Andersson H, Wetmore C, Lindqvist E, Luthman J, Olson L
Department of Neuroscience, Karolinska Institute, Stockholm, Sweden.
Neurotoxicology. 1997;18(1):147-59.
Trimethyltin chloride (TMT) treatment in adult rats leads to limbic brain lesions that are detectable with classical neuropathological techniques 3 days after exposure. In particular, the hippocampal cells of the CA3c region are affected. The temporal and regional characteristics of TMT toxicity as reflected in changes of activity-dependent factors were studied in adult male Sprague-Dawley rats using quantitative in situ hybridization and immunohistochemistry. No significant alterations in the BDNF mRNA were detected in hippocampus and cerebral cortex 1 and 4 h after 8 mg TMT/kg. Three days after TMT, a significant increase in BDNF mRNA was detected in CA1, and increases in BDNF mRNA were also seen in cortical layers. An increase in BDNF hybridization signal was seen over scattered neurons within and outside CA3c at 3 days. Four h after 8 mg TMT/kg, BDNF immunoreactivity was reduced in the pyramidal cells of the CA3c and CA1 regions as well as in the dentate gyrus. No significant change in BDNF immunoreactivity was seen in hippocampus or cerebral cortex 3 days after TMT. BDNF interacts with the high-affinity receptor tyrosine kinase B (trkB). No immediate alteration in trkB mRNA was seen in hippocampus or cerebral cortex after 8 mg TMT/kg, while at 3 days trkB mRNA was significantly reduced in the CA3c pyramidal cell layer. No changes could be detected in neurotrophin-3 mRNA at either 1, 4 h or 3 days after TMT. Three days after 8 mg TMT/kg, a major induction of hsp70 mRNA occurred in a subset of neurons in the CA3c region, concomitant with an increased expression of c-fos mRNA as well as Fos protein in the hilar region of hippocampus. Hence, an early and transient decrease in BDNF appears to occur after TMT exposure, which is succeeded at 3 days by increases in BDNF, c-fos and hsp 70 mRNAs, concomitant with a decrease in trkB mRNA in regions known to be vulnerable to TMT. These results demonstrate that TMT causes a delayed, spatially restricted increase in activity-dependent gene expression, making TMT-induced disturbances an interesting model of neurodegenerative events.
成年大鼠经三甲基氯化锡（TMT）处理后，会导致边缘脑区损伤，在暴露后3天可通过经典神经病理学技术检测到。特别是，CA3c区的海马细胞会受到影响。使用定量原位杂交和免疫组织化学方法，在成年雄性Sprague-Dawley大鼠中研究了TMT毒性在时间和区域上的特征，这些特征反映在活性依赖因子的变化中。8mg TMT/kg处理后1小时和4小时，海马和大脑皮层中未检测到脑源性神经营养因子（BDNF）mRNA的显著变化。TMT处理3天后，CA1区BDNF mRNA显著增加，皮层各层中BDNF mRNA也增加。3天时，在CA3c内外的散在神经元上可见BDNF杂交信号增加。8mg TMT/kg处理后4小时，CA3c和CA1区的锥体细胞以及齿状回中的BDNF免疫反应性降低。TMT处理3天后，海马或大脑皮层中BDNF免疫反应性未见显著变化。BDNF与高亲和力受体酪氨酸激酶B（trkB）相互作用。8mg TMT/kg处理后，海马或大脑皮层中trkB mRNA未见立即改变，而3天时CA3c锥体细胞层中trkB mRNA显著降低。TMT处理后1小时、4小时或3天，神经营养因子-3 mRNA均未检测到变化。8mg TMT/kg处理3天后，CA3c区的一部分神经元中hsp70 mRNA大量诱导，同时海马门区c-fos mRNA以及Fos蛋白表达增加。因此，TMT暴露后似乎会出现BDNF早期短暂下降，3天时BDNF、c-fos和hsp 70 mRNA增加，同时已知易受TMT影响的区域中trkB mRNA减少。这些结果表明，TMT导致活性依赖基因表达出现延迟的、空间受限的增加，使TMT诱导的干扰成为神经退行性事件的一个有趣模型。
