Modulation of α7nAchR by Melatonin Alleviates Ischemia and Reperfusion-Compromised Integrity of Blood-Brain Barrier Through Inhibiting HMGB1-Mediated Microglia Activation and CRTC1-Mediated Neuronal Loss.

Shuang Chen,Hui Li,Fei Li,Jianliang Zhang,Xinyu Zhang,Guo-Qing Zheng,Xinchun Jin,Yanyun Sun,Yixuan Li,Wenlan Liu,Xiaoyan Hu,Xiaoyun Zhao

doi:10.1007/s10571-021-01122-2

Abstract

The only food and drug administration (FDA)-approved drug currently available for the treatment of acute ischemic stroke is tissue plasminogen activator (tPA), yet the therapeutic benefits of this drug are partially outweighed by the increased risk of hemorrhagic transformation (HT). Analysis of the NIH trial has shown that cigarette smoking protected tPA-treated patients from HT; however, the underlying mechanism is not clear. Nicotinic acetylcholine receptors (nAChR) has shown anti-inflammatory effect and modulation nAChR could be a strategy to reduce ischemia/reperfusion-induced blood-brain barrier (BBB) damage. Since melatonin could regulate the expression of α7nAchR and melatonin's neuroprotective effect against ischemic injury is mediated via α7nAChR modulation, here, we aim to test the hypothesis that melatonin reduces ischemia and reperfusion (I/R)-induced BBB damage through modulation of α7nACh receptor (α7nAChR). Mice were subjected to 1.5 h ischemia and 24 h reperfusion and at the onset of reperfusion, mice received intraperitoneal administration (i.p.) of either drug or saline. Mice were randomly assigned into five groups: Saline; α7nAChR agonist PNU282987; Melatonin; Melatonin+Methyllycaconitine (MLA, α7nAChR antagonist), and MLA group. BBB permeability was assessed by detecting the extravasation of Evan's blue and IgG. Our results showed that I/R significantly increased BBB permeability accompanied by occludin degradation, microglia activation, and high mobility group box 1 (HMGB1) release from the neuron. In addition, I/R significantly induced neuronal loss accompanied by the decrease of CREB-regulated transcriptional coactivator 1 (CRTC1) and p-CREB expression. Melatonin treatment significantly inhibited the above changes through modulating α7nAChR. Taken together, these results demonstrate that melatonin provides a protective effect on ischemia/reperfusion-induced BBB damage, at least in part, depending on the modulation of α7nAChR.

Highlights

Blood brain barrier (BBB) damage after ischemia significantly influences stroke outcome (Liu et al 2020)
Our results indicated that melatonin significantly reduced ischemia and reperfusion (I/R)-induced blood brain barrier (BBB) disruption, occludin degradation, microglia activation, increased the loss of neuronal and the release of high mobility group box 1 (HMGB1) from the neuron, and decreased p-CREB and CREB regulated transcriptional coactivator 1 (CRTC1) expression
These results suggest that melatonin effectively alleviated I/R-induced BBB disruption and tight junction protein occludin degradation

Summary

Introduction

Blood brain barrier (BBB) damage after ischemia significantly influences stroke outcome (Liu et al 2020). Tissue plasminogen activator (tPA) is currently the only FDA-approved drug available for the treatment of acute ischemic stroke in the clinic. The therapeutic benefits of tPA are outweighed by its narrow treatment time window (3-4.5h) (Tissue plasminogen activator for acute ischemic stroke 1995) with the risk of a more than six-fold increase in hemorrhagic transformation (HT) after thrombolysis The NINDS t-PA Stroke Study Group 1997) and the high mortality following hemorrhage. These factors severely limited clinical application of tPA (Wardlaw et al 2012). Reperfusion-induced BBB injury has been an important research topic for decades and protecting the integrity of BBB is known to effectively alleviate cerebral ischemic damage (Won et al.2015; Chen et al 2009), there is no effective treatment that has been approved by the FDA to protect BBB from reperfusion-induced damage so far

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