Apoptosis induced by domoic acid in mouse cerebellar granule neurons involves activation of p38 and JNK MAP kinases
Apoptosis induced by domoic acid in mouse cerebellar granule neurons involves activation of p38 and JNK MAP kinases
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DOI：
10.1016/j.neuint.2007.11.004
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发表时间：
2008-05-01
影响因子：
4.2
通讯作者：
Costa, L. G.
中科院分区：
文献类型：
--
作者：
Giordano, G.;Klintworth, H. M.;Costa, L. G.
在小鼠小脑颗粒神经元（CGNs）中，海洋神经毒素软骨藻酸（DomA）根据其浓度的不同，以凋亡或坏死的方式诱导神经元细胞死亡，并以凋亡损伤为主。对低浓度（100 nM）的反应。doma诱导的细胞凋亡是由于AMPA/kainate受体的选择性激活，并由doma诱导的氧化应激介导，导致线粒体功能障碍和caspase-3的激活。p38 MAP激酶和c-Jun nh2末端蛋白激酶（JNK）被氧化应激优先激活。在这里，我们报道了DomA增加p38 MAP激酶和INK磷酸化，并且这种作用在Gclm（-/-）小鼠的cgn中更为明显，Gclm（-/-）小鼠缺乏谷氨酸-半胱氨酸连接酶修饰亚基，谷胱甘肽（GSH）水平非常低，并且对DomA诱导的凋亡比野生型小鼠的cgn更敏感。JNK和p38激酶磷酸化的增加与Erk 1/2磷酸化的降低是平行的。AMPA/kainate受体拮抗剂NBQX，而不是NMDA受体拮抗剂MK-801，可以阻止doma诱导的p38和JNK激酶的激活。几种抗氧化剂（谷胱甘肽乙酯、过氧化氢酶和苯基丁基硝基酮）也能阻止doma诱导的JNK和p38 MAP激酶的磷酸化。p38 （SB203580）和JNK （SP600125）抑制剂可拮抗doma诱导的细胞凋亡。这些结果表明氧化应激激活的JNK和p38 MAP激酶通路在doma诱导的CGNs凋亡中的重要性。(C) 2007 Elsevier Ltd.版权所有。
In mouse cerebellar granule neurons (CGNs) the marine neurotoxin domoic acid (DomA) induces neuronal cell death, either by apoptosis or by necrosis, depending on its concentration, with apoptotic damage predominating in. response to low concentrations (100 nM). DomA-induced apoptosis is due to selective activation of AMPA/kainate receptors, and is mediated by DomA-induced oxidative stress, leading to mitochondrial dysfunction and activation of caspase-3. The p38 MAP kinase and the c-Jun NH2-terminal protein kinase (JNK) have been shown to be preferentially activated by oxidative stress. Here we report that DomA increases p38 MAP kinase and INK phosphorylation, and that this effect is more pronounced in CGNs from Gclm (-/-) mice, which lack the modifier subunit of glutamate-cysteine ligase, have very low glutathione (GSH) levels, and are more sensitive to DomA-induced apoptosis than CGNs from wild-type mice. The increased phosphorylation of JNK and p38 kinase was paralleled by a decreased phosphorylation of Erk 1/2. The AMPA/kainate receptor antagonist NBQX, but not the NMDA receptor antagonist MK-801, prevents DomA-induced activation of p38 and JNK, kinases. Several antioxidants (GSH ethyl ester, catalase and phenylbutylnitrone) also prevent DomA-induced phosphorylation of JNK and p38 MAP kinases. Inhibitors of p38 (SB203580) and of JNK (SP600125) antagonize DomA-induced apoptosis. These results indicate the importance of oxidative stress-activated JNK and p38 MAP kinase pathways in DomA-induced apoptosis in CGNs. (C) 2007 Elsevier Ltd. All rights reserved.