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
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
复制标题
褪黑素对 α 7nAchR 的调节通过抑制 HMGB1 介导的小胶质细胞激活和 CRTC1 介导的神经元丢失来减轻缺血和再灌注导致的血脑屏障完整性受损
DOI：
10.1007/s10571-021-01122-2
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发表时间：
2021-07-01
影响因子：
4
通讯作者：
Jin, Xinchun
中科院分区：
文献类型：
--
作者：
Chen, Shuang;Sun, Yanyun;Jin, Xinchun
目前美国食品和药物管理局（FDA）唯一批准的用于治疗急性缺血性卒中的药物是组织纤溶酶原激活剂（tPA），然而这种药物的治疗益处部分被出血转化（HT）风险增加所抵消。对NIH试验的分析表明，吸烟可以保护接受tpa治疗的患者免受HT的侵害；然而，其潜在机制尚不清楚。烟碱乙酰胆碱受体（nAChR）具有抗炎作用，调节nAChR可能是减少缺血/再灌注诱导的血脑屏障（BBB）损伤的一种策略。由于褪黑素可以调节α 7nAchR的表达，而褪黑素对缺血损伤的神经保护作用是通过α 7nAchR的调节来介导的，因此，本研究旨在验证褪黑素通过调节α 7nAchR受体（α 7nAchR）来减轻缺血再灌注（I/R）诱导的血脑屏障损伤的假设。小鼠缺血1.5 h，再灌注24 h，再灌注开始时，小鼠腹腔注射药物或生理盐水。小鼠随机分为五组：生理盐水组；α 7nAChR激动剂PNU282987；褪黑素;褪黑素+甲基莱卡乌碱（MLA， α 7nAChR拮抗剂），以及MLA组。通过检测Evan’s blue和IgG的外渗来评估血脑屏障的通透性。我们的研究结果表明，I/R显著增加血脑屏障的通透性，同时伴有闭塞蛋白降解、小胶质细胞活化和高迁移率组盒1 （HMGB1）从神经元释放。此外，I/R显著诱导神经元丢失，并伴有creb调控的转录辅激活因子1 （CRTC1）和p-CREB表达的降低。褪黑素通过调节α - 7nAChR显著抑制上述变化。综上所述，这些结果表明褪黑素对缺血/再灌注诱导的血脑屏障损伤具有保护作用，至少部分依赖于α - 7nAChR的调节。
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 alpha 7nAchR and melatonin's neuroprotective effect against ischemic injury is mediated via alpha 7nAChR modulation, here, we aim to test the hypothesis that melatonin reduces ischemia and reperfusion (I/R)-induced BBB damage through modulation of alpha 7nACh receptor (alpha 7nAChR). 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; alpha 7nAChR agonist PNU282987; Melatonin; Melatonin+Methyllycaconitine (MLA, alpha 7nAChR 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 alpha 7nAChR. 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 alpha 7nAChR.