Novel dimeric acetylcholinesterase inhibitor bis(7)-tacrine, but not donepezil, prevents glutamate-induced neuronal apoptosis by blocking N-methyl-D-aspartate receptors
Chan, Hugh H.N.
Carlier, Paul R.
Tsim, Karl Wah Keung
|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.|
|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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