Excitotoxic glutamate insults block autophagic flux in hippocampal neurons.
Excitotoxic glutamate insults block autophagic flux in hippocampal neurons.
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DOI：
10.1016/j.brainres.2013.10.032
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发表时间：
2014-01-13
期刊：
影响因子：
2.9
通讯作者：
Bayer, K. Ulrich
中科院分区：
文献类型：
--
作者：
Kulbe, Jacqueline R.;Levy, Jean M. Mulcahy;Coultrap, Steven J.;Thorburn, Andrew;Bayer, K. Ulrich
脑缺血等兴奋性毒性损伤被认为可增强神经元自噬，进而促进神经元细胞死亡。兴奋性毒性损伤确实增加了自噬标志物。然而，值得注意的是，自噬标志物可以通过自噬诱导（因为这增强了它们的产生）或晚期自噬抑制（因为这防止了它们在自噬通量期间的降解）来增加。通过比较有和没有阻止自噬标志物自噬降解的蛋白酶抑制剂的情况，本研究的结果表明，兴奋毒性谷氨酸通过阻滞自噬的晚期来增加自噬标志物。最初，本研究旨在测试CaMKII抑制剂tatCN21是否通过调节自噬介导其损伤后神经保护作用。虽然tatCN21部分抑制了海马神经元的基底自噬，但对兴奋毒性谷氨酸损伤后已经被阻断的自噬没有影响，表明自噬抑制不是其神经保护机制。此外，虽然自噬抑制剂氯喹没有作用，但雷帕霉素（mTOR依赖性）和海藻糖（mTOR非依赖性）这两种不同机制增强自噬诱导的药物却有显著的神经保护作用。这表明治疗方法应该寻求增强而不是抑制自噬，不仅在神经退行性疾病中（这种方法被广泛接受），而且在急性兴奋性毒性损伤后也是如此。总之，这些发现显著地重塑了目前关于自噬和兴奋毒性相互交叉调节的观点。
Excitotoxic insults such as cerebral ischemia are thought to enhance neuronal autophagy, which is then thought to promote neuronal cell death. Excitotoxic insults indeed increase autophagy markers. Notably, however, autophagy markers can be increased either by autophagy induction (as this enhances their production) or by late-stage autophagy inhibition (as this prevents their degradation during autophagic flux). By comparing each condition with and without protease inhibitors that prevent autophagic degradation of the autophagy marker, the results of this study show that excitotoxic glutamate increases autophagy markers by a late-stage block of autophagy. Initially, this study set out to test if the CaMKII inhibitor tatCN21 mediates its post-insult neuroprotection by regulating autophagy. While tatCN21 partially inhibited basal autophagy in hippocampal neurons, it had no effects on the already blocked autophagy after excitotoxic glutamate insults, indicating that autophagy inhibition is not its neuroprotective mechanism. Additionally, while the autophagy inhibitor chloroquine had no effect, significant neuroprotection was seen instead with two drugs that enhance autophagy induction by different mechanisms, rapamycin (mTOR dependent) and trehalose (mTOR-independent). This suggests that therapeutic approaches should seek to enhance rather than inhibit autophagy, not only in neurodegenerative diseases (where such approach is widely accepted) but also after acute excitotoxic insults. Together, these findings significantly reshape the current view on the mutual cross-regulation of autophagy and excitotoxicity.
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