{"title":"原阿片碱通过激活 AMPK/PGC1α 通路对新生大鼠缺氧缺血性脑损伤产生神经保护作用","authors":"Liying Lu, Mengdan Pang, Tingting Chen, Yingying Hu, Likai Chen, Xiaoyue Tao, Shangqin Chen, Jianghu Zhu, Mingchu Fang, XiaoLing Guo, Zhenlang Lin","doi":"10.2147/DDDT.S484969","DOIUrl":null,"url":null,"abstract":"<p><strong>Introduction: </strong>Neonatal hypoxic-ischemic encephalopathy (HIE), caused by perinatal asphyxia, is characterized by high morbidity and mortality, but there are still no effective therapeutic drugs. Mitochondrial biogenesis and apoptosis play key roles in the pathogenesis of HIE. Protopine (Pro), an isoquinoline alkaloid, has anti-apoptotic and neuro-protective effects. However, the protective roles of Pro on neonatal hypoxic-ischemic brain injury remain unclear.</p><p><strong>Methods: </strong>In this study, we established a CoCl<sub>2</sub>-induced PC12 cell model in vitro and a neonatal rat hypoxic-ischemic (HI) brain damage model in vivo to explore the neuro-protective effects of Pro and try to elucidate the potential mechanisms.</p><p><strong>Results: </strong>Our results showed that Pro significantly reduced cerebral infarct volume, alleviated brain edema, inhibited glia activation, improved mitochondrial biogenesis, relieved neuron cell loss, decreased cell apoptosis and reactive oxygen species (ROS) after HI damage. In addition, Pro intervention upregulated the levels of p-AMPK/AMPK and PGC1α as well as the downstream mitochondrial biogenesis related factors, such as nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (TFAM), but the AMPK inhibitor compound c (CC) could significantly reverse these effects of Pro.</p><p><strong>Discussion: </strong>Pro may exert neuroprotective effects on neonatal hypoxic-ischemic brain damage via activation of the AMPK/PGC1α pathway, suggesting that Pro may be a promising therapeutic candidate for HIE, and our study firstly demonstrate the neuro-protective roles of Pro in HIE models.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"18 ","pages":"4975-4992"},"PeriodicalIF":4.7000,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11549892/pdf/","citationCount":"0","resultStr":"{\"title\":\"Protopine Exerts Neuroprotective Effects on Neonatal Hypoxic-Ischemic Brain Damage in Rats via Activation of the AMPK/PGC1α Pathway.\",\"authors\":\"Liying Lu, Mengdan Pang, Tingting Chen, Yingying Hu, Likai Chen, Xiaoyue Tao, Shangqin Chen, Jianghu Zhu, Mingchu Fang, XiaoLing Guo, Zhenlang Lin\",\"doi\":\"10.2147/DDDT.S484969\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Introduction: </strong>Neonatal hypoxic-ischemic encephalopathy (HIE), caused by perinatal asphyxia, is characterized by high morbidity and mortality, but there are still no effective therapeutic drugs. 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引用次数: 0
摘要
导言：围产期窒息导致的新生儿缺氧缺血性脑病（HIE）具有高发病率和高死亡率的特点，但目前仍没有有效的治疗药物。线粒体生物生成和细胞凋亡在 HIE 的发病机制中起着关键作用。异喹啉生物碱 Protopine（Pro）具有抗细胞凋亡和保护神经的作用。然而，Pro 对新生儿缺氧缺血性脑损伤的保护作用仍不清楚：本研究在体外建立了氯化钠诱导的 PC12 细胞模型，在体内建立了新生大鼠缺氧缺血性脑损伤模型，以探讨 Pro 的神经保护作用，并尝试阐明其潜在机制：结果表明，Pro能明显降低HI损伤后的脑梗死体积、减轻脑水肿、抑制胶质细胞活化、改善线粒体生物生成、缓解神经元细胞丢失、减少细胞凋亡和活性氧（ROS）。此外，Pro干预还能上调p-AMPK/AMPK和PGC1α的水平，以及线粒体生物生成相关的下游因子，如核呼吸因子1（NRF1）和线粒体转录因子A（TFAM），但AMPK抑制剂化合物c（CC）能显著逆转Pro的这些作用：讨论：Pro可通过激活AMPK/PGC1α通路对新生儿缺氧缺血性脑损伤发挥神经保护作用，这表明Pro可能是治疗HIE的一种有前途的候选药物，我们的研究首次证明了Pro在HIE模型中的神经保护作用。
Protopine Exerts Neuroprotective Effects on Neonatal Hypoxic-Ischemic Brain Damage in Rats via Activation of the AMPK/PGC1α Pathway.
Introduction: Neonatal hypoxic-ischemic encephalopathy (HIE), caused by perinatal asphyxia, is characterized by high morbidity and mortality, but there are still no effective therapeutic drugs. Mitochondrial biogenesis and apoptosis play key roles in the pathogenesis of HIE. Protopine (Pro), an isoquinoline alkaloid, has anti-apoptotic and neuro-protective effects. However, the protective roles of Pro on neonatal hypoxic-ischemic brain injury remain unclear.
Methods: In this study, we established a CoCl2-induced PC12 cell model in vitro and a neonatal rat hypoxic-ischemic (HI) brain damage model in vivo to explore the neuro-protective effects of Pro and try to elucidate the potential mechanisms.
Results: Our results showed that Pro significantly reduced cerebral infarct volume, alleviated brain edema, inhibited glia activation, improved mitochondrial biogenesis, relieved neuron cell loss, decreased cell apoptosis and reactive oxygen species (ROS) after HI damage. In addition, Pro intervention upregulated the levels of p-AMPK/AMPK and PGC1α as well as the downstream mitochondrial biogenesis related factors, such as nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (TFAM), but the AMPK inhibitor compound c (CC) could significantly reverse these effects of Pro.
Discussion: Pro may exert neuroprotective effects on neonatal hypoxic-ischemic brain damage via activation of the AMPK/PGC1α pathway, suggesting that Pro may be a promising therapeutic candidate for HIE, and our study firstly demonstrate the neuro-protective roles of Pro in HIE models.
期刊介绍：
Drug Design, Development and Therapy is an international, peer-reviewed, open access journal that spans the spectrum of drug design, discovery and development through to clinical applications.
The journal is characterized by the rapid reporting of high-quality original research, reviews, expert opinions, commentary and clinical studies in all therapeutic areas.
Specific topics covered by the journal include:
Drug target identification and validation
Phenotypic screening and target deconvolution
Biochemical analyses of drug targets and their pathways
New methods or relevant applications in molecular/drug design and computer-aided drug discovery*
Design, synthesis, and biological evaluation of novel biologically active compounds (including diagnostics or chemical probes)
Structural or molecular biological studies elucidating molecular recognition processes
Fragment-based drug discovery
Pharmaceutical/red biotechnology
Isolation, structural characterization, (bio)synthesis, bioengineering and pharmacological evaluation of natural products**
Distribution, pharmacokinetics and metabolic transformations of drugs or biologically active compounds in drug development
Drug delivery and formulation (design and characterization of dosage forms, release mechanisms and in vivo testing)
Preclinical development studies
Translational animal models
Mechanisms of action and signalling pathways
Toxicology
Gene therapy, cell therapy and immunotherapy
Personalized medicine and pharmacogenomics
Clinical drug evaluation
Patient safety and sustained use of medicines.
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