Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Xuanwu District, Beijing, China.
Eur J Pharmacol. 2009 Oct 25;621(1-3):38-45. doi: 10.1016/j.ejphar.2009.08.036. Epub 2009 Sep 6.
Alzheimer's disease is the most common form of dementia. Amyloid-beta protein is considered as a key factor of pathogenesis of Alzheimer's disease. l-3-n-butylphthalide (L-NBP), an anti-cerebral ischemia drug, has been shown to have therapeutic effects in vascular dementia animal models. In the present study, we investigated the potential of L-NBP to protect against cognitive impairment, oxidative damage and neuropathological changes induced by intracerebroventricular infusion of amyloid-beta peptide in rats. Daily treatments of 10 and 30 mg/kg L-NBP significantly improved spatial learning deficits and attenuated working memory deficits in Morris water maze task. L-NBP partially reversed the reduction of glutathione peroxidase activities and decreased malondialdehyde levels in the cortex and hippocampus. Furthermore, L-NBP markedly inhibited amyloid-beta-induced neuronal apoptosis, possibly by blocking caspase-3 activation. In addition, L-NBP reduced activation of glycogen synthase kinase-3beta and tau protein phosphorylation. Our results demonstrate that L-NBP protects against amyloid-beta-induced neurodegeneration and cognitive decline in a rat model, suggesting that it may have potential as a therapy for Alzheimer's disease.
阿尔茨海默病是最常见的痴呆症形式。淀粉样β蛋白被认为是阿尔茨海默病发病机制的关键因素。l-3-正丁基苯酞（L-NBP），一种抗脑缺血药物，已被证明在血管性痴呆动物模型中具有治疗作用。在本研究中，我们研究了 L-NBP 对保护认知障碍、氧化损伤和淀粉样β肽脑室内注射诱导的神经病理变化的潜力。每天用 10 和 30 mg/kg L-NBP 治疗可显著改善 Morris 水迷宫任务中的空间学习缺陷，并减轻工作记忆缺陷。L-NBP 部分逆转了皮质和海马中谷胱甘肽过氧化物酶活性的降低和丙二醛水平的降低。此外，L-NBP 明显抑制了淀粉样β诱导的神经元凋亡，可能通过阻断半胱天冬酶-3 的激活。此外，L-NBP 降低了糖原合酶激酶-3β和 tau 蛋白磷酸化的激活。我们的研究结果表明，L-NBP 可预防大鼠模型中淀粉样β诱导的神经退行性变和认知下降，表明其可能具有治疗阿尔茨海默病的潜力。
