Department of Neurology, Tianjin TEDA Hospital, Tianjin, China.
Department of Physiology and Pharmacology, Loma Linda University, 11041 Campus St, Loma Linda, CA, 92354, USA.
J Neuroinflammation. 2018 Jul 30;15(1):215. doi: 10.1186/s12974-018-1256-8.
Neuroinflammation is a crucial factor contributing to neurological injuries after intracerebral hemorrhage (ICH). C1q/TNF-related protein 9 (CTRP9), an agonist of adiponectin receptor 1 (AdipoR1), has recently been shown to reduce inflammatory responses in systemic diseases. The objective of this study was to investigate the protective role of CTRP9 against neuroinflammation after ICH in a mouse model and to explore the contribution of adenosine monophosphate-activated protein kinase (AMPK)/nuclear factor kappa B (NFκB) pathway in AdipoR1-mediated protection.
Adult male CD1 mice (n = 218) were randomly assigned to different groups for the study. ICH was induced via intrastriatal injection of bacterial collagenase. Recombinant CTRP9 (rCTRP9) was administered intranasally at 1 h after ICH. To elucidate the underlying mechanism, AdipoR1 small interfering ribonucleic acid (siRNA) and selective phosphorylated AMPK inhibitor Dorsomorphin were administered prior to rCTRP9 treatment. Brain edema, short- and long-term neurobehavior evaluation, blood glucose level, western blot, and immunofluorescence staining were performed.
Endogenous CTRP9 and AdipoR1 expression was increased and peaked at 24 h after ICH. AdipoR1 was expressed by microglia, neurons, and astrocytes. Administration of rCTRP9 reduced brain edema, improved short- and long-term neurological function, enhanced the expression of AdipoR1 and p-AMPK, and decreased the expression of phosphorylated NFκB and inflammatory cytokines after ICH. The protective effects of rCTRP9 were abolished by administration of AdipoR1 siRNA and Dorsomorphin.
Our findings demonstrated that administration of rCTRP9 attenuated neuroinflammation through AdipoR1/AMPK/NFκB signaling pathway after ICH in mice, thereby reducing brain edema and improving neurological function after experimental ICH in mice. Therefore, CTRP9 may provide a potential therapeutic strategy to alleviate neuroinflammation in ICH patients.
神经炎症是导致脑出血（ICH）后神经损伤的关键因素。C1q/TNF 相关蛋白 9（CTRP9）是脂联素受体 1（AdipoR1）的激动剂，最近已被证明可减轻全身性疾病中的炎症反应。本研究旨在探讨 CTRP9 在小鼠 ICH 模型中对神经炎症的保护作用，并探讨 AdipoR1 介导的保护作用中腺苷酸活化蛋白激酶（AMPK）/核因子 kappa B（NFκB）通路的贡献。
成年雄性 CD1 小鼠（n=218）被随机分为不同组进行研究。ICH 通过纹状体注射细菌胶原酶诱导。ICH 后 1 小时通过鼻腔给予重组 CTRP9（rCTRP9）。为了阐明潜在机制，在给予 rCTRP9 治疗之前给予 AdipoR1 小干扰 RNA（siRNA）和选择性磷酸化 AMPK 抑制剂 Dorsomorphin。进行脑水肿、短期和长期神经行为评估、血糖水平、western blot 和免疫荧光染色。
内源性 CTRP9 和 AdipoR1 表达增加，并在 ICH 后 24 小时达到峰值。AdipoR1 由小胶质细胞、神经元和星形胶质细胞表达。rCTRP9 给药可减少脑水肿，改善短期和长期神经功能，增强 AdipoR1 和 p-AMPK 的表达，并降低 ICH 后磷酸化 NFκB 和炎症细胞因子的表达。给予 AdipoR1 siRNA 和 Dorsomorphin 可消除 rCTRP9 的保护作用。
我们的研究结果表明，在小鼠 ICH 后，rCTRP9 通过 AdipoR1/AMPK/NFκB 信号通路减轻神经炎症，从而减轻实验性 ICH 后小鼠的脑水肿和改善神经功能。因此，CTRP9 可能为减轻 ICH 患者的神经炎症提供一种潜在的治疗策略。
