Department of Chemico-Pharmacological Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan.
J Pharmacol Exp Ther. 2011 Sep;338(3):741-9. doi: 10.1124/jpet.111.182519. Epub 2011 May 24.
Intracerebral hemorrhage (ICH) resulting from the leakage of blood into the brain parenchyma triggers severe tissue damage involving neurodegeneration and inflammation. Increasing lines of evidence indicate that the stimulation of central nicotinic acetylcholine receptors affords neuroprotection against various insults and also suppresses the proinflammatory activation of microglia. Therefore, the present study aimed to determine whether the administration of nicotine modifies the pathological consequences of ICH, using a mouse model of ICH induced by intrastriatal injection of collagenase. Daily intraperitoneal administration of nicotine (2 mg/kg), starting from 3 h after the induction of ICH, inhibited apoptosis and decreased the number of remaining striatal neurons at 3 days after the insult. We also found that nicotine administration increased the relative expression level of the antiapoptotic protein B cell lymphoma-2 versus that of the proapoptotic protein Bax in the brain. In addition, nicotine administration attenuated the activation of microglia/macrophages, infiltration of neutrophils, and increases in oxidative stress associated with ICH, without affecting hematoma expansion and brain edema. It is noteworthy that mice treated with nicotine exhibited improved sensorimotor performance and a marked increase in survival rate after ICH. These results indicate that nicotinic acetylcholine receptors may serve as a novel target for emergency therapy for ICH.
脑出血（ICH）导致血液漏入脑实质，引发严重的组织损伤，涉及神经退行性变和炎症。越来越多的证据表明，中枢烟碱型乙酰胆碱受体的刺激对各种损伤提供神经保护作用，并抑制小胶质细胞的促炎激活。因此，本研究旨在使用胶原酶诱导纹状体注射的 ICH 小鼠模型，确定尼古丁给药是否会改变 ICH 的病理后果。ICH 诱导后 3 小时开始，每天腹腔内给予尼古丁（2mg/kg），可抑制 3 天后的细胞凋亡并减少纹状体神经元的数量。我们还发现，尼古丁给药增加了脑内抗凋亡蛋白 B 细胞淋巴瘤-2 与促凋亡蛋白 Bax 的相对表达水平。此外，尼古丁给药减轻了与 ICH 相关的小胶质细胞/巨噬细胞激活、中性粒细胞浸润和氧化应激的增加，而不影响血肿扩大和脑水肿。值得注意的是，给予尼古丁的小鼠在 ICH 后表现出更好的感觉运动表现和明显增加的存活率。这些结果表明，烟碱型乙酰胆碱受体可能成为 ICH 紧急治疗的新靶点。
