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Brain Res. 2017 Dec 15;1677:118-128. doi: 10.1016/j.brainres.2017.09.015. Epub 2017 Sep 27.

(-)-Phenserine inhibits neuronal apoptosis following ischemia/reperfusion injury.

Author information

1
Department of Neurosurgery, Taipei City Hospital, Zhongxiao Branch, Taiwan; Department of Surgery, College of Medicine, Taipei Medical University, Taipei, Taiwan; Translational Laboratory, Department of Medical Research, Taipei Medical University Hospital, Taipei, Taiwan.
2
Department of Surgery, College of Medicine, Taipei Medical University, Taipei, Taiwan; Translational Laboratory, Department of Medical Research, Taipei Medical University Hospital, Taipei, Taiwan; Center for Neurotrauma and Neuroregeneration, Taipei Medical University, Taipei, Taiwan.
3
Department of Surgery, College of Medicine, Taipei Medical University, Taipei, Taiwan; Translational Laboratory, Department of Medical Research, Taipei Medical University Hospital, Taipei, Taiwan; Center for Neurotrauma and Neuroregeneration, Taipei Medical University, Taipei, Taiwan; Department of Neurosurgery, Taipei Medical University Hospital, Taipei, Taiwan.
4
Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA. Electronic address: greign@mail.nih.gov.
5
Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA; Aristea Translational Medicine, Park City, UT, USA.
6
Department of Neurosurgery, Case Western Reserve University, School of Medicine, Cleveland, OH, USA.
7
Department of Surgery, College of Medicine, Taipei Medical University, Taipei, Taiwan; Translational Laboratory, Department of Medical Research, Taipei Medical University Hospital, Taipei, Taiwan; Center for Neurotrauma and Neuroregeneration, Taipei Medical University, Taipei, Taiwan; Department of Neurosurgery, Taipei Medical University Hospital, Taipei, Taiwan; Graduate Institute of Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan. Electronic address: ychiang@tmu.edu.tw.
8
Translational Laboratory, Department of Medical Research, Taipei Medical University Hospital, Taipei, Taiwan; Center for Neurotrauma and Neuroregeneration, Taipei Medical University, Taipei, Taiwan; Graduate Institute of Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan. Electronic address: kychen08@tmu.edu.tw.

Abstract

Stroke commonly leads to adult disability and death worldwide. Its major symptoms are spastic hemiplegia and discordant motion, consequent to neuronal cell death induced by brain vessel occlusion. Acetylcholinesterase (AChE) is upregulated and allied with inflammation and apoptosis after stroke. Recent studies suggest that AChE inhibition ameliorates ischemia-reperfusion injury and has neuroprotective properties. (-)-Phenserine, a reversible AChE inhibitor, has a broad range of actions independent of its AChE properties, including neuroprotective ones. However, its protective effects and detailed mechanism of action in the rat middle cerebral artery occlusion model (MCAO) remain to be elucidated. This study investigated the therapeutic effects of (-)-phenserine for stroke in the rat focal cerebral ischemia model and oxygen-glucose deprivation/reperfusion (OGD/RP) damage model in SH-SY5Y neuronal cultures. (-)-Phenserine mitigated OGD/PR-induced SH-SY5Y cell death, providing an inverted U-shaped dose-response relationship between concentration and survival. In MCAO challenged rats, (-)-phenserine reduced infarction volume, cell death and improved body asymmetry, a behavioral measure of stoke impact. In both cellular and animal studies, (-)-phenserine elevated brain-derived neurotrophic factor (BDNF) and B-cell lymphoma 2 (Bcl-2) levels, and decreased activated-caspase 3, amyloid precursor protein (APP) and glial fibrillary acidic protein (GFAP) expression, potentially mediated through the ERK-1/2 signaling pathway. These actions mitigated neuronal apoptosis in the stroke penumbra, and decreased matrix metallopeptidase-9 (MMP-9) expression. In synopsis, (-)-phenserine significantly reduced neuronal damage induced by ischemia/reperfusion injury in a rat model of MCAO and cellular model of OGD/RP, demonstrating that its anti-apoptotic/neuroprotective/neurotrophic cholinergic and non-cholinergic properties warrant further evaluation in conditions of brain injury.

KEYWORDS:

(−)-Phenserine; Activated-caspase 3; Amyloid precursor protein (APP); B-cell lymphoma 2 (Bcl-2) expression; Brain-derived neurotrophic factor (BDNF); ERK-1/2 signaling pathway; Glial fibrillary acidic protein (GFAP); Ischemia/reperfusion injury; Metallopeptidase-9 (MMP-9); Middle cerebral artery occlusion (MCAO); Stroke

PMID:
28963051
PMCID:
PMC6703552
DOI:
10.1016/j.brainres.2017.09.015
[Indexed for MEDLINE]
Free PMC Article

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