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Open AccessArticle

Reduced Apoptotic Injury by Phenothiazine in Ischemic Stroke through the NOX-Akt/PKC Pathway

1
Luhe Institute of Neuroscience, Capital Medical University, Beijing 101100, China
2
Department of Neurology, Luhe Clinical Institute, Capital Medical University, Beijing 101100, China
3
Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI 48201, USA
4
Department of Research & Development Center, John D. Dingell VA Medical Center, Detroit, MI 4820, USA
5
Department of General Surgery, Luhe Clinical Institute, Capital Medical University, Beijing 101100, China
6
China-America Institute of Neuroscience, Xuanwu Clinical Institute, Capital Medical University, Beijing 100053, China
*
Author to whom correspondence should be addressed.
Brain Sci. 2019, 9(12), 378; https://doi.org/10.3390/brainsci9120378
Received: 17 October 2019 / Revised: 12 December 2019 / Accepted: 12 December 2019 / Published: 15 December 2019
(This article belongs to the Collection Collection on Molecular and Cellular Neuroscience)
Phenothiazine treatment has been shown to reduce post-stroke ischemic injury, though the underlying mechanism remains unclear. This study sought to confirm the neuroprotective effects of phenothiazines and to explore the role of the NOX (nicotinamide adenine dinucleotide phosphate oxidase)/Akt/PKC (protein kinase C) pathway in cerebral apoptosis. Sprague-Dawley rats underwent middle cerebral artery occlusion (MCAO) for 2 h and were randomly divided into 3 different cohorts: (1) saline, (2) 8 mg/kg chlorpromazine and promethazine (C+P), and (3) 8 mg/kg C+P as well as apocynin (NOX inhibitor). Brain infarct volumes were examined, and cell death/NOX activity was determined by assays. Western blotting was used to assess protein expression of kinase C-δ (PKC-δ), phosphorylated Akt (p-Akt), Bax, Bcl-XL, and uncleaved/cleaved caspase-3. Both C+P and C+P/NOX inhibitor administration yielded a significant reduction in infarct volumes and cell death, while the C+P/NOX inhibitor did not confer further reduction. In both treatment groups, anti-apoptotic Bcl-XL protein expression generally increased, while pro-apoptotic Bax and caspase-3 proteins generally decreased. PKC protein expression was decreased in both treatment groups, demonstrating a further decrease by C+P/NOX inhibitor at 6 and 24 h of reperfusion. The present study confirms C+P-mediated neuroprotection and suggests that the NOX/Akt/PKC pathway is a potential target for efficacious therapy following ischemic stroke. View Full-Text
Keywords: middle cerebral artery occlusion (MCAO); chlorpromazine and promethazine (C+P); neuroprotection; reperfusion middle cerebral artery occlusion (MCAO); chlorpromazine and promethazine (C+P); neuroprotection; reperfusion
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MDPI and ACS Style

Tong, Y.; Elkin, K.B.; Peng, C.; Shen, J.; Li, F.; Guan, L.; Ji, Y.; Wei, W.; Geng, X.; Ding, Y. Reduced Apoptotic Injury by Phenothiazine in Ischemic Stroke through the NOX-Akt/PKC Pathway. Brain Sci. 2019, 9, 378.

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