Substantial Neuroprotective and Neurite Outgrowth-Promoting Activities by Bis(propyl)-cognitin via the Activation of Alpha7-nAChR, a Promising Anti-Alzheimer鈥檚 Dimer

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• 作者：Shengquan Hu ; Wei Cui ; Shinghung Mak ; Daping Xu ; Yuanjia Hu ; Jing Tang ; Chunglit Choi ; Mingyuen Lee ; Yuanping Pang ; Yifan Han
• 刊名：ACS Chemical Neuroscience
• 出版年：2015
• 出版时间：September 16, 2015
• 年：2015
• 卷：6
• 期：9
• 页码：1536-1545
• 全文大小：616K
• ISSN：1948-7193

文摘

The cause of Alzheimer鈥檚 disease (AD) could be ascribed to the progressive loss of functional neurons in the brain, and hence, agents with neuroprotection and neurite outgrowth-promoting activities that allow for the replacement of lost neurons may have significant therapeutic value. In the current study, the neuroprotective and the neurite outgrowth-promoting activities and molecular mechanisms of bis(propyl)-cognitin (B3C), a multifunctional anti-AD dimer, were investigated. Briefly, B3C (24 h pretreatment) fully protected against glutamate-induced neuronal death in primary cerebellar granule neurons with an IC₅₀ value of 0.08 渭M. The neuroprotection of B3C could be abrogated by methyllycaconitine, a specific antagonist of alpha7-nicotinic acetylcholine receptor (伪7-nAChR). In addition, B3C significantly promoted neurite outgrowth in both PC12 cells and primary cortical neurons, as evidenced by the increase in the percentage of cells with extended neurites as well as the up-regulation of neuronal markers growth-associated protein-43 and 尾-III-tubulin. Furthermore, B3C rapidly upregulated the phosphorylation of extracellular signal-regulated kinase (ERK), a critical signaling molecule in neurite outgrowth that is downstream of the 伪7-nAChR signal pathway. Specific inhibitors of ERK and 伪7-nAChR, but not those of p38 mitogen-activated protein kinase and c-Jun NH(2)-terminal kinase, blocked the neurite outgrowth as well as ERK activation in PC12 cells induced by B3C. Most importantly, genetic depletion of 伪7-nAChR significantly abolished B3C-induced neurite outgrowth in PC12 cells. Taken together, our results suggest that B3C provided neuroprotection and neurite outgrowth-promoting activities through the activation of 伪7-nAChR, which offers a novel molecular insight into the potential application of B3C in AD treatment.