Inhibition of RhoA/ROCK signalling pathway activity improves neural damage and cognitive deficits in the fluorosis model.
Inhibition of RhoA/ROCK signalling pathway activity improves neural damage and cognitive deficits in the fluorosis model.
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DOI：
10.1016/j.ecoenv.2023.115554
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发表时间：
2023-10
影响因子：
6.8
通讯作者：
Lingli Chen;H. Ning;Penghuan Jia;Hongli Zhang;Liu Yuye;Wang Rui;Ren Fei;Zhihong Yin;
中科院分区：
文献类型：
--
作者：
Lingli Chen;H. Ning;Penghuan Jia;Hongli Zhang;Liu Yuye;Wang Rui;Ren Fei;Zhihong Yin;
过量摄入氟化物对人类和动物构成健康风险。许多研究表明，氟暴露可损伤细胞骨架和突触，对人类和动物的智力发育产生负面影响。我们以前的研究表明，RhoA/ROCK信号通路被NaF暴露激活HT-22细胞，并在细胞骨架组装和突触发生中起着至关重要的作用。然而，氟诱导的RhoA/ROCK介导的细胞骨架损伤的机制尚不清楚。本研究采用Neuro-2A细胞和ICR小鼠研究RhoA/ROCK激活抑制对NaF诱导的突触功能障碍和认知障碍的影响。检测GAP、RhoA、ROCK 1/2和（p）-MLC在体内和体外模型中的表达。结果表明，NaF暴露激活了RhoA/ROCK/MLC信号通路。我们检测了RhoA/ROCK抑制剂对NaF所致的突触损伤和智能障碍的影响。在体外，Y-27632抑制激活的RhoA/ROCK，减轻NaF所致的形态学和超微结构损伤，降低存活率和突触功能蛋白表达。在体内，结果显示法舒地尔抑制RhoA/ROCK/MLC通路，改善海马病理损伤，认知功能障碍和NaF诱导的神经功能蛋白表达减少。总之，这些结果表明，法舒地尔和Y-27632可以逆转氟暴露引起的神经毒性。此外，RhoA/ROCK的抑制可能是CNS损伤的未来治疗方法，需要对其他神经退行性疾病模型进行更详细的研究以确认其有效性。
Excessive fluoride intake poses health risks to humans and animals. Many studies have indicated that fluoride exposure can damage the cytoskeleton and synapses, which has negative effects on the intellectual development of humans and animals. Our previous study suggested that the RhoA/ROCK signalling pathway is activated by NaF exposure in HT-22 cells and plays a vital role in cytoskeletal assembly and synaptogenesis. However, the mechanism underlying RhoA/ROCK-mediated cytoskeletal injury induced by fluoride remains unclear. In this study, Neuro-2A cells and ICR mice were used to investigate the effects of RhoA/ROCK activation inhibition on NaF-induced synaptic dysfunction and cognitive impairment. We detected the expression of GAP, RhoA, ROCK1/2, and (p)-MLCin vivoandin vitro model. The results showed that NaF exposure activated the RhoA/ROCK/MLC signalling pathway. We measured the effects of RhoA/ROCK inhibition on synaptic injury and intellectual impairment induced by NaF exposure.In vitro, Y-27632 suppressed activated RhoA/ROCK, attenuated morphological and ultrastructural damage, and decreased the survival rate and synapse-functional protein expression caused by NaF.In vivo, the results showed that the RhoA/ROCK/MLC pathway was inhibited by fasudil and improved pathological damage in the hippocampus, cognitive impairment, and decreased expression of neurofunctional proteins induced by NaF. Overall, these results suggest that fasudil and Y-27632 can reverse neurotoxicity caused by fluoride exposure. Furthermore, inhibition of RhoA/ROCK may be a future treatment for CNS injury, and more detailed studies on other neurodegenerative disease models are required to confirm its effectiveness.