PDF(Pubmed)
Abstract：
Rasagiline (Azilect®) is a selective monoamine oxidase B (MAO-B) inhibitor that provides symptomatic benefits in Parkinson\'s disease (PD) treatment and has been found to exert preclinical neuroprotective effects. Here, we investigated the neuroprotective signaling pathways of acute rasagiline treatment for 22 h in PC12 neuronal cultures exposed to oxygen-glucose deprivation (OGD) for 4 h, followed by 18 h of reoxygenation (R), causing 40% aponecrotic cell death. In this study, 3-10 µM rasagiline induced dose-dependent neuroprotection of 20-80%, reduced the production of the neurotoxic reactive oxygen species by 15%, and reduced the nuclear translocation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) by 75-90%. In addition, 10 µM rasagiline increased protein kinase B (Akt) phosphorylation by 50% and decreased the protein expression of the ischemia-induced α-synuclein protein by 50% in correlation with the neuroprotective effect. Treatment with 1-5 µM rasagiline induced nuclear shuttling of transcription factor Nrf2 by 40-90% and increased the mRNA levels of the antioxidant enzymes heme oxygenase-1, (NAD (P) H- quinone dehydrogenase, and catalase by 1.8-2.0-fold compared to OGD/R insult. These results indicate that rasagiline provides neuroprotection to the ischemic neuronal cultures through the inhibition of α-synuclein and GAPDH-mediated aponecrotic cell death, as well as via mitochondrial protection, by increasing mitochondria-specific antioxidant enzymes through a mechanism involving the Akt/Nrf2 redox-signaling pathway. These findings may be exploited for neuroprotective drug development in PD and stroke therapy.
摘要：
雷沙吉兰（Azilect®）是一种选择性单胺氧化酶B（MAO-B）抑制剂，可在帕金森病（PD）治疗中提供症状益处，并已发现具有临床前神经保护作用。这里,我们研究了急性雷沙吉兰治疗22小时的PC12神经元培养物暴露于氧-葡萄糖剥夺（OGD）4小时的神经保护性信号通路，随后是18小时的复氧(R)，导致40%的细胞死亡.在这项研究中,3-10µM雷沙吉兰诱导的20-80％的剂量依赖性神经保护，减少15%的神经毒性活性氧的产生，并将甘油醛-3-磷酸脱氢酶（GAPDH）的核易位减少75-90％。此外,10µM雷沙吉兰使蛋白激酶B（Akt）磷酸化增加50％，并使缺血诱导的α-突触核蛋白的蛋白表达减少50％，与神经保护作用相关。用1-5µM雷沙吉兰处理可诱导转录因子Nrf2的核穿梭达40-90％，并增加了抗氧化酶血红素加氧酶-1（NAD（P）H-醌脱氢酶，过氧化氢酶是OGD/R损伤的1.8-2.0倍。这些结果表明，雷沙吉兰通过抑制α-突触核蛋白和GAPDH介导的无核细胞死亡为缺血性神经元培养物提供神经保护，以及通过线粒体保护，通过涉及Akt/Nrf2氧化还原信号通路的机制增加线粒体特异性抗氧化酶。这些发现可用于PD和中风治疗中的神经保护药物开发。
