BMS-470539 Attenuates Oxidative Stress and Neuronal Apoptosis via MC1R/cAMP/PKA/Nurr1 Signaling Pathway in a Neonatal Hypoxic-Ischemic Rat Model.
BMS-470539 Attenuates Oxidative Stress and Neuronal Apoptosis via MC1R/cAMP/PKA/Nurr1 Signaling Pathway in a Neonatal Hypoxic-Ischemic Rat Model.
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DOI：
10.1155/2022/4054938
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发表时间：
2022
影响因子：
--
通讯作者：
Zhang JH
中科院分区：
文献类型：
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作者：
Yu S;Doycheva DM;Gamdzyk M;Gao Y;Guo Y;Travis ZD;Tang J;Chen WX;Zhang JH
氧化应激诱导的神经元凋亡在缺氧缺血性脑病（HIE）的发病和进展中起重要作用。先前的研究报道，黑素皮质素-1受体（MC1R）的激活在各种神经系统疾病中具有抗氧化应激、抗凋亡和神经保护作用。然而，MC1R激活是否能减轻缺氧缺血性脑损伤后的氧化应激和神经元凋亡尚不清楚。在此，我们研究了BMS-470539激活MC1R在减轻HI诱导的氧化应激和神经元凋亡中的作用及其机制。使用159只10日龄的无性鼠幼鼠。右颈总动脉结扎后缺氧2.5 h诱导HI。新型选择性MC1R激动剂BMS-470539在HI诱导后1小时经鼻给药。MC1R CRISPR - KO质粒和Nurr1 CRISPR - KO质粒于HI诱导前48 h给予脑室内注射。脑梗死面积百分比、短期神经行为测试、Western blot、免疫荧光染色、Fluoro-Jade C染色和MitoSox染色。我们发现MC1R和Nurr1的表达增加，在hi后48 h达到峰值。MC1R和Nurr1在hi后48 h在神经元上表达。BMS-470539显著减轻了短期神经功能缺损和梗死面积，并在hi后48小时伴有caspase-3阳性神经元的减少。此外，BMS-470539显著上调MC1R、cAMP、p-PKA、Nurr1、HO-1和Bcl-2的表达。然而，在hi后48 h，它下调了4-HNE和Bax的表达，减少了fjc阳性细胞、mitosox阳性细胞和8- ohdg阳性细胞的表达。MC1R CRISPR和Nurr1 CRISPR可消除BMS-470539的抗氧化应激、抗凋亡和神经保护作用。总之，我们的研究结果表明，BMS-470539可以减轻新生儿HI大鼠模型的氧化应激和神经元凋亡，并改善神经功能缺陷，部分通过MC1R/cAMP/PKA/Nurr1信号通路。早期给予BMS-470539可能是新生儿HIE的一种新的治疗策略。
Neuronal apoptosis induced by oxidative stress plays an important role in the pathogenesis and progression of hypoxic-ischemic encephalopathy (HIE). Previous studies reported that activation of melanocortin-1 receptor (MC1R) exerts antioxidative stress, antiapoptotic, and neuroprotective effects in various neurological diseases. However, whether MC1R activation can attenuate oxidative stress and neuronal apoptosis after hypoxic-ischemic- (HI-) induced brain injury remains unknown. Herein, we have investigated the role of MC1R activation with BMS-470539 in attenuating oxidative stress and neuronal apoptosis induced by HI and the underlying mechanisms. 159 ten-day-old unsexed Sprague-Dawley rat pups were used. HI was induced by right common carotid artery ligation followed by 2.5 h of hypoxia. The novel-selective MC1R agonist BMS-470539 was administered intranasally at 1 h after HI induction. MC1R CRISPR KO plasmid and Nurr1 CRISPR KO plasmid were administered intracerebroventricularly at 48 h before HI induction. Percent brain infarct area, short-term neurobehavioral tests, Western blot, immunofluorescence staining, Fluoro-Jade C staining, and MitoSox Staining were performed. We found that the expression of MC1R and Nurr1 increased, peaking at 48 h post-HI. MC1R and Nurr1 were expressed on neurons at 48 h post-HI. BMS-470539 administration significantly attenuated short-term neurological deficits and infarct area, accompanied by a reduction in cleaved caspase-3-positive neurons at 48 h post-HI. Moreover, BMS-470539 administration significantly upregulated the expression of MC1R, cAMP, p-PKA, Nurr1, HO-1, and Bcl-2. However, it downregulated the expression of 4-HNE and Bax, as well as reduced FJC-positive cells, MitoSox-positive cells, and 8-OHdG-positive cells at 48 h post-HI. MC1R CRISPR and Nurr1 CRISPR abolished the antioxidative stress, antiapoptotic, and neuroprotective effects of BMS-470539. In conclusion, our findings demonstrated that BMS-470539 administration attenuated oxidative stress and neuronal apoptosis and improved neurological deficits in a neonatal HI rat model, partially via the MC1R/cAMP/PKA/Nurr1 signaling pathway. Early administration of BMS-470539 may be a novel therapeutic strategy for infants with HIE.