Post-treatment with Posiphen Reduces Endoplasmic Reticulum Stress and Neurodegeneration in Stroke Brain

Acetylcholinesterase (AChE) inhibitors have protective and anti-inflammatory actions against brain injury, mediated by nicotinic α7 cholinergic receptor activation. The use of AChE inhibitors in patients is limited by systemic cholinergic side effects. Posiphen, a stereoisomer of the AChE inhibitor...

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Published iniScience Vol. 23; no. 2; p. 100866
Main Authors Yu, Seong-Jin, Wu, Kuo-Jen, Bae, Eunkyung, Wang, Yu –Syuan, Chiang, Chia-Wen, Kuo, Li-Wei, Harvey, Brandon K., Greig, Nigel H., Wang, Yun
Format Journal Article
LanguageEnglish
Published United States Elsevier Inc 21.02.2020
Elsevier
Subjects
Cell Biology
Clinical Neuroscience
Drugs
Molecular Biology
Drugs
Clinical Neuroscience
Molecular Biology
Cell Biology
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Summary:Acetylcholinesterase (AChE) inhibitors have protective and anti-inflammatory actions against brain injury, mediated by nicotinic α7 cholinergic receptor activation. The use of AChE inhibitors in patients is limited by systemic cholinergic side effects. Posiphen, a stereoisomer of the AChE inhibitor Phenserine, lacks AChE inhibitor activity. The purpose of this study is to determine the protective effect of Posiphen in cellular and animal models of stroke. Both Posiphen and Phenserine reduced glutamate-mediated neuronal loss in co-cultures of primary cortical cells and microglia. Phenserine-, but not Posiphen-, mediated neuroprotection was diminished by the nicotinic α7 receptor antagonist methyllycaconitine. Posiphen antagonized NMDA-mediated Ca++ influx, thapsigargin-mediated neuronal loss and ER stress in cultured cells. Early post-treatment with Posiphen reduced ER stress signals, IBA1 immunoreactivity, TUNEL and infarction in the ischemic cortex, as well as neurological deficits in stroke rats. These findings indicate that Posiphen is neuroprotective against stroke through regulating Ca++i and ER stress. [Display omitted] •Posiphen induces protection in cell culture through noncholinergic mechanism•Posiphen attenuates glutamate-mediated Ca++i and ER stress in neuronal culture•Posiphen mitigates ER stress in stroke brain•Posiphen reduces neurodegeneration in stroke rats Drugs; Molecular Biology; Clinical Neuroscience; Cell Biology
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ISSN:2589-0042
2589-0042
DOI:10.1016/j.isci.2020.100866