal nitric oxide synthase (nNOS). Calpain I, a cytosolic enzyme, translocates to mitochondrial and lysosomal membranes, causing release of cytochrome c, endonuclease G, and apoptosis‐inducing factor (AIF) from mitochondria and DNase II and cathepsins B and D from lysosomes. These all translocate to neuronal nuclei, creating DNA damage, which activates poly(ADP) ribose polymerase‐1 (PARP‐1) to form excessive amounts of poly(ADP) ribose (PAR) polymers, which translocate to mitochondrial membranes, causing release of truncated AIF (tAIF). The free radicals that are released from mitochondria and peroxynitrite, formed from nitric oxide (NO) from nNOS catalysis of L‐arginine to L‐citrulline, damage mitochondrial and lysosomal membranes and DNA. The end result is the necrotic death of neurons. Another programmed necrotic pathway, necroptosis, occurs through a parallel pathway. As investigators of necroptosis do not recognize the excitotoxic pathway, it is unclear to what extent each contributes to programmed neuronal necrosis. We are studying the extent to which each contributes to acute neuronal necrosis and the extent of cross‐talk between these pathways.
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影响因子：
5.3
作者：
Eliasson, MJL;Huang, ZH;Moskowitz, MA
通讯作者：
Moskowitz, MA
DOI：
10.1073/pnas.0606526103
发表时间：
2006-11-28
影响因子：
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作者：
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影响因子：
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作者：
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