Premium
Bis(7)‐tacrine attenuates β amyloid‐induced neuronal apoptosis by regulating L‐type calcium channels
Author(s) -
Fu Hongjun,
Li Wenming,
Lao Yuanzhi,
Luo Jialie,
Lee Nelson T. K.,
Kan Kelvin K. W.,
Tsang Hing Wai,
Tsim Karl W. K.,
Pang Yuanping,
Li Zhiwang,
Chang Donald C.,
Li Mingtao,
Han Yifan
Publication year - 2006
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2006.03960.x
Subject(s) - tacrine , neurotoxicity , chemistry , pharmacology , p type calcium channel , voltage dependent calcium channel , acetylcholinesterase , neuroprotection , calcium , biochemistry , t type calcium channel , biology , toxicity , organic chemistry , enzyme
β Amyloid protein (Aβ) 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 Aβ‐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 Aβ‐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 Ca 2+ channels (VDCCs), attenuated Aβ neurotoxicity, whereas N‐, P/Q‐ or R‐type VDCCs blockers and ionotropic glutamate receptor antagonists did not. Fluorescence Ca 2+ imaging assay revealed that, similar to nimodipine, bis(7)‐tacrine reversed Aβ‐triggered intracellular Ca 2+ increase, which was mainly contributed by the extracellular Ca 2+ instead of endoplasmic reticulum and mitochondria Ca 2+ . 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 Aβ. These results suggest that bis(7)‐tacrine attenuates Aβ‐induced neuronal apoptosis by regulating L‐type VDCCs, offers a novel modality as to how the agent exerts neuroprotective effects.