Activation of MC1R with BMS-470539 attenuates neuroinflammation via cAMP/PKA/Nurr1 pathway after neonatal hypoxic-ischemic brain injury in rats.
Activation of MC1R with BMS-470539 attenuates neuroinflammation via cAMP/PKA/Nurr1 pathway after neonatal hypoxic-ischemic brain injury in rats.
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在大鼠新生儿缺氧缺血性脑损伤后，用 BMS-470539 激活 MC1R 可通过 cAMP/PKA/Nurr1 通路减轻神经炎症。
DOI：
10.1186/s12974-021-02078-2
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发表时间：
2021-01-19
影响因子：
9.3
通讯作者：
Zhang JH
中科院分区：
文献类型：
--
作者：
Yu S;Doycheva DM;Gamdzyk M;Yang Y;Lenahan C;Li G;Li D;Lian L;Tang J;Lu J;Zhang JH
小胶质细胞介导的神经炎症在缺氧缺血性（HI）诱导的脑损伤发病机制中起着关键作用。黑素皮质素 - 1受体（MC1R）的激活已被证明在几种神经系统疾病中具有抗炎和神经保护作用。在本研究中，我们探讨了MC1R激活在大鼠新生儿缺氧缺血性脑损伤后对神经炎症的作用以及潜在的机制。
共使用了169只出生后第10天的未区分性别的幼鼠。通过右侧颈总动脉结扎后缺氧2.5小时诱导HI。BMS - 470539是一种特异性选择性MC1R激动剂，在HI诱导后1小时经鼻给药。为了阐明潜在的机制，在HI诱导前48小时通过脑室内注射给予MC1R CRISPR基因敲除质粒或Nurr1 CRISPR基因敲除质粒。进行了脑梗死面积百分比、短期和长期神经行为测试、尼氏染色、免疫荧光染色和蛋白质印迹分析。
HI后MC1R和Nurr1的表达水平随时间增加。HI后48小时，MC1R和Nurr1在小胶质细胞上表达。用BMS - 470539激活MC1R显著降低了HI后48小时和28天的梗死面积百分比、脑萎缩和炎症，并改善了短期和长期的神经功能缺损。MC1R激活增加了CD206（小胶质细胞M2标志物）的表达并降低了MPO的表达。此外，用BMS - 470539激活MC1R显著提高了HI后48小时MC1R、cAMP、p - PKA和Nurr1的表达水平，同时下调了促炎细胞因子（TNFα、IL - 6和IL - 1β）的表达。然而，通过特异性CRISPR敲除MC1R或Nurr1逆转了HI后MC1R激活的神经保护作用。
我们的研究表明，用BMS - 470539激活MC1R可减轻大鼠新生儿缺氧缺血性脑损伤后的神经炎症，并改善神经功能缺损。这种抗炎和神经保护作用至少部分是通过cAMP/PKA/Nurr1信号通路介导的。因此，MC1R激活可能是缺氧缺血性脑病（HIE）婴儿的一个有前途的治疗靶点。
网络版包含补充材料，可在10.1186/s12974 - 021 - 02078 - 2获取。
Microglia-mediated neuroinflammation plays a crucial role in the pathogenesis of hypoxic-ischemic (HI)-induced brain injury. Activation of melanocortin-1 receptor (MC1R) has been shown to exert anti-inflammatory and neuroprotective effects in several neurological diseases. In the present study, we have explored the role of MC1R activation on neuroinflammation and the potential underlying mechanisms after neonatal hypoxic-ischemic brain injury in rats. A total of 169 post-natal day 10 unsexed rat pups were used. HI was induced by right common carotid artery ligation followed by 2.5 h of hypoxia. BMS-470539, a specific selective MC1R agonist, was administered intranasally at 1 h after HI induction. To elucidate the potential underlying mechanism, MC1R CRISPR KO plasmid or Nurr1 CRISPR KO plasmid was administered via intracerebroventricular injection at 48 h before HI induction. Percent brain infarct area, short- and long-term neurobehavioral tests, Nissl staining, immunofluorescence staining, and Western blot were conducted. The expression levels of MC1R and Nurr1 increased over time post-HI. MC1R and Nurr1 were expressed on microglia at 48 h post-HI. Activation of MC1R with BMS-470539 significantly reduced the percent infarct area, brain atrophy, and inflammation, and improved short- and long-term neurological deficits at 48 h and 28 days post-HI. MC1R activation increased the expression of CD206 (a microglial M2 marker) and reduced the expression of MPO. Moreover, activation of MC1R with BMS-470539 significantly increased the expression levels of MC1R, cAMP, p-PKA, and Nurr1, while downregulating the expression of pro-inflammatory cytokines (TNFα, IL-6, and IL-1β) at 48 h post-HI. However, knockout of MC1R or Nurr1 by specific CRISPR reversed the neuroprotective effects of MC1R activation post-HI. Our study demonstrated that activation of MC1R with BMS-470539 attenuated neuroinflammation, and improved neurological deficits after neonatal hypoxic-ischemic brain injury in rats. Such anti-inflammatory and neuroprotective effects were mediated, at least in part, via the cAMP/PKA/Nurr1 signaling pathway. Therefore, MC1R activation might be a promising therapeutic target for infants with hypoxic-ischemic encephalopathy (HIE). The online version contains supplementary material available at 10.1186/s12974-021-02078-2.
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影响因子：
2.9
作者：
Gursoy-Özdemir, Y;Bolay, H;Dalkara, T
通讯作者：
Dalkara, T
影响因子：
64.8
作者：
Chen S;Zhu B;Yin C;Liu W;Han C;Chen B;Liu T;Li X;Chen X;Li C;Hu L;Zhou J;Xu ZX;Gao X;Wu X;Goding CR;Cui R
通讯作者：
Cui R
DOI：
10.1111/j.1365-2990.1994.tb01173.x
发表时间：
1994-04-01
影响因子：
5
作者：
DELBIGIO, MR;BECKER, LE
通讯作者：
BECKER, LE
影响因子：
8.3
作者：
Gelderblom, Mathias;Leypoldt, Frank;Magnus, Tim
通讯作者：
Magnus, Tim
影响因子：
11.2
作者：
Chen X;Chen H;Cai W;Maguire M;Ya B;Zuo F;Logan R;Li H;Robinson K;Vanderburg CR;Yu Y;Wang Y;Fisher DE;Schwarzschild MA
通讯作者：
Schwarzschild MA