The neuroprotective effects of cordycepin inhibit glutamate-induced oxidative and ER stress-associated apoptosis in hippocampal HT22 cells.
Glutamate toxicity increases the formation of reactive oxygen species (ROS) and intracellular calcium levels, resulting in neuronal dysfunction, neurodegenerative disorders, and death. Cordycepin is a derivative of the nucleoside adenosine, and is believed to exert neuroprotective effects against glutamate-induced oxidative toxicity in HT22 neuronal cells. Excessive glutamate induces oxidative and endoplasmic reticulum (ER) stress, gradually increasing ER-related pro-apoptotic transcription factor C/EBP homologous protein (CHOP) expression, and eventually up-regulating expression of the pro-apoptotic factor Bax. Cordycepin inhibits CHOP and Bax expressions, as well as p-ERK, p-JNK, and p-p38, all of which are involved in oxidative or ER stress-induced apoptosis. In addition, the increased production of ROS from excessive glutamate leads to elevation of mitochondrial membrane potential (MMP), a hallmark of mitochondrial dysfunction. Cordycepin retains MMP and reduces the elevated levels of ROS and Ca(2+) induced by glutamate. Caspases are crucial mediators involved in mitochondrial apoptosis, and while glutamate disrupts mitochondrial function, it does not change expression levels of caspase 3 and caspase 9. Similarly, cordycepin has no effect on caspase 3 and caspase 9 expressions; however, it decreases the expression of ER stress-specific caspase 12, which plays a key role in the initiation of ER stress-induced apoptosis. Finally, we found that the anti-apoptotic effects of cordycepin are partially dependent on activation of the adenosine A1 receptor, whereas an antagonist selectively attenuated the neuroprotective effects of cordycepin. Collectively, these results suggest that cordycepin could be a potential future therapeutic agent for neuronal disorders.
['Jin|Mei Ling|ML|', 'Park|Sun Young|SY|', 'Kim|Young Hun|YH|', 'Oh|Jeong-Il|JI|', 'Lee|Sang Joon|SJ|', 'Park|Geuntae|G|']
D000818:Animals D017209:Apoptosis D002453:Cell Cycle D002461:Cell Line, Transformed D003839:Deoxyadenosines D004305:Dose-Response Relationship, Drug D004347:Drug Interactions D059865:Endoplasmic Reticulum Stress D018698:Glutamic Acid D006624:Hippocampus D020287:In Situ Nick-End Labeling D053078:Membrane Potential, Mitochondrial D051379:Mice D009474:Neurons D018696:Neuroprotective Agents D018384:Oxidative Stress D017382:Reactive Oxygen Species D018709:Statistics, Nonparametric
Neuroprotection Cordycepin Apoptosis Hippocampal ER stress