Bis(7)-tacrine attenuates beta amyloid-induced neuronal apoptosis by regulating L-type calcium channels.
Beta amyloid protein (Abeta) and acetylcholinesterase (AChE) have been shown to be closely implicated in the pathogenesis of Alzheimer's disease. In the current study, we investigated the effects of bis(7)-tacrine, a novel dimeric AChE inhibitor, on Abeta-induced neurotoxicity in primary cortical neurons. Bis(7)-tacrine, but not other AChE inhibitors, elicited a marked reduction of both fibrillar and soluble oligomeric forms of Abeta-induced apoptosis as evidenced by chromatin condensation and DNA specific fragmentation. Both nicotinic and muscarinic receptor antagonists failed to block the effects of bis(7)-tacrine. Instead, nimodipine, a blocker of L-type voltage-dependent Ca2+ channels (VDCCs), attenuated Abeta neurotoxicity, whereas N-, P/Q- or R-type VDCCs blockers and ionotropic glutamate receptor antagonists did not. Fluorescence Ca2+ imaging assay revealed that, similar to nimodipine, bis(7)-tacrine reversed Abeta-triggered intracellular Ca2+ increase, which was mainly contributed by the extracellular Ca2+ instead of endoplasmic reticulum and mitochondria Ca2+. Concurrently, using whole cell patch-clamping technique, it was found that bis(7)-tacrine significantly reduced the augmentation of high voltage-activated inward calcium currents induced by Abeta. These results suggest that bis(7)-tacrine attenuates Abeta-induced neuronal apoptosis by regulating L-type VDCCs, offers a novel modality as to how the agent exerts neuroprotective effects.
Fu
Hongjun
H
Department of Biochemistry, Hong Kong University of Science and Technology, Hong Kong, P.R. China.
Li
Wenming
W
Lao
Yuanzhi
Y
Luo
Jialie
J
Lee
Nelson T K
NT
Kan
Kelvin K W
KK
Tsang
Hing Wai
HW
Tsim
Karl W K
KW
Pang
Yuanping
Y
Li
Zhiwang
Z
Chang
Donald C
DC
Li
Mingtao
M
Han
Yifan
Y
D000110:Acetylcholinesterase / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D002800:Cholinesterase Inhibitors; D000077265:Donepezil; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004622:Embryo, Mammalian; D006624:Hippocampus / Q000166:cytology; D007189:Indans / Q000494:pharmacology; D007531:Isoflurophate / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects*; D009553:Nimodipine / Q000494:pharmacology; D018408:Patch-Clamp Techniques / Q000379:methods; D010446:Peptide Fragments / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D013619:Tacrine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013997:Time Factors
C122128:1,7-N-heptylene-bis-9,9'-amino-1,2,3,4-tetrahydroacridine; D016229:Amyloid beta-Peptides; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D002800:Cholinesterase Inhibitors; D007189:Indans; D010446:Peptide Fragments; D010880:Piperidines; C075222:amyloid beta-protein (1-42); C074636:amyloid beta-protein (25-35); D007531:Isoflurophate; D013619:Tacrine; D009553:Nimodipine; D000077265:Donepezil; D000110:Acetylcholinesterase; D002118:Calcium