Department of Applied Biology and Chemical Technology, Institute of Modern Medicine, The Hong Kong Polytechnic University, Hong Kong.
Neurochem Int. 2011 Nov;59(6):945-53. doi: 10.1016/j.neuint.2011.07.005. Epub 2011 Jul 12.
Vascular endothelial growth factor (VEGF), a specific pro-angiogenic peptide, has shown neuroprotective effects in the Parkinson's disease (PD) models, but the underlying mechanisms remain elusive. In this study, the neuroprotective properties of VEGF on 1-methyl-4-phenylpyridinium ion (MPP(+))-induced neurotoxicity in primary cerebellar granule neurons were investigated. Pretreatment of VEGF prevented MPP(+)-induced neuronal apoptosis in a concentration- and time-dependent manner. And this prevention was blocked by PTK787/ZK222584, a VEGF receptor-2 specific inhibitor. Both inhibition of the Akt pathway and activation of the extracellular signal-regulated kinase (ERK) pathway contribute to MPP(+)-induced neuronal apoptosis. VEGF reversed the inhibition of phosphoinositide 3-kinase (PI3-K)/Akt pathway caused by MPP(+), but further enhanced the activation of ERK induced by MPP(+). Interestingly, VEGF and PD98059 (an ERK kinase inhibitor) play a synergistic role in protecting neurons from MPP(+)-induced toxicity. Collectively, these findings suggest that the PI3-K/Akt and ERK pathways activated by VEGF play opposite roles in MPP(+)-induced neuronal apoptosis. This finding offers not only a new and clinically significant modality as to how VEGF exerts its neuroprotective effects but also a novel therapeutic strategy for PD by differentially regulating PD-associated signaling pathways.
血管内皮生长因子 (VEGF) 是一种特异性促血管生成肽，已在帕金森病 (PD) 模型中显示出神经保护作用，但潜在机制仍不清楚。在这项研究中，研究了 VEGF 对原代小脑颗粒神经元中 1-甲基-4-苯基吡啶离子 (MPP(+)) 诱导的神经毒性的神经保护特性。VEGF 的预处理以浓度和时间依赖的方式防止 MPP(+)-诱导的神经元凋亡。这种预防作用被 VEGF 受体-2 特异性抑制剂 PTK787/ZK222584 阻断。Akt 通路的抑制和细胞外信号调节激酶 (ERK) 通路的激活均有助于 MPP(+)-诱导的神经元凋亡。VEGF 逆转了 MPP(+）引起的磷酸肌醇 3-激酶 (PI3-K)/Akt 通路的抑制，但进一步增强了 MPP(+)诱导的 ERK 激活。有趣的是，VEGF 和 PD98059（ERK 激酶抑制剂）在保护神经元免受 MPP(+)-诱导的毒性方面发挥协同作用。总之，这些发现表明 VEGF 激活的 PI3-K/Akt 和 ERK 通路在 MPP(+)-诱导的神经元凋亡中发挥相反的作用。这一发现不仅为 VEGF 发挥其神经保护作用的机制提供了新的临床意义，而且为通过差异调节与 PD 相关的信号通路为 PD 提供了新的治疗策略。
