Involvement of BDNF/ERK signaling in spontaneous recovery from trimethyltin-induced hippocampal neurotoxicity in mice.
Involvement of BDNF/ERK signaling in spontaneous recovery from trimethyltin-induced hippocampal neurotoxicity in mice.
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DOI：
10.1016/j.brainresbull.2016.01.002
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发表时间：
2016-03
影响因子：
3.8
通讯作者：
Moon C
中科院分区：
文献类型：
--
作者：
Lee S;Yang M;Kim J;Son Y;Kim J;Kang S;Ahn W;Kim SH;Kim JC;Shin T;Wang H;Moon C
三甲基锡（Trimethyltin，TMT）毒性可引起小鼠海马组织病理学损伤，诱发癫痫发作。随着时间的推移，病变和症状自发恢复;然而，对TMT毒性恢复的确切机制知之甚少。我们研究了脑源性神经营养因子/细胞外信号调节激酶（BDNF/ERK）信号通路的变化，在小鼠海马TMT中毒。小鼠（7周龄，C57 BL/6）给予TMT（2.6 mg/kg，腹腔注射）表现出急性和严重的神经变性，海马齿状回（DG）中TUNEL阳性细胞增加。TMT处理后海马BDNF的mRNA和蛋白水平升高。免疫组化分析显示，TMT处理后1-4 d，海马磷酸化ERK 1/2表达显著增加，而苔藓纤维ERK免疫反应强度在处理后1-8 d下降。此外，ERK免疫阳性细胞主要位于DG的doublecortin阳性的未成熟祖神经元中。在原代培养的未成熟海马神经元（体外培养4天）中，BDNF治疗通过激活ERK信号通路减轻了TMT诱导的神经毒性。因此，我们认为BDNF/ERK信号通路可能与未成熟前体神经元的细胞分化和存活有关，并最终导致TMT诱导的海马神经元变性的自发恢复。
Trimethyltin (TMT) toxicity causes histopathological damage in the hippocampus and induces seizure behaviors in mice. The lesions and symptoms recover spontaneously over time; however, little is known about the precise mechanisms underlying this recovery from TMT toxicity. We investigated changes in the brain-derived neurotrophic factor/extracellular signal-regulated kinases (BDNF/ERK) signaling pathways in the mouse hippocampus following TMT toxicity. Mice (7 weeks old, C57BL/6) administered TMT (2.6 mg/kg intraperitoneally) showed acute and severe neurodegeneration with increased TUNEL-positive cells in the dentate gyrus (DG) of the hippocampus. The mRNA and protein levels of BDNF in the hippocampus were elevated by TMT treatment. Immunohistochemical analysis showed that TMT treatment markedly increased phosphorylated ERK1/2 expression in the mouse hippocampus 1-4 days after TMT treatment, although the intensity of ERK immunoreactivity in mossy fiber decreased at 1-8 days post-treatment. In addition, ERK-immunopositive cells were localized predominantly in doublecortin-positive immature progenitor neurons in the DG. In primary cultured immature hippocampal neurons (4 days in vitro), BDNF treatment alleviated TMT-induced neurotoxicity, via activation of the ERK signaling pathway. Thus, we suggest that BDNF/ERK signaling pathways may be associated with cell differentiation and survival of immature progenitor neurons, and will eventually lead to spontaneous recovery in TMT-induced hippocampal neurodegeneration.