NGF-Dependent Activation of TrkA Pathway: A Mechanism for the Neuroprotective Effect of Troxerutin in D-Galactose-Treated Mice
NGF-Dependent Activation of TrkA Pathway: A Mechanism for the Neuroprotective Effect of Troxerutin in D-Galactose-Treated Mice
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DOI：
10.1111/j.1750-3639.2010.00397.x
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发表时间：
2010-09-01
期刊：
影响因子：
6.4
通讯作者：
Wang, Yong-jian
中科院分区：
文献类型：
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作者：
Lu, Jun;Wu, Dong-mei;Wang, Yong-jian
D-半乳糖(D-Gal)处理的认知障碍小鼠已被用于神经毒性研究和抗神经毒性药理研究。在这项研究中，我们研究了曲克芦丁的神经保护作用的机制。结果表明，曲克芦丁可通过提高铜锌超氧化物歧化酶活性和降低活性氧水平来改善D-半乳糖处理小鼠的行为表现。此外，我们的结果显示，曲克芦丁显著促进神经生长因子(NGF)的mRNA表达，从而导致TrkA激活。一方面，NGF/TrkA诱导Akt和ERK1/2的激活，导致神经元存活；另一方面，NGF/TrkA介导CaMKII和CREB的磷酸化，增加PSD95的表达，从而改善认知功能。然而，TrkA的拮抗剂K252a可阻断曲克芦丁的神经保护作用。K252a或曲克芦丁单独治疗的小鼠未观察到神经毒性。总之，给注射D-半乳糖的小鼠注射曲克芦丁可以通过激活NGF/TrkA信号通路来减轻认知障碍和大脑氧化应激。
D-galactose-(D-gal)-treated mouse, with cognitive impairment, has been used for neurotoxicity investigation and anti-neurotoxicity pharmacology research. In this study, we investigated the mechanism underlying the neuroprotective effect of troxerutin. The results showed that troxerutin improved behavioral performance in D-gal-treated mice by elevating Cu, Zn-superoxide dismutases (Cu, Zn-SOD) activity and decreasing reactive oxygen species levels. Furthermore, our results showed that troxerutin significantly promoted nerve growth factor (NGF) mRNA expression which resulted in TrkA activation. On one hand, NGF/TrkA induced activation of Akt and ERK1/2, which led to neuronal survival; on the other hand, NGF/TrkA mediated CaMKII and CREB phosphorylation and increased PSD95 expression, which improved cognitive performance. However, the neuroprotective effect of troxerutin was blocked by treatment with K252a, an antagonist for TrkA. No neurotoxicity was observed in mice treated with K252a or troxerutin alone. In conclusion, administration of troxerutin to D-gal-injected mice attenuated cognitive impairment and brain oxidative stress through the activation of NGF/TrkA signaling pathway.