title: Autophagy and Akt/CREB signalling play an important role in the neuroprotective effect of nimodipine in a rat model of vascular dementia.
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 10mg/kg), and Nimodipine20 (2VO+nimodipine 20mg/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.
authors.affiliation: Department of Neurology, Hebei General Hospital, No. 348 Heping West Road, Xinhua District, Shijiazhuang 050051, Hebei Province, People's Republic of China.
authors.forename: Ming
authors.initials: M
authors.lastname: Hu
authors.affiliation: Department of Neurology, Hebei General Hospital, No. 348 Heping West Road, Xinhua District, Shijiazhuang 050051, Hebei Province, People's Republic of China.
authors.forename: Zhijuan
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Neurology, Hebei General Hospital, No. 348 Heping West Road, Xinhua District, Shijiazhuang 050051, Hebei Province, People's Republic of China. Electronic address: peiyuanlu@163.com.
authors.forename: Peiyuan
authors.initials: P
authors.lastname: Lv
authors.affiliation: Department of Neurology, Hebei General Hospital, No. 348 Heping West Road, Xinhua District, Shijiazhuang 050051, Hebei Province, People's Republic of China.
authors.forename: Hebo
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Neurology, The Second Hospital of Hebei Medical University, No.215 Heping West Road, Xinhua District, Shijiazhuang 050000, Hebei Province, People's Republic of China.
authors.forename: Yifei
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Neurology, Hebei General Hospital, No. 348 Heping West Road, Xinhua District, Shijiazhuang 050051, Hebei Province, People's Republic of China.
authors.forename: Qianqian
authors.initials: Q
authors.lastname: Qi
authors.affiliation: Department of Neurology, Hebei General Hospital, No. 348 Heping West Road, Xinhua District, Shijiazhuang 050051, Hebei Province, People's Republic of China.
authors.forename: Jing
authors.initials: J
authors.lastname: Xu
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000473:pathology; D002121:Calcium Channel Blockers / Q000008:administration & dosage; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D015140:Dementia, Vascular / Q000378:metabolism*; D004195:Disease Models, Animal; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D009553:Nimodipine / Q000008:administration & dosage*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D065853:Spatial Learning / Q000187:drug effects; D065852:Spatial Memory / Q000187:drug effects
chemical_list: D002121:Calcium Channel Blockers; D017362:Cyclic AMP Response Element-Binding Protein; D008869:Microtubule-Associated Proteins; D018696:Neuroprotective Agents; D009553:Nimodipine; D051057:Proto-Oncogene Proteins c-akt; C508137:Creb1 protein, rat; C526109:Anxa3 protein, rat
keywords: 2VO; Akt/CREB signalling; Autophagy; Nimodipine; Rat; Vascular dementia