Pharmacology Department, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, No.1, Xiannongtan Street, Beijing 100050, China.
Naunyn Schmiedebergs Arch Pharmacol. 2011 Jan;383(1):91-9. doi: 10.1007/s00210-010-0575-9. Epub 2010 Nov 10.
Alzheimer's disease (AD) is the most common form of dementia. Oxidative stress is one of the earliest events in the neurological and pathological changes of AD. L-3-n-butyl-phthalide (L-NBP), an anti-cerebral ischemia agent, has been shown a potential in AD treatment. In this study, we investigated the neuroprotective effect of L-NBP on hydrogen peroxide (H₂O₂)-induced apoptosis in human neuroblastoma SK-N-SH cells. H₂O₂ significantly reduced cell viability and increased the number of apoptotic-like cells, indicating that H₂O₂ induced neurotoxicity. In addition, real-time PCR and western blot studies showed that Bcl-2 and Bcl-w expressions were decreased, and Bax expression was increased with H₂O₂ treatment. Moreover, protein kinase C (PKC) α expression was down-regulated after H₂O₂ treatment. All of these phenotypes induced by H₂O₂ were markedly reversed by L-NBP. Pretreatment with L-NBP significantly increased cell viability of H₂O₂-damaged cells, and reduced H₂O₂-induced neuronal apoptosis. L-NBP treatment at dose of 10 μM inhibited H₂O₂-induced down-regulation of Bcl-2, Bcl-w, and PKCα but also attenuated the overexpression of Bax. PKC inhibitor, calphostin C, significantly attenuated the protective effects of L-NBP. Our findings suggest that L-NBP may protect neurons against H₂O₂-induced apoptosis by modulating apoptosis-related genes and activating PKCα pathway.
阿尔茨海默病（AD）是最常见的痴呆症形式。氧化应激是 AD 神经和病理变化中最早的事件之一。L-3-正丁基苯酞（L-NBP），一种抗脑缺血药物，已被证明在 AD 治疗中有一定的潜力。在这项研究中，我们研究了 L-NBP 对过氧化氢（H₂O₂）诱导的人神经母细胞瘤 SK-N-SH 细胞凋亡的神经保护作用。H₂O₂显著降低细胞活力并增加凋亡样细胞的数量，表明 H₂O₂诱导了神经毒性。此外，实时 PCR 和 Western blot 研究表明，Bcl-2 和 Bcl-w 的表达减少，Bax 的表达增加。此外，H₂O₂处理后蛋白激酶 C（PKC）α的表达下调。H₂O₂引起的所有这些表型均被 L-NBP 明显逆转。L-NBP 预处理可显著增加 H₂O₂损伤细胞的活力，并减少 H₂O₂诱导的神经元凋亡。10 μM 的 L-NBP 处理可抑制 H₂O₂诱导的 Bcl-2、Bcl-w 和 PKCα下调，同时减轻 Bax 的过表达。PKC 抑制剂 calphostin C 显著减弱了 L-NBP 的保护作用。我们的研究结果表明，L-NBP 可能通过调节凋亡相关基因和激活 PKCα 通路来保护神经元免受 H₂O₂诱导的凋亡。
