Department of Pharmacology, Toxicology and Therapeutic Chemistry, Pharmacology Section and Institute of Biomedicine (IBUB), Faculty of Pharmacy, University of Barcelona, 08028 Barcelona, Spain.
Department of Analytical Chemistry and Applied (Chromatography Section), School of Engineering, Institut Químic de Sarrià-Universitat Ramon Llull, 08017 Barcelona, Spain.
Int J Mol Sci. 2024 Nov 14;25(22):12248. doi: 10.3390/ijms252212248.
The secondary neurotoxicity induced by severe organophosphorus (OP) poisoning, including paraoxon (POX), is associated with cognitive impairments in survivors, who, despite receiving appropriate emergency treatments, may still experience lasting neurological deficits. Thus, the present study provides a survival mouse model of acute and severe POX poisoning to examine secondary neurotoxicity. Swiss CD-1 male mice were injected with POX (4 mg/kg, s.c.) followed by atropine (4 mg/kg, i.p.), pralidoxime (2-PAM; Pyridine-2-aldoxime methochloride) (25 mg/kg, i.p., twice, 1 h apart) and diazepam (5 mg/kg, i.p.), resulting in a survival rate >90% and Racine score of 5-6. Our results demonstrated that the model showed increased lipid peroxidation, downregulation of antioxidant enzymes and astrogliosis in the mouse hippocampus (HP) and prefrontal cortex (PFC), brain areas involved in cognitive functions. Moreover, dopamine (DA) levels were reduced in the hp, but increased in the PFC. Furthermore, the survival mouse model of acute POX intoxication did not exhibit phenotypic manifestations of depression, anxiety or motor incoordination. However, our results demonstrated long-term recognition memory impairments, which are in accordance with the molecular and neurochemical effects observed. In conclusion, this mouse model can aid in researching POX exposure's effects on memory and developing potential countermeasures against the secondary neurotoxicity induced by severe OP poisoning.
严重有机磷（OP）中毒引起的继发性神经毒性，包括对氧磷（POX），与幸存者的认知障碍有关，尽管接受了适当的紧急治疗，但幸存者仍可能出现持久的神经缺陷。因此，本研究提供了一种急性和严重 POX 中毒的存活小鼠模型，以研究继发性神经毒性。将瑞士 CD-1 雄性小鼠皮下注射 POX（4 mg/kg），然后腹腔注射阿托品（4 mg/kg）、氯解磷定（2-PAM；吡啶-2-醛肟甲氯化物）（25 mg/kg，两次，间隔 1 小时）和地西泮（5 mg/kg），结果存活率>90%，Racine 评分为 5-6。我们的结果表明，该模型在小鼠海马体（HP）和前额叶皮层（PFC）中表现出脂质过氧化增加、抗氧化酶下调和星形胶质细胞增生，这些区域与认知功能有关。此外，DA 水平在 hp 中降低，但在 PFC 中增加。此外，急性 POX 中毒的存活小鼠模型没有表现出抑郁、焦虑或运动不协调的表型表现。然而，我们的结果表明存在长期的识别记忆障碍，这与观察到的分子和神经化学效应一致。总之，该小鼠模型有助于研究 POX 暴露对记忆的影响，并开发针对严重 OP 中毒引起的继发性神经毒性的潜在对策。
