Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Neurochem Res. 2011 Jan;36(1):67-75. doi: 10.1007/s11064-010-0264-6. Epub 2010 Sep 17.
Oxidative stress is one of the most important pathological mechanisms in neurodegenerative diseases and ischemia. Recent studies have indicated that the sonic hedgehog (SHH) signaling pathway is involved in these diseases, but the underlying mechanisms remains elusive. Here we report that the SHH pathway was activated in primary cultured cortical neurons after exposure to hydrogen peroxide (H₂O₂). H₂O₂ treatment decreased the cell viability of neurons, and inhibition of endogenous SHH signaling exacerbated its neurotoxicity. Activation of SHH signaling protected neurons from H₂O₂-induced apoptosis and increased the cell viability while those effects were partially reversed by blocking SHH signals. Exogenous SHH increased the activities of Superoxide dismutase (SOD) and Glutathione peroxidase (GSH-PX) in H₂O₂-treated neurons and decreased production of Malondialdehyde (MDA). It also promoted expression of the anti-apoptotic gene Bcl-2 and inhibited expression of pro-apoptotic gene Bax. Activation of SHH signals upregulated both Neurotrophic factors vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF). Pretreatment with SHH inhibited the activation of ERK (extracellular signal-regulated kinases) signals induced by H₂O₂. Our findings demonstrate that activation of SHH signaling protects cortical neurons against oxidative stress and suggest a potential role of SHH for the clinic treatments of brain ischemia and neurodegenerative disorders.
氧化应激是神经退行性疾病和缺血性疾病的最重要病理机制之一。最近的研究表明，刺猬信号通路（SHH）参与了这些疾病，但潜在的机制仍不清楚。在这里，我们报告在过氧化氢（H₂O₂）暴露后，原代培养的皮质神经元中 SHH 信号通路被激活。H₂O₂处理降低了神经元的细胞活力，而内源性 SHH 信号的抑制加剧了其神经毒性。SHH 信号的激活保护神经元免受 H₂O₂诱导的凋亡并增加细胞活力，而阻断 SHH 信号部分逆转了这些作用。外源性 SHH 增加了 H₂O₂处理神经元中超氧化物歧化酶（SOD）和谷胱甘肽过氧化物酶（GSH-PX）的活性，减少了丙二醛（MDA）的产生。它还促进了抗凋亡基因 Bcl-2 的表达，并抑制了促凋亡基因 Bax 的表达。SHH 信号的激活上调了神经营养因子血管内皮生长因子（VEGF）和脑源性神经营养因子（BDNF）的表达。SHH 的预处理抑制了 H₂O₂诱导的细胞外信号调节激酶（ERK）信号的激活。我们的研究结果表明，SHH 信号的激活可保护皮质神经元免受氧化应激，表明 SHH 在治疗脑缺血和神经退行性疾病方面具有潜在作用。
