Non-selective calcium channel blocker bepridil decreases secondary pathology in mice after photothrombotic cortical lesion

• Published in: PloS one Vol. 8; no. 3; p. e60235
• Main Authors: Lipsanen, Anu, Flunkert, Stefanie, Kuptsova, Kristina, Hiltunen, Mikko, Windisch, Manfred, Hutter-Paier, Birgit, Jolkkonen, Jukka
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 26.03.2013; Public Library of Science (PLoS)
• Subjects: Accumulation; Alzheimer's disease; Alzheimers disease; Amyloid beta-Peptides - metabolism; Animal cognition; Animals; Bepridil - therapeutic use; Biology; Brain Ischemia - drug therapy; Brain Ischemia - etiology; Brain Ischemia - metabolism; Brain research; Calcium; Calcium Channel Blockers - therapeutic use; Calcium homeostasis; Clinical medicine; Cortex; Homeostasis; Hypertension; Hypotheses; Intracranial Thrombosis - drug therapy; Intracranial Thrombosis - etiology; Intracranial Thrombosis - metabolism; Ischemia; Laboratory animals; Light - adverse effects; Male; Medicine; Mice; Mice, Transgenic; Neurochemistry; Neurodegeneration; Neurology; Neurosciences; Pathology; Phosphorylation; Proteins; Rodents; Thalamus; Thalamus - drug effects; Thalamus - pathology; Thalamus - radiation effects; Transgenic animals; Transgenic mice; Traumatic brain injury; β-Amyloid; Austria; Finland
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0060235

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.