Endogenous and Exogenous Glucocorticoids Prevent Trimethyltin From Causing Neuronal Degeneration of the Mouse Brain In Vivo: Involvement of Oxidative Stress Pathways
Endogenous and Exogenous Glucocorticoids Prevent Trimethyltin From Causing Neuronal Degeneration of the Mouse Brain In Vivo: Involvement of Oxidative Stress Pathways
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DOI：
10.1254/jphs.09107fp
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发表时间：
2009-08-01
影响因子：
3.5
通讯作者：
Ogita, Kiyokazu
中科院分区：
文献类型：
--
作者：
Shuto, Makoto;Higuchi, Kei;Ogita, Kiyokazu
已知有机锡三甲基锡（TMT）引起小鼠脑中的神经元变性。早期的研究表明，TMT诱导的神经元变性增强肾上腺切除术。然而，没有评估已试图确定的机制，增强TMT神经毒性肾上腺切除术及其影响神经元变性。为了评估肾上腺切除引起的TMT神经毒性增强的影响并确定其机制，我们研究了肾上腺切除小鼠的神经元变性和相关信号通路。肾上腺切除术显著增强了TMT诱导的某些脑区神经元损伤，包括齿状回，嗅球和前嗅核，除了加剧行为异常。TMT诱导的caspase-3和calpain的激活也增强肾上腺切除术。地塞米松治疗几乎完全预防了TMT引起的上述事件。除上述事件外，肾上腺切除术明显增强了TMT治疗后齿状回中c-Jun-N-末端激酶的激活和4-羟基壬烯醛的形成。米非司酮（一种糖皮质激素受体拮抗剂）可加重TMT诱导的齿状核颗粒细胞损伤。总之，我们的数据表明，内源性和外源性糖皮质激素通过减弱强烈的氧化应激和相关的信号通路来预防TMT诱导的中枢神经系统神经变性。
The organotin trimethyltin (TMT) is known to cause neuronal degeneration in the murine brain. Earlier studies indicate that TMT-induced neuronal degeneration is enhanced by adrenalectomy. However, no evaluation has been attempted to determine the mechanism underlying the enhancement of TMT neurotoxicity by adrenalectomy and its implications in neuronal degeneration. To assess the implications and determine the mechanism of adrenalectomy-elicited enhancement of TMT neurotoxicity, we examined neuronal degeneration and associated signaling pathways in adrenalectomized mice. Adrenalectomy dramatically enhanced the TMT-induced neuronal damage in certain brain regions including the dentate gyrus, olfactory bulb, and anterior olfactory nucleus, in addition to exacerbating the behavioral abnormalities. TMT-induced activation of caspase-3 and calpain was also enhanced by adrenalectomy. The above events elicited by TMT were almost entirely prevented by treatment with dexamethasone. In addition to the above events, adrenalectomy clearly enhanced the activation of c-Jun-N-terminal kinases and the formation of 4-hydroxynonenal in the dentate gyrus following TMT treatment. The dentate granule cell damage induced by TMT was exacerbated by mifepristone, a glucocorticoid-receptor antagonist. Taken together, our data suggest that endogenous and exogenous glucocorticoids prevent neurodegeneration induced by TMT in the central nervous system by attenuating intensive oxidative stress and associated signaling pathways.