Bis(12)-hupyridone, a novel acetylcholinesterase inhibitor, protects against glutamate-induced neuronal excitotoxicity via activating α7 nicotinic acetylcholine receptor/phosphoinositide 3-kinase/Akt cascade

Wei Cui, Shengquan Hu, Hugh H.N. Chan, Jialie Luo, Wenming Li, Shinghung Mak, Tony Chunglit Choi, Jianhui Rong, Paul R. Carlier, Yifan Han

Research output: Journal article publicationJournal articleAcademic researchpeer-review

16 Citations (Scopus)

Abstract

Bis(12)-hupyridone (B12H), derived from the Chinese medicinal component huperzine A, was originally designed as a novel acetylcholinesterase (AChE) inhibitor. In this paper, we report that B12H (24-h pretreatment) effectively blocked glutamate-induced neuronal excitotoxicity in cerebellar granule neurons (CGNs). However, the huge discrepancy between the EC50value and IC50value of B12H, to protect against neuronal toxicity (0.09 μM) and to block the NMDA receptor (21.8 μM) respectively, suggests that the neuroprotection of B12H might be not primarily due to the blockade of the NMDA receptor. Pretreatment by specific antagonists of alpha7-nicotinic acetylcholine receptor (α7nAChR), but not muscarinic acetylcholine receptor (mAChR) or α4β2nAChR, decreased the neuroprotection of B12H. The neuroprotection of B12H could also be abolished by the pretreatment of specific PI3-K inhibitors. Furthermore, B12H restored the suppressed activation of the Akt pathway caused by glutamate as evidenced by the decreased expressions of pSer473-Akt and pSer9-GSK3β. All these results suggest that B12H substantially protected CGNs against glutamate-induced neuronal excitotoxicity via activating α7nAChR/PI3-K/Akt cascade.
Original languageEnglish
Pages (from-to)365-370
Number of pages6
JournalChemico-Biological Interactions
Volume203
Issue number1
DOIs
Publication statusPublished - 25 Mar 2013

Keywords

  • α7nAChR
  • Akt
  • Bis(12)-hupyridone
  • Glutamate
  • NMDA receptor

ASJC Scopus subject areas

  • Toxicology

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