Miao Hongsheng, Li Runming, Han Cong, Lu Xiuzhen, Zhang Hang
Department of Neurosurgery, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine.
Department of Neurosurgery, No. 205 Hospital of People's Liberation Army of China, Jingzhou, China.
J Neurophysiol. 2018 Sep 1;120(3):1307-1317. doi: 10.1152/jn.00234.2018. Epub 2018 May 23.
Intracerebral hemorrhage (ICH) is a devastating disease worldwide with increasing mortality. The present study investigated whether minocycline was neuroprotective and induced M2 microglial polarization via upregulation of the TrkB/BDNF pathway after ICH. ICH was induced via injection of autologous blood into 150 Sprague-Dawley rats. A selective TrkB antagonist [N2-2-2-oxoazepan-3-yl amino] carbonyl phenyl benzo (b) thiophene-2-carboxamide (ANA 12)] and agonist [ N-[2-(5-hydroxy-1H-indol-3-yl) ethyl]-2-oxopiperidine-3-carboxamide (HIOC)] were used to investigate the mechanism of minocycline-induced neuroprotection. Minocycline improved ICH-induced neurological deficits and reduced M1 microglia marker protein (CD68, CD16) expression as well as M2 microglial polarization (CD206 and arginase 1 protein). Minocycline administration enhanced microglia-neuron cross talk and promoted the proliferation of neuronal progenitor cells, such as DCX- and Tuj-1-positive cells, 24 h after ICH. Minocycline also increased M2 microglia-derived brain-derived neurotrophic factors (BDNF) and the upstream TrkB pathway. ANA 12 reversed the neuroprotective effects of minocycline. HIOC exhibited the same effects as minocycline and accelerated neurogenesis after ICH. This study demonstrated for the first time that minocycline promoted M2 microglia polarization via upregulation of the TrkB/BDNF pathway and promoted neurogenesis after ICH. This study contributes to our understanding of the therapeutic potential of minocycline in ICH. NEW & NOTEWORTHY The present study gives several novel points: 1) Minocycline promotes neurogenesis after intracerebral hemorrhage in rats. 2) Minocycline induces activated M1 microglia into M2 neurotrophic phenotype. 3) M2 microglia secreting BDNF remodel the damaged neurocircuit.
脑出血（ICH）是一种在全球范围内具有毁灭性且死亡率不断上升的疾病。本研究调查了米诺环素在脑出血后是否具有神经保护作用，并通过上调TrkB/BDNF通路诱导M2小胶质细胞极化。通过向150只Sprague-Dawley大鼠注射自体血诱导脑出血。使用选择性TrkB拮抗剂[N2-2-2-氧代氮杂环庚烷-3-基氨基]羰基苯基苯并（b）噻吩-2-甲酰胺（ANA 12）]和激动剂[N-[2-(5-羟基-1H-吲哚-3-基)乙基]-2-氧代哌啶-3-甲酰胺（HIOC）]来研究米诺环素诱导神经保护的机制。米诺环素改善了脑出血诱导的神经功能缺损，降低了M1小胶质细胞标记蛋白（CD68、CD16）的表达以及M2小胶质细胞极化（CD206和精氨酸酶1蛋白）。给药米诺环素增强了小胶质细胞与神经元的相互作用，并促进了神经元祖细胞的增殖，如脑出血后24小时的双皮质素（DCX）和βⅢ微管蛋白（Tuj-1）阳性细胞。米诺环素还增加了M2小胶质细胞衍生的脑源性神经营养因子（BDNF）和上游TrkB通路。ANA 12逆转了米诺环素的神经保护作用。HIOC表现出与米诺环素相同的作用，并加速了脑出血后的神经发生。本研究首次证明米诺环素通过上调TrkB/BDNF通路促进M2小胶质细胞极化，并在脑出血后促进神经发生。本研究有助于我们理解米诺环素在脑出血中的治疗潜力。新发现与值得注意之处：本研究提出了几个新观点：1）米诺环素促进大鼠脑出血后的神经发生。2）米诺环素诱导活化的M1小胶质细胞转变为M2神经营养表型。3）分泌BDNF的M2小胶质细胞重塑受损神经回路。
