Atorvastatin inhibits neuronal apoptosis via activating cAMP/PKA/p‐CREB/BDNF pathway in hypoxic‐ischemic neonatal rats
Atorvastatin inhibits neuronal apoptosis via activating cAMP/PKA/p‐CREB/BDNF pathway in hypoxic‐ischemic neonatal rats
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DOI：
10.1096/fj.202101654rr
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发表时间：
2022-03
期刊：
影响因子：
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通讯作者：
Luting Yu;Shixi Liu;Ruixi Zhou;Hao Sun;Xiaojuan Su;Qian Liu;Shiping Li;Junjie Ying;F. Zh
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文献类型：
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作者：
Luting Yu;Shixi Liu;Ruixi Zhou;Hao Sun;Xiaojuan Su;Qian Liu;Shiping Li;Junjie Ying;F. Zh
神经细胞凋亡是新生儿缺氧缺血性脑损伤（HIBD）的主要病理过程之一，参与新生儿缺氧缺血性脑病（HIE）的发生发展。阿托伐他汀在某些神经系统疾病中具有神经保护作用，但其在新生儿HIBD发病机制中的作用尚不清楚。因此，本研究旨在探讨阿托伐他汀对新生大鼠缺氧缺血性脑损伤后神经细胞凋亡的调控作用及其相关机制。常规建立大鼠HIBD模型和神经元氧糖剥夺（OGD）模型。采用阿托伐他汀、cAMP抑制剂（SQ 22536）和BDNF抑制剂（ANA-12）治疗HIBD大鼠和OGD神经元。然后检查脑梗死、学习和记忆能力、cAMP/PKA/p-CREB/BDNF信号分子和凋亡相关指标（TUNEL、切割的caspase-3和Bax/Bcl 2）。在体内，阿托伐他汀可减少HIBD后大脑皮层的脑梗死，改善学习记忆能力，减少TUNEL阳性神经元数量，抑制切割的caspase-3和Bax/Bcl 2的表达，激活cAMP/PKA/p-CREB/BDNF通路。在体外，阿托伐他汀还降低了细胞凋亡相关指标，并激活了OGD后神经元中的cAMP/PKA/p-CREB/BDNF通路。此外，cAMP或BDNF的抑制减弱了阿托伐他汀对神经元凋亡减少的作用，表明阿托伐他汀主要通过激活cAMP/PKA/p‐CREB/BDNF途径抑制HIBD诱导的神经元凋亡并减轻新生大鼠的脑损伤。结论：阿托伐他汀有可能成为治疗新生儿缺氧缺血性脑病的潜在药物。
Neuronal apoptosis is one of the main pathological processes of hypoxic‐ischemic brain damage (HIBD) and is involved in the development of hypoxic‐ischemic encephalopathy (HIE) in neonates. Atorvastatin has been found to have neuroprotective effects in some nervous system diseases, but its role in regulating the pathogenesis of neonatal HIBD remains elusive. Thus, this study aimed to explore the effects and related mechanisms of atorvastatin on the regulation of neuronal apoptosis after HIBD in newborn rats. The rat HIBD model and the neuronal oxygen glucose deprivation (OGD) model were established routinely. Atorvastatin, cAMP inhibitor (SQ22536), and BDNF inhibitor (ANA‐12) were used to treat HIBD rats and OGD neurons. Cerebral infarction, learning and memory ability, cAMP/PKA/p‐CREB/BDNF signaling molecules, and apoptosis‐related indicators (TUNEL, cleaved caspase‐3, and Bax/Bcl2) were then examined. In vivo, atorvastatin reduced cerebral infarction, improved learning and memory ability, decreased the number of TUNEL‐positive neurons, inhibited the expression of cleaved caspase‐3 and Bax/Bcl2, and activated the cAMP/PKA/p‐CREB/BDNF pathway in the cerebral cortex after HIBD. In vitro, atorvastatin also decreased the apoptosis‐related indicators and activated the cAMP/PKA/p‐CREB/BDNF pathway in neurons after OGD. Furthermore, inhibition of cAMP or BDNF attenuated the effect of atorvastatin on the reduction of neuronal apoptosis, suggesting that atorvastatin inhibits HIBD‐induced neuronal apoptosis and alleviates brain injury in neonatal rats mainly by activating the cAMP/PKA/p‐CREB/BDNF pathway. In conclusion, atorvastatin may be developed as a potential drug for the treatment of neonatal HIE.