Stress primes microglial polarization after global ischemia: Therapeutic potential of progesterone
Stress primes microglial polarization after global ischemia: Therapeutic potential of progesterone
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DOI：
10.1016/j.bbi.2017.06.012
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发表时间：
2017-11-01
影响因子：
15.1
通讯作者：
Stein, Donald G.
中科院分区：
文献类型：
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作者：
Espinosa-Garcia, Claudia;Sayeed, Iqbal;Stein, Donald G.
尽管压力与卒中风险增加和预后恶化有关，但大多数临床前研究都忽略了这一合并症因素，特别是在测试神经保护治疗的背景下。临床前研究表明，应激刺激小胶质细胞，导致对后续损伤的反应增强，并可能增加中风的易感性。缺血诱导的活化小胶质细胞可以分化为产生促炎细胞因子的有害表型Ml，或释放抗炎细胞因子和神经营养因子的保护性表型M2。通过抑制M1或刺激M2选择性调节小胶质细胞极化可能是治疗脑缺血的潜在治疗策略。我们的实验室和其他实验室已经证明黄体酮对啮齿类动物的缺血性中风具有神经保护作用，但尚不清楚它在慢性应激共病条件下是否同样有效。在这里，我们评估了黄体酮对暴露于应激和全身缺血后海马炎症反应的神经保护作用。我们重点研究了应激缺血性动物小胶质细胞M1/M2极化和促炎和抗炎介质的作用。雄性Sprague-Dawley大鼠连续8天遭受社会失败应激，然后进行全身缺血或假手术。大鼠缺血后2 h腹腔注射黄体酮（8 mg/kg）或对照物，6 h皮下注射，伤后每24 h皮下注射1次，连续7 d。动物在缺血后7天和14天被杀死，脑被切除，并使用组织学、免疫组织化学和分子生物学技术对结果进行评估。缺血前应激(1)加剧了选择性易感海马CA1区神经元丢失和神经退行性变以及小胶质细胞活化；(2)小胶质细胞极化失调，导致M1和M2表型标志物上调；(3)促炎细胞因子表达增加；(4)缺血海马抗炎细胞因子和神经营养因子表达降低。黄体酮治疗通过调节极化小胶质细胞和海马（最易受缺血性损伤的区域）的炎症环境，显著减弱应激诱导的小胶质细胞启动。我们的研究结果表明，黄体酮有潜力作为缺血性中风临床试验的候选药物，其中高压力可能是一个促成因素。(C) 2017爱思唯尔公司版权所有。
Despite the fact that stress is associated with increased risk of stroke and worsened outcome, most preclinical studies have ignored this comorbid factor, especially in the context of testing neuroprotective treatments. Preclinical research suggests that stress primes microglia, resulting in an enhanced reactivity to a subsequent insult and potentially increasing vulnerability to stroke. Ischemia-induced activated microglia can be polarized into a harmful phenotype, Ml, which produces pro -inflammatory cytokines, or a protective phenotype, M2, which releases antiinflammatory cytokines and neurotrophic factors. Selective modulation of microglial polarization by inhibiting M1 or stimulating M2 may be a potential therapeutic strategy for treating cerebral ischemia. Our laboratory and others have shown progesterone to be neuroprotective against ischemic stroke in rodents, but it is not known whether it will be as effective under a comorbid condition of chronic stress. Here we evaluated the neuroprotective effect of progesterone on the inflammatory response in the hippocampus after exposure to stress followed by global ischemia. We focused on the effects of microglial M1/M2 polarization and pro- and anti-inflammatory mediators in stressed ischemic animals. Male Sprague-Dawley rats were exposed to 8 consecutive days of social defeat stress and then subjected to global ischemia or sham surgery. The rats received intraperitoneal injections of progesterone (8 mg/kg) or vehicle at 2 h post-ischemia followed by subcutaneous injections at 6 h and once every 24 h post-injury for 7 days. The animals were killed at 7 and 14 days post-ischemia, and brains were removed and processed to assess outcome measures using histological, immunohistochemical and molecular biology techniques. Pre-ischemic stress (1) exacerbated neuronal loss and neurodegeneration as well as microglial activation in the selectively vulnerable CA1 hippocampal region, (2) dysregulated microglial polarization, leading to upregulation of both M1 and M2 phenotype markers, (3) increased pro -inflammatory cytokine expression, and (4) reduced anti-inflammatory cytokine and neurotrophic factor expression in the ischemic hippocampus. Treatment with progesterone significantly attenuated stress-induced microglia priming by modulating polarized microglia and the inflammatory environment in the hippocampus, the area most vulnerable to ischemic injury. Our findings can be taken to suggest that progesterone holds potential as a candidate for clinical testing in ischemic stroke where high stress may be a contributing factor. (C) 2017 Elsevier Inc. All rights reserved.