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Title: 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
Pi, Rongbiao
Chan, Hugh H. N.
Fu, Hongjun
Lee, Nelson T. K.
Tsang, Hing Wai
Pu, Yongmei
Chang, Donald C.
Li, Chaoying
Luo, Jialie
Xiong, Keming
Li, Zhiwang
Xue, Hong
Carlier, Paul R.
Pang, Yuan-Ping
Tsim, Karl Wah-Keung
Li, Mingtao
Han, Yi-Fan
Keywords: Bis(7)-tacrine
Dimeric acetylcholinesterase inhibitor
Glutamate-induced neuronal apoptosis
Issue Date: May-2005
Citation: Journal of biological chemistry, v. 280, no. 18, May 2005, p. 18179-18188
Abstract: 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 μм glutamate resulted in neuronal apoptosis as demonstrated by Hoechst staining, TUNEL, and DNA fragmentation assays. The bis(7)-tacrine treatment (0.01–1 μм) 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 μм bis(7)-tacrine, failed to prevent glutamate-induced excitotoxicity in CGNs; moreover, both atropine and dihydro-β-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 co-application of PD98059 and SB203580. Furthermore, using fluorescence Ca2+ imaging, patchclamp, 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 [3H]MK-801 with an IC50 value of 0.763 μм 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.
Rights: We would like to give credit to American Society for Biochemistry and Molecular Biology for granting us permission to repost this article
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