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

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.

KB-R7943, an inhibitor of the reverse Na+/Ca2+ exchanger, does not modify secondary pathology in the thalamus following focal cerebral stroke in rats

“…The extent of thalamic atrophy in MCAO rats has been demonstrated to correlate with the late sensory deficits revealed through the adhesive-removal test and in other tests measuring skilled forelimb function [41,42]. In line with this, prevention of thalamic pathology/atrophy by pharmacotherapy alleviates sensorimotor impairment [16,43]. The behavioral tests that we used to follow functional impairment and recovery after MCAO did not show any treatment effect, which is consistent with the biochemical data.…”

“…both calcium and A␤ pathology in the thalamus after focal cerebral ischemia [16,17]. Since KB-R7943 was not able to reverse the secondary pathology, bepridil may exert [39] its effects independently from calcium channels, as suggested by Mitterreiter et al [40].…”

“…More interestingly, chronic bepridil treatment significantly decreases calcium and soluble A␤ 40 /A␤ 42 levels in the ipsilateral thalamus of MCAO rats [16] and mice after cortical photothrombosis [17]. Since bepridil has a broad pharmacological profile including inhibition of the reverse mode of NCX, we hypothesized that the more selective inhibitor, KB-R7943 [18][19][20], would prevent delayed retrograde degeneration of thalamocortical connections, lessen Ca 2+ overload and A␤ burden in the thalamus, and lead eventually to improved behavioral outcome in MCAO rats.…”

Unexpected Complication in a Rat Stroke Model: Exacerbation of Secondary Pathology in the Thalamus by Subacute Intraarterial Administration of Human Bone Marrow-Derived Mesenchymal Stem Cells

“…in MCAO rats 14 and furthermore that thalamus pathology is linked with the late sensory deficit in MCAO rats. 15 The present study is also consistent with this concept, i.e., the more prominent the sensorimotor impairment, the more severe the thalamic pathology.…”

Non-Selective Calcium Channel Blocker Bepridil Decreases Secondary Pathology in Mice after Photothrombotic Cortical Lesion

“…Sarajärvi et al [19] showed that chronic treatment of MCAO rats with the non-selective calcium channel blocker, bepridil, significantly decreases the levels of soluble Aβ 40 and Aβ 42 , and calcium, in the ipsilateral thalamus as compared to vehicle treated rats, when treatment was started 2 days after operation. Since Aβ and calcium seem to be intimately linked in AD and cerebral ischemia [20]–[22], we subjected transgenic AD mice (hAPP SL ) to a cortical photothrombotic lesion followed by daily treatment with a non-selective calcium channel blocker, bepridil (50 mg/kg).…”