<br>1,2-二氯乙烷通过干扰 GABA 代谢和抑制 cAMP-PKA-CREB 信号通路引起小鼠焦虑和认知功能障碍,Ecotoxicology and Environmental Safety

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1,2-二氯乙烷通过干扰 GABA 代谢和抑制 cAMP-PKA-CREB 信号通路引起小鼠焦虑和认知功能障碍
Ecotoxicology and Environmental Safety ( IF 6.2 ) Pub Date : 2024-05-17 , DOI: 10.1016/j.ecoenv.2024.116464
Yuchen Qin ₁ , Weiyu Huang ₁ , Zijiang Wang ₂ , Chunting Wang ₁ , Chen Wang ₁ , Meng Zhang ₁ , Shengting Wu ₁ , Gaoyang Wang ₁ , Fenghong Zhao ₁

Affiliation

1,2-二氯乙烷（1,2-DCE）是一种毒性很强的神经毒素，是一种常见的环境污染物。研究表明，长期接触 1,2-DCE 会导致不良反应。然而，确切的机制仍然未知。在这项研究中，行为结果显示 1,2-DCE 长期暴露会导致小鼠焦虑和学习和记忆能力受损。小鼠前额叶皮层中 γ-氨基丁酸（GABA）和谷氨酰胺（Gln）的含量降低，而谷氨酸（Glu）的含量增加。随着剂量的增加，谷氨酸脱羧酶（GAD）活性降低，GABA 转氨酶（GABA-T）活性增加。GABA转运蛋白-3（GAT-3）、囊泡GABA转运蛋白（VGAT）、GABA A受体α2（GABAARα2）、GABAARγ2、K-Cl协同转运蛋白亚型2（KCC2）、GABA B受体1（GABABR1）、GABABR2、蛋白激酶A（PKA）、cAMP反应元件结合蛋白（CREB）、p-CREB、脑源性神经营养因子（BDNF）、c-fos、c-Jun以及谷氨酸脱氢酶（GDH）和PKA-C蛋白的蛋白和mRNA表达降低，而 GABA 转运蛋白-1 （GAT-1）和 Na-K-2Cl 协同转运蛋白亚型 1 （NKCC1）的表达水平升高。然而，琥珀酸半醛脱氢酶（SSADH）的蛋白质含量没有显着变化。腺苷酸环化酶（AC）和环磷酸腺苷（cAMP）含量的表达也降低。总之，本研究结果表明，暴露于 1,2-DCE 可导致小鼠焦虑和认知障碍，这可能与 GABA 代谢及其受体以及 cAMP-PKA-CREB 通路的紊乱有关。

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1,2-Dichloroethane causes anxiety and cognitive dysfunction in mice by disturbing GABA metabolism and inhibiting the cAMP-PKA-CREB signaling pathway

1,2-Dichloroethane (1,2-DCE) is a powerfully toxic neurotoxin, which is a common environmental pollutant. Studies have indicated that 1,2-DCE long-term exposure can result in adverse effects. Nevertheless, the precise mechanism remains unknown. In this study, behavioral results revealed that 1,2-DCE long-term exposure could cause anxiety and learning and memory ability impairment in mice. The contents of γ-aminobutyric acid (GABA) and glutamine (Gln) in mice’s prefrontal cortex decreased, whereas that of glutamate (Glu) increased. With the increase in dose, the activities of glutamate decarboxylase (GAD) decreased and those of GABA transaminase (GABA-T) increased. The protein and mRNA expressions of GABA transporter-3 (GAT-3), vesicular GABA transporter (VGAT), GABA A receptor α2 (GABAARα2), GABAARγ2, K-Cl cotransporter isoform 2 (KCC2), GABA B receptor 1 (GABABR1), GABABR2, protein kinase A (PKA), cAMP-response element binding protein (CREB), p-CREB, brain-derived neurotrophic factor (BDNF), c-fos, c-Jun and the protein of glutamate dehydrogenase (GDH) and PKA-C were decreased, while the expression levels of GABA transporter-1 (GAT-1) and Na-K-2Cl cotransporter isoform 1 (NKCC1) were increased. However, there was no significant change in the protein content of succinic semialdehyde dehydrogenase (SSADH). The expressions of adenylate cyclase (AC) and cyclic adenosine monophosphate (cAMP) contents were also reduced. In conclusion, the results of this study show that exposure to 1,2-DCE could lead to anxiety and cognitive impairment in mice, which may be related to the disturbance of GABA metabolism and its receptors along with the cAMP-PKA-CREB pathway.

更新日期：2024-05-17

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