Andrew Peter M, Feng Wei, Calsbeek Jonas J, Antrobus Shane P, Cherednychenko Gennady A, MacMahon Jeremy A, Bernardino Pedro N, Liu Xiuzhen, Harvey Danielle J, Lein Pamela J, Pessah Isaac N
Department of Molecular Biosciences, UC Davis School of Veterinary Medicine, Davis, CA 95616, USA.
Department of Public Health Sciences, UC Davis School of Medicine, Davis, CA 95616, USA.
Toxics. 2024 Mar 31;12(4):263. doi: 10.3390/toxics12040263.
Acute intoxication with organophosphorus (OP) cholinesterase inhibitors can produce seizures that rapidly progress to life-threatening status epilepticus. Significant research effort has been focused on investigating the involvement of muscarinic acetylcholine receptors (mAChRs) in OP-induced seizure activity. In contrast, there has been far less attention on nicotinic AChRs (nAChRs) in this context. Here, we address this data gap using a combination of in vitro and in vivo models. Pharmacological antagonism and genetic deletion of α4, but not α7, nAChR subunits prevented or significantly attenuated OP-induced electrical spike activity in acute hippocampal slices and seizure activity in mice, indicating that α4 nAChR activation is necessary for neuronal hyperexcitability triggered by acute OP exposures. These findings not only suggest that therapeutic strategies for inhibiting the α4 nAChR subunit warrant further investigation as prophylactic and immediate treatments for acute OP-induced seizures, but also provide mechanistic insight into the role of the nicotinic cholinergic system in seizure generation.
有机磷（OP）胆碱酯酶抑制剂急性中毒可引发癫痫发作，并迅速发展为危及生命的癫痫持续状态。大量研究致力于探究毒蕈碱型乙酰胆碱受体（mAChRs）在OP诱导的癫痫活动中的作用。相比之下，在这种情况下，对烟碱型乙酰胆碱受体（nAChRs）的关注要少得多。在此，我们结合体外和体内模型来填补这一数据空白。药理学拮抗作用以及α4而非α7烟碱型乙酰胆碱受体亚基的基因缺失，可预防或显著减轻急性海马切片中OP诱导的电尖峰活动以及小鼠的癫痫发作活动，这表明α4烟碱型乙酰胆碱受体的激活是急性OP暴露引发神经元过度兴奋所必需的。这些发现不仅表明，抑制α4烟碱型乙酰胆碱受体亚基的治疗策略作为急性OP诱导癫痫发作的预防性和即时治疗方法值得进一步研究，还为烟碱能胆碱能系统在癫痫发作产生中的作用提供了机制性见解。
