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Novel dimeric acetylcholinesterase inhibitor bis(7)-tacrine, but not donepezil, prevents glutamate-induced neuronal apoptosis by blocking N-methyl-D-aspartate receptors

Authors Li, Wenming HKUST affiliated (currently or previously)
Pi, Rongbiao
Chan, Hugh H.N.
Fu, Hongjun HKUST affiliated (currently or previously)
Lee, Nelson HKUST affiliated (currently or previously)
Tsang, HingWai HKUST affiliated (currently or previously)
Pu, Yongmei HKUST affiliated (currently or previously)
Chang, Donald HKUST affiliated (currently or previously)
Li, Chaoying
Luo, Jialie HKUST affiliated (currently or previously)
Xiong, Keming
Li, Zhiwang
Xue, Hong View this author's profile
Carlier, Paul R.
Pang, Yuan-Ping
Tsim, Karl Wah Keung View this author's profile
Li, Mingtao
Han, Yifan HKUST affiliated (currently or previously)
Issue Date 2005
Source Journal of biological chemistry , v. 280, (18), 2005, MAY 6, p. 18179-18188
Summary The neuroprotective properties of bis(7)-tacrine, a novel dimeric acetylcholinesterase (AChE) inhibitor, on glutamate-induced excitotoxicity were investigated in primary cultured cerebellar granule neurons (CGNs). Exposure of CGNs to 75 mu M glutamate resulted in neuronal apoptosis as demonstrated by Hoechst staining, TUNEL, and DNA fragmentation assays. The bis(7)-tacrine treatment ( 0.01 - 1 mu M) on CGNs markedly reduced glutamate-induced apoptosis in dose-and time-dependent manners. However, donepezil and other AChE inhibitors, even at concentrations of inhibiting AChE to the similar extents as 1 mu M bis( 7)- tacrine, failed to prevent glutamate-induced excitotoxicity in CGNs; moreover, both atropine and dihydro-beta-erythroidine, the cholinoreceptor antagonists, did not affect the anti-apoptotic properties of bis( 7)- tacrine, suggesting that the neuroprotection of bis( 7)- tacrine appears to be independent of inhibiting AChE and cholinergic transmission. In addition, ERK1/2 and p38 pathways, downstream signals of N-methyl-D-aspartate ( NMDA) receptors, were rapidly activated after the exposure of glutamate to CGNs. Bis(7)-tacrine inhibited the apoptosis and the activation of these two signals with the same efficacy as the coapplication of PD98059 and SB203580. Furthermore, using fluorescence Ca2+ imaging, patch clamp, and receptor-ligand binding techniques, bis( 7)- tacrine was found effectively to buffer the intracellular Ca2+ increase triggered by glutamate, to reduce NMDA-activated currents and to compete with [H-3] MK-801 with an IC50 value of 0.763 mu M in rat cerebellar cortex membranes. These findings strongly suggest that bis( 7)- tacrine prevents glutamate-induced neuronal apoptosis through directly blocking NMDA receptors at the MK-801-binding site, which offers a new and clinically significant modality as to how the agent exerts neuroprotective effects.
ISSN 0021-9258
Rights We would like to give credit to American Society for Biochemistry and Molecular Biology for granting us permission to repost this article
Language English
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