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

Abstract

Experimental studies have identified a complex link between neurodegeneration, β-amyloid (Aβ) and calcium homeostasis. Here we asked whether early phase β-amyloid pathology in transgenic hAPPSL mice exaggerates the ischemic lesion and remote secondary pathology in the thalamus, and whether a non-selective calcium channel blocker reduces these pathologies. Transgenic hAPPSL (n = 33) and non-transgenic (n = 30) male mice (4–5 months) were subjected to unilateral cortical photothrombosis and treated with the non-selective calcium channel blocker bepridil (50 mg/kg, p.o., once a day) or vehicle for 28 days, starting administration 2 days after the operation. Animals were then perfused for histological analysis of infarct size, Aβ and calcium accumulation in the thalamus. Cortical photothrombosis resulted in a small infarct, which was associated with atypical Aβ and calcium accumulation in the ipsilateral thalamus. Transgenic mice had significantly smaller infarct volumes than non-transgenic littermates (P<0.05) and ischemia-induced rodent Aβ accumulation in the thalamus was lower in transgenic mice compared to non-transgenic mice (P<0.01). Bepridil decreased calcium load in the thalamus (P<0.01). The present data suggest less pronounced primary and secondary pathology in hAPPSL transgenic mice after ischemic cortical injury. Bepridil particularly decreased calcium pathology in the thalamus following ischemia.

Reciprocal expression of Annexin A6 and RasGRF2 discriminates rapidly growing from invasive triple negative breast cancer subsets

“…We next determined whether other CCBs can elicit the reciprocal expression of AnxA6 and GRF2 in TNBC cells. Treatment of HCC1806 cells with bepridil, a non-selective CCB [25] led to increased AnxA6 and decreased RasGRF2 expression in a concentration dependent manner (Fig 1E and 1F), while treatment with amlodipine, an L-Type CCB [26] did not consistently lead to the reciprocal expression of AnxA6 and GRF2 (Fig 1E and 1G). As demonstrated in S1…”

Inflammatory Responses in the Secondary Thalamic Injury After Cortical Ischemic Stroke

“…Pharmacological inhibition of CathB reduces inflammation and prevents neuronal injury and apoptosis in the ipsilesional thalamus (101), indicating the importance of this gene and the autophagy process in secondary thalamic injury after stroke. Other treatments such as the non-selective calcium channel blocker bepridil (102) and antioxidant ebselen (103) also decrease secondary thalamic injury in different cortical stroke models.…”

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

“…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.…”