Dataset Information

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

ABSTRACT: Acetylcholinesterase (AChE) inhibitors have protective and anti-inflammatory actions against brain injury, mediated by nicotinic ?7 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 ?7 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.

SUBMITTER: Yu SJ

PROVIDER: S-EPMC7013187 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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

Yu Seong-Jin SJ Wu Kuo-Jen KJ Bae Eunkyung E Wang Yu-Syuan YS Chiang Chia-Wen CW Kuo Li-Wei LW Harvey Brandon K BK Greig Nigel H NH Wang Yun Y

iScience 20200128 2

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 glu ...[more]

PMID: 32058974

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Project description:We investigated the effects of the administration of docosahexaenoic acid (DHA) post-traumatic brain injury (TBI) on reducing neuroinflammation. TBI was induced by cortical contusion injury in Sprague Dawley rats. Either DHA (16?mg/kg in dimethyl sulfoxide) or vehicle dimethyl sulfoxide (1?ml/kg) was administered intraperitonially at 5?min after TBI, followed by a daily dose for 3 to 21 days. TBI triggered activation of microglia or macrophages, detected by an increase of Iba1 positively stained microglia or macrophages in peri-lesion cortical tissues at 3, 7, and 21 days post-TBI. The inflammatory response was further characterized by expression of the proinflammatory marker CD16/32 and the anti-inflammatory marker CD206 in Iba1(+) microglia or macrophages. DHA-treated brains showed significantly fewer CD16/32(+) microglia or macrophages, but an increased CD206(+) phagocytic microglial or macrophage population. Additionally, DHA treatment revealed a shift in microglial or macrophage morphology from the activated, amoeboid-like state into the more permissive, surveillant state. Furthermore, activated Iba1(+) microglial or macrophages were associated with neurons expressing the endoplasmic reticulum (ER) stress marker CHOP at 3 days post-TBI, and the administration of DHA post-TBI concurrently reduced ER stress and the associated activation of Iba1(+) microglial or macrophages. There was a decrease in nuclear translocation of activated nuclear factor kappa-light-chain-enhancer of activated B cells protein at 3 days in DHA-treated tissue and reduced neuronal degeneration in DHA-treated brains at 3, 7, and 21 days after TBI. In summary, our study demonstrated that TBI mediated inflammatory responses are associated with increased neuronal ER stress and subsequent activation of microglia or macrophages. DHA administration reduced neuronal ER stress and subsequent association with microglial or macrophage polarization after TBI, demonstrating its therapeutic potential to ameliorate TBI-induced cellular pathology.

Dataset Information

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

Publications

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

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