Bepridil decreases Aβ and calcium levels in the thalamus after middle cerebral artery occlusion in rats

Journal of Cellular and Molecular Medicine

Timo Sarajärvi²  Anu Lipsanen²  Petra Mäkinen²  Sirpa Peräniemi¹  Hilkka Soininen²  Annakaisa Haapasalo²  Jukka Jolkkonen² 

[1] School of Pharmacy, Biocenter Kuopio, University of Eastern Finland, Kuopio, Finland;Institute of Clinical Medicine – Neurology, University of Eastern Finland, Kuopio, Finland

关键词: Alzheimer's disease;    amyloid precursor protein;    β‐amyloid;    calcium;    β‐secretase;    transient middle cerebral artery occlusion;    sensorimotor function;    bepridil;    seladin‐1/DHCR24;   

DOI  :  10.1111/j.1582-4934.2012.01599.x

来源: Wiley

【 摘 要 】

Abstract

Alzheimer's disease (AD) and cerebral ischaemia share similar features in terms of altered amyloid precursor protein (APP) processing and β-amyloid (Aβ) accumulation. We have previously shown that Aβ and calcium deposition, and β-secretase activity, are robustly increased in the ipsilateral thalamus after transient middle cerebral artery occlusion (MCAO) in rats. Here, we investigated whether the non-selective calcium channel blocker bepridil, which also inhibits β-secretase cleavage of APP, affects thalamic accumulation of Aβ and calcium and in turn influences functional recovery in rats subjected to MCAO. A 27-day bepridil treatment (50 mg/kg, p.o.) initiated 2 days after MCAO significantly decreased the levels of soluble Aβ40, Aβ42 and calcium in the ipsilateral thalamus, as compared with vehicle-treated MCAO rats. Expression of seladin-1/DHCR24 protein, which is a potential protective factor against neuronal damage, was decreased at both mRNA and protein levels in the ipsilateral thalamus of MCAO rats. Conversely, bepridil treatment restored seladin-1/DHCR24 expression in the ipsilateral thalamus. Bepridil treatment did not significantly affect heme oxygenase-1- or NAD(P)H quinone oxidoreductase-1-mediated oxidative stress or inflammatory responses in the ipsilateral thalamus of MCAO rats. Finally, bepridil treatment mitigated MCAO-induced alterations in APP processing in the ipsilateral thalamus and improved contralateral forelimb use in MCAO rats. These findings suggest that bepridil is a plausible therapeutic candidate in AD or stroke owing to its multifunctional role in key cellular events that are relevant for the pathogenesis of these diseases.

【 授权许可】

Unknown   
© 2012 The Authors Journal of Cellular and Molecular Medicine © 2012 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd