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

Shengquan Hu, Wei Cui, Shinghung Mak, Daping Xu, Yuanjia Hu, Jing Tang, Chunglit Choi, Mingyuen Lee, Yuan-Ping Pang, Yifan Han

Research output: Contribution to journalArticle

18 Scopus citations

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<inf>50</inf> 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.

Original languageEnglish (US)
Pages (from-to)1536-1545
Number of pages10
JournalACS Chemical Neuroscience
Volume6
Issue number9
DOIs
StatePublished - Jul 6 2015

Keywords

  • alpha7-nicotinic acetylcholine receptor
  • Alzheimer's disease
  • bis(propyl)-cognitin
  • extracellular signal-regulated kinase
  • neurite outgrowth
  • neuroprotection

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Physiology
  • Cognitive Neuroscience

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