Autophagy and Akt/CREB signalling play an important role in the neuroprotective effect of nimodipine in a rat model of vascular dementia

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Abstract

The Akt/CREB signalling pathway is involved in neuronal survival and protection. Autophagy is also likely to be involved in survival mechanisms. Nimodipine is an L-type calcium channel antagonist that reduces excessive calcium influx during pathological conditions (contributing to its neuroprotective properties). However, the potential role of nimodipine in autophagic and Akt/CREB signalling is not well understood. In addition, little is known about the relationship between autophagic and Akt/CREB signalling. Here, we designed a way to evaluate these issues. Adult male Sprague-Dawley rats were subjected to permanent bilateral occlusion of the common carotid artery (2VO) and randomly divided into three groups: the Vehicle (2VO), Nimodipine10 (2VO + nimodipine 10 mg/kg), and Nimodipine20 (2VO + nimodipine 20 mg/kg) groups. A fourth group of animals served as Sham controls. Each group was investigated at 4 and 8 weeks post-operatively and assessed using the Morris water maze. Nimodipine significantly alleviated spatial learning and memory impairments and inhibited the loss of neurons in the CA1 region of the hippocampus. These drug effects were more pronounced at 8 weeks than at 4 weeks. The activities of LC3 II p-Akt and p-CREB were examined using immunohistochemistry and western blotting. Suppressing autophagy induced pyramidal cell death without affecting increased pro-survival signalling induced by nimodipine. Nimodipine protected the brain from chronic cerebral hypoperfusion by activating the Akt/CREB signalling pathway. Autophagy has a neuroprotective effect on rats after 2VO. Autophagy is likely part of an integrated survival signalling network involving the Akt/CREB pathway.

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