多巴胺 D1 受体的激活可降低脑出血小鼠中 NLRP3 介导的炎症反应。
Activation of dopamine D1 receptor decreased NLRP3-mediated inflammation in intracerebral hemorrhage mice.
机构信息
Department of Anesthesiology and Physiology, School of Medicine, Loma Linda University, 11041 Campus St, Risley Hall, Room 219, Loma Linda, CA, 92354, USA.
School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, 264005, Shandong, People's Republic of China.
出版信息
J Neuroinflammation. 2018 Jan 4;15(1):2. doi: 10.1186/s12974-017-1039-7.
BACKGROUND
Inflammasomes are involved in diverse inflammatory diseases. Previous study reported that the neurotransmitter dopamine inhibited NLRP3 inflammasome activation via dopamine D1 receptor (DRD1). The present study aims to investigate the role of DRD1 on neuroinflammation in intracerebral hemorrhage (ICH) mice and the potential mechanism mediated by NLRP3 inhibition.
METHODS
One hundred and six male CD-1 mice were subjected to intrastriatal injection of bacterial collagenase or PBS. A68930 (DRD1 specific agonist) was administered by subcutaneous injection at 1 h after collagenase injection. Behavioral deficits and brain water content were assayed. The expression of Iba 1 and MPO levels were measured by immunofluorescence staining. The expressions of proteins in the DRD1/interferon-beta (IFN-beta)/NLRP3 signaling pathway were evaluated by western blotting.
RESULTS
Activation of the DRD1 by A68930 decreased brain edema and improved behavior at 24 and 72 h of ICH. A68930 inhibited partly the activation of microglia and the neutrophil infiltration after 24 h of ICH. IFN-beta, p-STAT1 increased while NLRP3, caspase 1, and IL-1beta decreased after A68930 administration in ICH mice. DRD1 antagonist and IFN-beta siRNA reversed effects of A68930 on neurological outcome and brain edema. DRD1 antagonist and IFN-beta siRNA blocked not only A68930-mediated increases of IFN-beta, p-STAT1 but also A68930-mediated decreases of NLRP3, caspase 1, and IL-1beta.
CONCLUSIONS
DRD1 activation by A68930 improves neurological outcome through inhibition of NLRP3-mediated inflammation in ICH mice.
背景
炎症小体参与多种炎症性疾病。先前的研究报道，神经递质多巴胺通过多巴胺 D1 受体（DRD1）抑制 NLRP3 炎症小体的激活。本研究旨在探讨 DRD1 在脑出血（ICH）小鼠神经炎症中的作用及其通过抑制 NLRP3 介导的潜在机制。
方法
106 只雄性 CD-1 小鼠接受纹状体内注射细菌胶原酶或 PBS。胶原酶注射后 1 小时通过皮下注射 A68930（DRD1 特异性激动剂）。测定行为缺陷和脑水含量。通过免疫荧光染色测定 Iba1 和 MPO 水平的表达。通过 Western blot 评估 DRD1/干扰素-β（IFN-β）/NLRP3 信号通路中蛋白的表达。
结果
A68930 激活 DRD1 可降低 ICH 后 24 和 72 小时的脑水肿并改善行为。A68930 抑制 ICH 后 24 小时小胶质细胞的激活和中性粒细胞浸润。A68930 给药后 ICH 小鼠中 IFN-β、p-STAT1 增加，NLRP3、caspase 1 和 IL-1β 减少。DRD1 拮抗剂和 IFN-β siRNA 逆转了 A68930 对神经功能和脑水肿的影响。DRD1 拮抗剂和 IFN-β siRNA 不仅阻断了 A68930 介导的 IFN-β、p-STAT1 的增加，还阻断了 A68930 介导的 NLRP3、caspase 1 和 IL-1β 的减少。
结论
A68930 通过激活 DRD1 抑制 NLRP3 介导的炎症反应，改善 ICH 小鼠的神经功能预后。
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