Abstract
There are numerous evidences suggesting that inhibition of apoptosis of neurons play a critical role in preventing the damage and even death of neurons after brain ischemia/reperfusion, which shows therapeutic potential for clinical treatment of brain injury induced by stroke. In this study, we aimed to investigate the neuroprotective effect of Clematichinenoside (AR) and its underlying mechanisms. MCAO mode was performed in rats and OGD/R model in primary cortical neurons to investigate the neuroprotective effect of AR. The rate of apoptotic cells was measured using TUNEL assay in cerebral cortex and flow cytometric assay in cortical neurons. Apoptosis-related proteins such as bcl-2, bcl-xl, and bax and the phosphorylation of ERK1/2, cPKC, p90RSK, and CREB in ischemic penumbra were assayed by western blot. Furthermore, we made a thorough inquiry about how these proteins play roles in the anti-apoptotic mechanism using targets-associated inhibitors step by step. The results revealed that AR could activate both ERK1/2 and cPKC which resulted in p90RSK phosphorylation and translocation into the nucleus. Moreover, CREB, a downstream target of p90RSK, was phosphorylated and then bound to cAMP-regulated enhancer (CRE) to activate apoptosis-related genes, and finally ameliorate ischemic stroke through preventing neuron death. In conclusion, these data strongly suggest that AR could be used as an effective neuroprotective agent to protect against ischemic stroke after cerebral I/R injury through regulating both ERK1/2 and cPKC mediated p90RSK/CREB apoptotic pathways.
Highlights
Ischemic stroke which accounts for 85% of all stroke cases is associated with high morbidity and mortality worldwide (Lu et al, 2012; Zhao et al, 2013)
Further evidences provided that the the present study was designed: (1) to investigate the possible regulation of ERK1/2 was dependent on the activity of classical neuroprotective effect of AR against ischemic stroke after or conventional PKC via the modulation of the kinase cerebral ischemia and reperfusion (I/R) injury in a rat middle cerebral artery occlusion (MCAO) model, (2) to determine
To further explore the mechanism, we demonstrated that p90RSK could markedly transfer from cytoplasm to nucleus after phosphorylation, and promote CREB phosphorylation and phospho-CREB binding to cAMP-regulated enhancer (CRE), which resulted in the alteration of bcl-2, bcl-xl, and bax expressions in cortical neurons
Summary
Ischemic stroke which accounts for 85% of all stroke cases is associated with high morbidity and mortality worldwide (Lu et al, 2012; Zhao et al, 2013). After cerebral ischemia and reperfusion (I/R) injury, the cerebral microcirculatory damage, and apoptotic death of neurons have been found to play a vital role in causing subsequent disability and mortality (Wang et al, 2014). Up to now, its effect on ischemic stroke including cell survival and apoptosis, and it plays remains largely unknown. According to our pre-experiment, a critical role in triggering neuroprotective action toward we found that AR could prevent OGD/R-induced apoptosis in neurodegeneration diseases and stroke Further evidences provided that the the present study was designed: (1) to investigate the possible regulation of ERK1/2 was dependent on the activity of classical neuroprotective effect of AR against ischemic stroke after or conventional PKC (cPKC) via the modulation of the kinase cerebral I/R injury in a rat MCAO model, (2) to determine
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