Curcumin attenuates glutamate-induced HT22 cell death by suppressing MAP kinase signaling
Curcumin attenuates glutamate-induced HT22 cell death by suppressing MAP kinase signaling
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DOI：
10.1007/s11010-006-9365-6
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发表时间：
2007-04-01
影响因子：
4.3
通讯作者：
Kwon, Ki-Sun
中科院分区：
文献类型：
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作者：
Suh, Hyun-Woo;Kang, Seongman;Kwon, Ki-Sun
在小鼠海马细胞系HT 22中，谷氨酸通过扰乱细胞氧化还原稳态诱导细胞死亡，称为氧化谷氨酸毒性。细胞外信号调节激酶（ERK）1/2是该过程中已知的关键参与者。在这里，我们表征了MAP激酶和细胞周期调节剂在介导氧化谷氨酸毒性和姜黄素在HT 22细胞中的神经保护机制中的作用。c-Jun N-末端激酶（INK）和p38激酶在谷氨酸诱导的HT 22细胞死亡期间被激活，但在比ERK激活更晚的阶段。用JNK抑制剂SP 600125或p38激酶抑制剂S13203580处理，部分减弱了这种细胞死亡。姜黄素是JNK信号传导的天然抑制剂，在纳摩尔浓度下比SP 600125更有效地保护HT 22细胞免受谷氨酸诱导的死亡。这些剂量的姜黄素既不影响细胞内谷胱甘肽的水平，也不影响活性氧的水平，但显著灭活JNK和p38。此外，姜黄素显着上调细胞周期抑制蛋白，p21 cip 1，下调细胞周期蛋白DI水平，这可能有助于细胞死亡的预防。我们的研究结果表明，姜黄素具有神经保护作用，对氧化谷氨酸毒性抑制MAP激酶信号和影响细胞周期调节。
Glutamate induces cell death by upsetting the cellular redox homeostasis, termed oxidative glutamate toxicity, in a mouse hippocampal cell line, HT22. Extracellular signal-regulated kinases (ERK) 1/2 are known key players in this process. Here we characterized the roles of both MAP kinases and cell cycle regulators in mediating oxidative glutamate toxicity and the neuroprotective mechanisms of curcumin in HT22 cells. c-Jun N-terminal kinase (INK) and p38 kinase were activated during the glutamate-induced HT22 cell death, but at a later stage than ERK activation. Treatment with a JNK inhibitor, SP600125, or a p38 kinase inhibitor, S13203580, partly attenuated this cell death. Curcumin, a natural inhibitor of JNK signaling, protected the HT22 cells from glutamate-induced death at nanomolar concentrations more efficiently than SP600125. These doses of curcumin affected neither the level of intracellular glutathione nor the level of reactive oxygen species, but inactivated JNK and p38 significantly. Moreover, curcumin markedly upregulated a cell-cycle inhibitory protein, p21cip1, and downregulated cyclin DI levels, which might help the cell death prevention. Our results suggest that curcumin has a neuroprotective effect against oxidative glutamate toxicity by inhibiting MAP kinase signaling and influencing cell-cycle regulation.