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

Seong-Jin Yu,Nigel H Greig,Yun Wang,Eunkyung Bae,Li-Wei Kuo,Chia-Wen Chiang,Brandon K Harvey,Kuo-Jen Wu,Yu –Syuan Wang

doi:10.1016/j.isci.2020.100866

Abstract

SummaryAcetylcholinesterase (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.

Highlights

Stroke is a major brain disease worldwide, being the second leading global cause of death in the past decade (2000–2012; www.who.int/mediacentre/factsheets/fs310/en/index.html)
The use of AChE inhibitors in patients is limited by systemic cholinergic side effects
Post-treatment with Posiphen reduced endoplasmic reticulum (ER) stress signals, ionized calcium-binding adapter molecule 1 (IBA1) immunoreactivity, transferase dUTP nick end labeling (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

Summary

Introduction

Stroke is a major brain disease worldwide, being the second leading global cause of death in the past decade (2000–2012; www.who.int/mediacentre/factsheets/fs310/en/index.html). TPA dissolves occluding blood clots at a very early stage of stroke, but its effectiveness is limited by a narrow therapeutic time window of 3 h. Less than 3% of patients with stroke receive tPA, because they do not arrive at a hospital early enough for treatment (Barber et al, 2001; Reed et al, 2001). Cholinergic mechanisms are involved in various models of neurodegeneration including stroke (Pavlov and Tracey, 2005; Vijayaraghavan et al, 2013). The efficacy of AChE inhibitor treatment depends on cholinergic integrity as seen in patients with early Alzheimer’s disease (Richter et al, 2018) and the use of AChE inhibitors can be limited by the systemic cholinergic adverse effects (Colombres et al, 2004; Doody, 2003; Snape et al, 1999)

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