Bepridil decreases Aβ and calcium levels in the thalamus after middle cerebral artery occlusion in rats.
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.
Institute of Clinical Medicine - Neurology, University of Eastern Finland, Kuopio, Finland.
Timo
T
Sarajärvi
Anu
A
Lipsanen
Petra
P
Mäkinen
Sirpa
S
Peräniemi
Hilkka
H
Soininen
Annakaisa
A
Haapasalo
Jukka
J
Jolkkonen
Mikko
M
Hiltunen
D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D015764:Bepridil / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000235:genetics; D051547:Heme Oxygenase-1 / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013788:Thalamus / Q000187:drug effects / Q000378:metabolism*
D016564:Amyloid beta-Protein Precursor; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; C419385:L-type calcium channel alpha(1C); D009419:Nerve Tissue Proteins; D015764:Bepridil; D051547:Heme Oxygenase-1; C000600134:DHCR24 protein, rat; D044925:Oxidoreductases Acting on CH-CH Group Donors; D016660:NAD(P)H Dehydrogenase (Quinone); C507703:NQO1 protein, rat; D053829:Amyloid Precursor Protein Secretases; D002118:Calcium