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.

中文翻译：

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褪黑素对 α7nAchR 的调节可通过抑制 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。

目前唯一经美国食品药品监督管理局 (FDA) 批准用于治疗急性缺血性中风的药物是组织纤溶酶原激活剂 (tPA)，但该药物的治疗益处部分被出血性转化 (HT) 风险增加所抵消。NIH 试验分析表明，吸烟可以保护接受 tPA 治疗的患者免受 HT 的影响。然而，其根本机制尚不清楚。烟碱乙酰胆碱受体 (nAChR) 已显示出抗炎作用，调节 nAChR 可能是减少缺血/再灌注引起的血脑屏障 (BBB) 损伤的策略。由于褪黑素可以调节 α7nAchR 的表达，并且褪黑素对缺血性损伤的神经保护作用是通过 α7nAChR 调节介导的，因此在这里，我们的目的是检验褪黑素通过调节 α7nACh 受体减少缺血再灌注 (I/R) 诱导的 BBB 损伤的假设。 α7nAChR)。使小鼠经历1.5小时的缺血和24小时的再灌注，并且在再灌注开始时，小鼠接受腹膜内施用(ip)药物或盐水。小鼠被随机分为五组：生理盐水组；α7nAChR 激动剂 PNU282987；褪黑激素；褪黑素+甲基乌头碱（MLA，α7nAChR 拮抗剂）和 MLA 组。通过检测伊文氏蓝和 IgG 的外渗来评估 BBB 通透性。我们的结果表明，I/R 显着增加了 BBB 通透性，并伴随着 occludin 降解、小胶质细胞激活和神经元释放高迁移率族蛋白 1 (HMGB1)。此外，I/R 显着诱导神经元损失，并伴有 CREB ​​调节的转录共激活因子 1 (CRTC1) 和 p-CREB ​​表达的减少。褪黑素治疗通过调节α7nAChR显着抑制上述变化。综上所述，这些结果表明褪黑激素对缺血/再灌注引起的 BBB 损伤具有保护作用，至少部分取决于 α7nAChR 的调节。