Nimodipine represses AMPK phosphorylation and excessive autophagy after chronic cerebral hypoperfusion in rats.

Abstract:

:Chronic cerebral hypofusion (CCH) after bilateral carotid artery occlusion (2VO) causes cognitive damage and neuronal degeneration in the cortex and hippocampal CA1 area, and influences the oxygen and glucose supply in the brain which often results in metabolic alterations and oxidative stress. AMP-activated protein kinase (AMPK) phosphorylation, a sensor of cellular energy status, directs metabolic adaptation to support cellular growth and survival after CCH. Autophagy is also likely to be involved in metabolic adaptation and plays an important role in neuronal deterioration and cognitive decline after CCH. Nimodipine, an L-type calcium channel antagonist, has been reported to exert neuroprotective effects. However, the potential role of nimodipine in autophagy and the energy sensing AMPK signal is not well understood. In addition, little is known about the relationship between autophagy and AMPK signal. Here, we designed a way to evaluate these issues. Adult male Wistar rats were subjected to 2VO and randomly divided into three groups: the Vehicle (2VO), Nimodipine (2VO + nimodipine 10 mg/kg) groups. A third group served as sham controls. Each group was investigated at 2 and 4 weeks post gavage and tested using the Morris water maze. The activities of LC3B and AMPK signal were examined using immunohistochemistry and western blotting. Nimodipine significantly alleviated spatial learning and memory impairments and the number of lesion neurons. At 2 weeks of durg administration, these drug effects, suppressing AMPK activation and excessive autophagy, were more pronounced at the cortex than at hippocampal CA1 area. The effects of nimodipine were significant in the hippocampal CA1 area after 4 weeks of administration. Furthermore, nimodipine inhibited expression of eIF2α/ATF4 signaling related to energy deficit stress in 2VO rats. These results suggest that excessive autophagy has promoted neuronal and tissue injury after 2VO in rats. Nimodipine protected the brain from CCH by inhibiting the autophagy activity. The p-AMPK and eIF2α/ATF4 pathway is likely part of an integrated pro-autophagy signaling network after CCH.

journal_name

Brain Res Bull

journal_title

Brain research bulletin

authors

Chen Y,Guo Z,Peng X,Xie W,Chen L,Tan Z

doi

10.1016/j.brainresbull.2018.03.019

subject

Has Abstract

pub_date

2018-06-01 00:00:00

pages

88-96

eissn

0361-9230

issn

1873-2747

pii

S0361-9230(17)30391-X

journal_volume

140

pub_type

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