Institute of Pharmacy, Chemistry and Biomedical Sciences, School of Health, Natural and Social Science, University of Sunderland, Sunderland, UK.
Eur J Neurosci. 2012 Feb;35(3):366-74. doi: 10.1111/j.1460-9568.2011.07965.x.
Intracerebral injection of ibotenate into mouse pups induced grey matter lesions and white matter cysts; co-administration of brain-derived neurotrophic factor (BDNF) produced a dose-dependent reduction in these lesions. In contrast, glial cell line-derived neurotrophic factor (GDNF) had no significant effect, whereas nerve growth factor (NGF) or interleukin-1β (IL-1β) resulted in dose-dependent exacerbation. The neuroprotective effects of BDNF were abolished by co-administration of anti-BDNF antibody or MEK inhibitors, or ABT-737, a BH3 mimetic and Bcl-2 antagonist. The actions of BDNF, GDNF and NGF were measured in a parallel in vitro study on the oxidative metabolism of mouse brain mitochondria. BDNF produced a concentration-dependent increase in the respiratory control index (RCI, a measure of respiratory coupling efficiency, ATP synthesis, and organelle integrity) when co-incubated with synaptosomes containing signal transduction pathways; but GDNF failed to modify RCI, and NGF had only weak effects. BDNF had no effect on pure mitochondria, and enhanced oxidation only when complex I substrates were used. The effect of BDNF was inhibited by anti-BDNF antibody, MEK inhibitors or ABT-737, and also by IL-1β, indicating that the mitochondrial effects are mediated via the same MEK-Bcl-2 pathway as the neuroprotection. The complex I inhibitor rotenone, a compound implicated in the aetiology of Parkinson's disease, inhibited both the in vitro mitochondrial and in vivo neuroprotective effects of BDNF. The ability of BDNF to modify brain metabolism and the efficiency of oxygen utilization via a MEK-Bcl-2 pathway may be an important component of the neuroprotective action observed with this neurotrophin.
将异硫氰酸胍注入幼鼠脑内会引起灰质损伤和白质囊肿；脑源性神经营养因子（BDNF）的共同给药会导致这些损伤呈剂量依赖性减少。相比之下，胶质细胞源性神经营养因子（GDNF）没有显著效果，而神经生长因子（NGF）或白细胞介素-1β（IL-1β）则导致剂量依赖性恶化。BDNF 的神经保护作用被共同给予抗 BDNF 抗体或 MEK 抑制剂，或 ABT-737（一种 BH3 模拟物和 Bcl-2 拮抗剂）所废除。BDNF、GDNF 和 NGF 的作用在一项关于小鼠脑线粒体氧化代谢的平行体外研究中进行了测量。当与含有信号转导途径的突触小体共同孵育时，BDNF 会导致呼吸控制指数（RCI，一种衡量呼吸偶联效率、ATP 合成和细胞器完整性的指标）呈浓度依赖性增加；但 GDNF 未能改变 RCI，而 NGF 的作用较弱。BDNF 对纯线粒体没有影响，只有在使用复合物 I 底物时才会增强氧化作用。BDNF 的作用被抗 BDNF 抗体、MEK 抑制剂或 ABT-737 抑制，并且也被 IL-1β 抑制，表明线粒体作用是通过与神经保护相同的 MEK-Bcl-2 途径介导的。复合物 I 抑制剂鱼藤酮，一种与帕金森病病因有关的化合物，抑制了 BDNF 的体外线粒体和体内神经保护作用。BDNF 通过 MEK-Bcl-2 途径改变大脑代谢和氧气利用效率的能力可能是观察到这种神经营养因子的神经保护作用的一个重要组成部分。
