Rosiglitazone polarizes microglia and protects against pilocarpine-induced status epilepticus
Rosiglitazone polarizes microglia and protects against pilocarpine-induced status epilepticus
复制标题
罗格列酮极化小胶质细胞并预防毛果芸香碱诱发的癫痫持续状态
DOI：
10.1111/cns.13265
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发表时间：
2019-11-14
影响因子：
5.5
通讯作者：
Guan, Yangtai
中科院分区：
文献类型：
--
作者：
Peng, Jing;Wang, Kan;Guan, Yangtai
目的 在颞叶癫痫（TLE）患者以及癫痫持续状态（SE）动物模型的前脑和海马体中，已发现有活化的小胶质细胞。过氧化物酶体增殖物激活受体γ（PPARγ）激动剂罗格列酮已被证实可预防小胶质细胞的活化。然而，其在毛果芸香碱诱导的癫痫持续状态中的作用仍不明确。我们旨在研究PPARγ激动剂罗格列酮对毛果芸香碱诱导的因过度活化所致癫痫持续状态的保护作用，并探究小胶质细胞表型变化这一潜在机制。
方法 将雄性C57BL/6小鼠分为三组：对照组、毛果芸香碱诱导（SE）组和罗格列酮治疗（SE + Rosi）组。对癫痫持续状态小鼠腹腔注射300 mg/kg毛果芸香碱。SE + Rosi组小鼠在癫痫持续状态发作后给予罗格列酮（0.1 mg/kg，腹腔注射）。采用流式细胞术、免疫荧光染色和实时定量聚合酶链反应（qRT - PCR）检测大脑中小胶质细胞的活化情况和表型变化，并评估神经炎症。
结果 我们发现，与对照组小鼠相比，毛果芸香碱诱导的癫痫持续状态小鼠大脑中促炎型CD86和诱导型一氧化氮合酶（iNOS）的表达增加，而抗炎型CD206和精氨酸酶 - 1（Arg - 1）的表达降低。大脑中促炎和抗炎细胞因子的mRNA水平无显著变化。罗格列酮治疗显著抑制了小胶质细胞的促炎极化，并挽救了癫痫持续状态后大脑颞叶和海马体中的神经元丢失。
结论 罗格列酮可逆转癫痫持续状态小鼠大脑中的小胶质细胞极化，还能对毛果芸香碱诱导的癫痫持续状态起到神经保护作用，且不会引起大脑炎症的显著变化。
Aims Activated microglia have been found in the forebrains and hippocampi of temporal lobe epilepsy (TLE) patients and status epileptic (SE) animal models. The peroxisome proliferator-activated receptor gamma (PPAR gamma) agonist rosiglitazone has been shown to prevent microglial activation. However, its role in pilocarpine-induced status epilepticus remains unknown. We aimed to examine the effect of the PPAR gamma agonist rosiglitazone in protecting against pilocarpine-induced status epileptic resulting from over-activation and to explore phenotypic changes in microglia as the underlying mechanism. Methods Male C57BL/6 mice were assigned to three groups: the control group, pilocarpine-induced (SE) group, and rosiglitazone-treated (SE+Rosi) group. Status epileptic mice were administered 300 mg/kg pilocarpine via intraperitoneal injection. SE+Rosi mice were administered rosiglitazone (0.1 mg/kg, i.p.) after SE. Flow cytometry, immunofluorescence staining, and quantitative real-time PCR were used to examine the activation of and phenotypic changes in microglia in the brain and to evaluate neuroinflammation. Results We found that the expression of proinflammatory CD86 and iNOS was increased and that the expression of antiinflammatory CD206 and Arg-1 was decreased in the brains of pilocarpine-induced SE mice compared to control mice. The mRNA levels of proinflammatory and antiinflammatory cytokines were not significantly changed in the brain. Rosiglitazone treatment significantly inhibited the proinflammatory polarization of microglia and rescued neuron loss in the temporal lobe and hippocampi of the brain after SE. Conclusion Rosiglitazone reverses microglial polarization in the brains of SE mice and also affords neuroprotection against pilocarpine-induced status epilepticus without inducing significant changes in brain inflammation.