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

Cheng Fu Chang, Jing Huei Lai, John Chung Che Wu, Nigel H. Greig, Robert E. Becker, Yu Luo, Yen Hua Chen, Shuo Jhen Kang, Yung Hsiao Chiang, Kai Yun Chen

Research output: Research - peer-reviewArticle

  • 2 Citations

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.

LanguageEnglish
Pages118-128
Number of pages11
JournalBrain Research
Volume1677
DOIs
StatePublished - Dec 15 2017

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Reperfusion Injury
Apoptosis
phenserine
Stroke
Middle Cerebral Artery Infarction
Acetylcholinesterase
Cell Death
Oxygen
Glucose
Hemiplegia
Amyloid beta-Protein Precursor
Glial Fibrillary Acidic Protein
Cholinesterase Inhibitors
Brain-Derived Neurotrophic Factor
Metalloproteases
B-Cell Lymphoma
Therapeutic Uses
Brain Ischemia
Caspase 3
Brain Injuries

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

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology

Cite this

(−)-Phenserine inhibits neuronal apoptosis following ischemia/reperfusion injury. / Chang, Cheng Fu; Lai, Jing Huei; Wu, John Chung Che; Greig, Nigel H.; Becker, Robert E.; Luo, Yu; Chen, Yen Hua; Kang, Shuo Jhen; Chiang, Yung Hsiao; Chen, Kai Yun.

In: Brain Research, Vol. 1677, 15.12.2017, p. 118-128.

Research output: Research - peer-reviewArticle

Chang, CF, Lai, JH, Wu, JCC, Greig, NH, Becker, RE, Luo, Y, Chen, YH, Kang, SJ, Chiang, YH & Chen, KY 2017, '(−)-Phenserine inhibits neuronal apoptosis following ischemia/reperfusion injury' Brain Research, vol 1677, pp. 118-128. DOI: 10.1016/j.brainres.2017.09.015
Chang CF, Lai JH, Wu JCC, Greig NH, Becker RE, Luo Y et al. (−)-Phenserine inhibits neuronal apoptosis following ischemia/reperfusion injury. Brain Research. 2017 Dec 15;1677:118-128. Available from, DOI: 10.1016/j.brainres.2017.09.015
Chang, Cheng Fu ; Lai, Jing Huei ; Wu, John Chung Che ; Greig, Nigel H. ; Becker, Robert E. ; Luo, Yu ; Chen, Yen Hua ; Kang, Shuo Jhen ; Chiang, Yung Hsiao ; Chen, Kai Yun. / (−)-Phenserine inhibits neuronal apoptosis following ischemia/reperfusion injury. In: Brain Research. 2017 ; Vol. 1677. pp. 118-128
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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.",
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AU - Becker,Robert E.

AU - Luo,Yu

AU - Chen,Yen Hua

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KW - Ischemia/reperfusion injury

KW - Metallopeptidase-9 (MMP-9)

KW - Middle cerebral artery occlusion (MCAO)

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