L-type calcium channel blockade alleviates molecular and reversal spatial learning and memory alterations induced by entorhinal amyloid pathology in rats

The entorhinal cortex (EC) is one of the most vulnerable brain regions that is affected by beta amyloid (A beta) in the early phases of Alzheimer's disease (AD). Calcium dyshomeostasis is one reason of A beta pathology and the role of calcium channel blockers (CCBs) in this phenomenon has not fully understood. In this study, we investigated the possible neuroprotective effect of CCBs, nimodipine and isradipine against amyloid pathogenesis in EC. The A beta 1-42 was injected bilaterally into the EC of male rats and spatial performance was assessed between 7 and 12 days after A beta injection by Morris water maze test. Animals were daily treated by injection of various doses of nimodipine or isradipine (both at 3, 10, or 30 mu g/2 mu l) or their vehicles into the lateral ventricle until the start of behavioral test. Lesion in EC was assessed by measuring some proteinases involved in calcium dependent apoptotic pathway (calpain 2, caspase 12 and 3). Despite normal performance in probe test, A beta treated rats showed delayed acquisition in a spatial reference memory task. A beta treated rats revealed delayed acquisition in reversal memory and had deficit in probe test. The observed impairments were attenuated by isradipine (10 and 30 mu g but not 3 mu g) and nimodipine (30 mu g). Calpain 2, caspase 12 and 3 were increased in the A beta treated animals which was partially antagonized by isradipine and nimodipine. It is concluded that CCBs might have beneficial therapeutic effects in AD especially in the early phases of this disease. (C) 2012 Elsevier B.V. All rights reserved.