Pharmacological Activation of RXR-α Promotes Hematoma Absorption via a PPAR-γ-dependent Pathway After Intracerebral Hemorrhage
Pharmacological Activation of RXR-α Promotes Hematoma Absorption via a PPAR-γ-dependent Pathway After Intracerebral Hemorrhage
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DOI：
10.1007/s12264-021-00735-3
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发表时间：
2021-06
影响因子：
5.6
通讯作者：
Chao-ran Xu;Huaijun Chen;Shengjun Zhou;Chenjun Sun;Xiaolong Xia;Yucong Peng;Jianfeng Zhuang
中科院分区：
文献类型：
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作者：
Chao-ran Xu;Huaijun Chen;Shengjun Zhou;Chenjun Sun;Xiaolong Xia;Yucong Peng;Jianfeng Zhuang
内源性清除血肿是治疗脑出血(ICH)的有利策略。本研究试图确定维甲酸X受体-α(RXR-α)在脑出血后血肿吸收中的作用。我们的结果表明，用贝沙罗汀药理激活RXR-α可显著加速血肿清除，减轻脑出血后的神经功能障碍。RXR-α表达于小胶质细胞/巨噬细胞、神经元和星形胶质细胞。在机制上，贝沙罗汀通过调节小胶质细胞/巨噬细胞从M1表型重编程到M2表型，促进RxR-α和PPAR-γ的核移位，并减轻神经炎症。此外，RXR-α在脑出血中的所有有益作用都被PPAR-γ抑制剂GW9662逆转。总之，RXR-α的药理激活通过促进血肿清除和通过PPAR-γ相关机制将小胶质细胞/巨噬细胞重新极化为M2表型，提供了强大的脑出血神经保护作用。我们的数据支持RXR-α可能是脑出血一个有前途的治疗靶点的观点。
Endogenously eliminating the hematoma is a favorable strategy in addressing intracerebral hemorrhage (ICH). This study sought to determine the role of retinoid X receptor-α (RXR-α) in the context of hematoma absorption after ICH. Our results showed that pharmacologically activating RXR-α with bexarotene significantly accelerated hematoma clearance and alleviated neurological dysfunction after ICH. RXR-α was expressed in microglia/macrophages, neurons, and astrocytes. Mechanistically, bexarotene promoted the nuclear translocation of RXR-α and PPAR-γ, as well as reducing neuroinflammation by modulating microglia/macrophage reprograming from the M1 into the M2 phenotype. Furthermore, all the beneficial effects of RXR-α in ICH were reversed by the PPAR-γ inhibitor GW9662. In conclusion, the pharmacological activation of RXR-α confers robust neuroprotection against ICH by accelerating hematoma clearance and repolarizing microglia/macrophages towards the M2 phenotype through PPAR-γ-related mechanisms. Our data support the notion that RXR-α might be a promising therapeutic target for ICH.