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Substantial Neuroprotective and Neurite Outgrowth-Promoting Activities by Bis(propyl)-cognitin via the Activation of Alpha7-nAChR, a Promising Anti-Alzheimer's Dimer
Hu S.1,2,3,4; Cui W.1,3; Mak S.1,3; Xu D.1,3; Hu Y.4; Tang J.5; Choi C.1; Lee M.4; Pang Y.5; Han Y.1,3
2015-07-06
Source PublicationACS Chemical Neuroscience
ISSN19487193
Volume6Issue:9Pages:1536-1545
Abstract

The cause of Alzheimer's 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 IC value of 0.08 μM. The neuroprotection of B3C could be abrogated by methyllycaconitine, a specific antagonist of alpha7-nicotinic acetylcholine receptor (α7-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 β-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 α7-nAChR signal pathway. Specific inhibitors of ERK and α7-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 α7-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 α7-nAChR, which offers a novel molecular insight into the potential application of B3C in AD treatment.

KeywordAlpha7-nicotinic Acetylcholine Receptor Alzheimer's Disease Bis(Propyl)-cognitin Extracellular Signal-regulated Kinase Neurite Outgrowth Neuroprotection
DOI10.1021/acschemneuro.5b00108
URLView the original
Indexed BySCIE
Language英语
WOS Research AreaBiochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Neurosciences & Neurology
WOS SubjectBiochemistry & Molecular Biology ; Chemistry, Medicinal ; Neurosciences
WOS IDWOS:000361505100005
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Cited Times [WOS]:16   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionInstitute of Chinese Medical Sciences
Corresponding AuthorHan Y.
Affiliation1.Department of Applied Biology and Chemical Technology, Institute of Modern Chinese Medicine, The Hong Kong Polytechnic University, Hung Hom, Hong Kong, China
2.Institute of New Drug Research, Guangdong Province Key Laboratory of Pharmacodynamic, Constituents of Traditional Chinese Medicine & New Drug Research, College of Pharmacy, Jinan University, Guangdong, China
3.The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen, China
4.State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, China
5.Mayo Cancer Center, Department of Pharmacology, Mayo Clinic, Rochester, Minnesota 55905, United States
First Author AffilicationInstitute of Chinese Medical Sciences
Recommended Citation
GB/T 7714
Hu S.,Cui W.,Mak S.,et al. Substantial Neuroprotective and Neurite Outgrowth-Promoting Activities by Bis(propyl)-cognitin via the Activation of Alpha7-nAChR, a Promising Anti-Alzheimer's Dimer[J]. ACS Chemical Neuroscience,2015,6(9):1536-1545.
APA Hu S..,Cui W..,Mak S..,Xu D..,Hu Y..,...&Han Y..(2015).Substantial Neuroprotective and Neurite Outgrowth-Promoting Activities by Bis(propyl)-cognitin via the Activation of Alpha7-nAChR, a Promising Anti-Alzheimer's Dimer.ACS Chemical Neuroscience,6(9),1536-1545.
MLA Hu S.,et al."Substantial Neuroprotective and Neurite Outgrowth-Promoting Activities by Bis(propyl)-cognitin via the Activation of Alpha7-nAChR, a Promising Anti-Alzheimer's Dimer".ACS Chemical Neuroscience 6.9(2015):1536-1545.
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