McCarren Hilary S, Arbutus Julia A, Ardinger Cherish, Dunn Emily N, Jackson Cecelia E, McDonough John H
USAMRICD, Medical Toxicology Research Division, Neuroscience Branch, 2900 Ricketts Point Rd, Aberdeen Proving Ground, MD 21010, United States.
USAMRICD, Medical Toxicology Research Division, Neuroscience Branch, 2900 Ricketts Point Rd, Aberdeen Proving Ground, MD 21010, United States.
Epilepsy Res. 2018 Mar;141:1-12. doi: 10.1016/j.eplepsyres.2018.01.010. Epub 2018 Jan 31.
Nerve agents are highly toxic chemicals that pose an imminent threat to soldiers and civilians alike. Nerve agent exposure leads to an increase in acetylcholine within the central nervous system, resulting in development of protracted seizures known as status epilepticus (SE). Currently, benzodiazepines are the standard of care for nerve agent-induced SE, but their efficacy quickly wanes as the time to treatment increases. Here, we examine the role of the α2-adrenoceptor in termination of nerve agent-induced SE using the highly specific agonist dexmedetomidine (DEX). Adult male rats were exposed to soman and entered SE as confirmed by electroencephalograph (EEG). We observed that administration of DEX in combination with the benzodiazepine midazolam (MDZ) 20 or 40 min after the onset of SE stopped seizures and returned processed EEG measurements to baseline levels. The protective effect of DEX was blocked by the α2-adrenoceptor antagonist atipamezole (ATI), but ATI failed to restore seizure activity after it was already halted by DEX in most cases, suggesting that α2-adrenoceptors may be involved in initiating SE cessation rather than merely suppressing seizure activity. Histologically, treatment with DEX + MDZ significantly reduced the number of dying neurons as measured by FluoroJade B in the amygdala, thalamus, and piriform cortex, but did not protect the hippocampus or parietal cortex even when SE was successfully halted. We conclude that DEX serves not just as a valuable potential addition to the anticonvulsant regimen for nerve agent exposure, but also as a tool for dissecting the neural circuitry that drives SE.
神经毒剂是剧毒化学品，对士兵和平民都构成迫在眉睫的威胁。接触神经毒剂会导致中枢神经系统内乙酰胆碱增加，从而引发被称为癫痫持续状态（SE）的持续性癫痫发作。目前，苯二氮䓬类药物是治疗神经毒剂所致SE的标准药物，但随着治疗时间的增加，其疗效会迅速减弱。在此，我们使用高特异性激动剂右美托咪定（DEX）来研究α2肾上腺素能受体在终止神经毒剂所致SE中的作用。成年雄性大鼠暴露于梭曼后，通过脑电图（EEG）确认进入SE状态。我们观察到，在SE发作后20或40分钟给予DEX联合苯二氮䓬类药物咪达唑仑（MDZ）可停止癫痫发作，并使处理后的EEG测量值恢复到基线水平。DEX的保护作用被α2肾上腺素能受体拮抗剂阿替美唑（ATI）阻断，但在大多数情况下，在DEX已经停止癫痫活动后，ATI未能恢复癫痫活动，这表明α2肾上腺素能受体可能参与启动SE的终止，而不仅仅是抑制癫痫活动。组织学上，用氟玉红B测量，DEX + MDZ治疗可显著减少杏仁核、丘脑和梨状皮质中死亡神经元的数量，但即使SE成功停止，也不能保护海马体或顶叶皮质。我们得出结论，DEX不仅是神经毒剂暴露抗惊厥方案中一种有价值的潜在补充药物，也是剖析驱动SE的神经回路的一种工具。
