Neuroscience Department, Medical Toxicology Research Division, U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD, 21010-5400, USA.
University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390-9162, USA.
Neurotox Res. 2024 Sep 4;42(5):41. doi: 10.1007/s12640-024-00717-z.
Recently a novel genetically modified mouse strain with serum carboxylesterase knocked-out and the human acetylcholinesterase gene knocked-in (KIKO) was created to simulate human responses to nerve agent (NA) exposure and its standard medical treatment. A adenosine receptor (AAR) agonist N-bicyclo-(2.2.1)-hept-2-yl-5'-chloro-5'-deoxyadenosine (ENBA) alone is a potent anticonvulsant and neuroprotectant (A/N) in both rat and KIKO mouse soman (GD) seizure models. In this study we utilized the KIKO mouse to evaluate further the basic pharmacologic A/N effects of ENBA as an adjunct to standard NA medical treatments (i.e., atropine sulfate, pralidoxime chloride [2-PAM], and midazolam). Male mice, implanted with cortical electroencephalographic (EEG) electrodes, were pretreated with asoxime (HI-6) and exposed to an epileptogenic dose of GD (33 µg/kg, s.c.) or saline (sham exposure) and then treated 15 min after seizure onset with ENBA at 15 mg/kg, i.p. (a minimum efficacy dose in suppressing NA-induced seizure) alone or as an adjunct to standard medical treatments. We collected EEG activity, seizure suppression outcomes, daily body temperature and weight, heart rate, toxic signs, neuropathology, and lethality data for up to 14 days. Without ENBA, death from NA exposure was 45%, while with ENBA, either alone or in combination with midazolam, the survival improved to 80% and 90%, respectively. Additionally, seizure was suppressed quickly and permanently, toxic signs, hypothermia, and bradycardia recovered by 48 h, and no neuropathology was evident. Our findings confirmed that ENBA is a potent A/N adjunct for delayed medical treatments of NA exposure.
最近，一种新型的基因修饰小鼠品系被创建，该品系的血清羧酸酯酶被敲除，而人乙酰胆碱酯酶基因被敲入（KIKO），以模拟人类对神经毒剂（NA）暴露及其标准治疗的反应。腺嘌呤受体（AAR）激动剂 N-双环-[2.2.1]-庚-2-基-5'-氯-5'-脱氧腺苷（ENBA）单独使用时，在大鼠和 KIKO 小鼠梭曼（GD）惊厥模型中都是一种有效的抗惊厥和神经保护剂（A/N）。在这项研究中，我们利用 KIKO 小鼠进一步评估了 ENBA 的基本药理 A/N 作用，作为标准 NA 治疗（即硫酸阿托品、氯解磷定[2-PAM]和咪达唑仑）的辅助治疗。雄性小鼠植入皮层脑电图（EEG）电极，用 Asoxime（HI-6）预处理，然后用 GD（33μg/kg，sc）或生理盐水（假暴露）进行致惊厥剂量暴露，然后在惊厥发作后 15 分钟，用 15mg/kg 的 ENBA 腹腔内注射（抑制 NA 诱导的惊厥的最小有效剂量）单独或与标准治疗联合治疗。我们收集了 EEG 活动、惊厥抑制结果、每天的体温和体重、心率、毒性体征、神经病理学和 14 天内的死亡率数据。没有 ENBA 的情况下，NA 暴露的死亡率为 45%，而单独使用 ENBA 或与咪达唑仑联合使用时，生存率分别提高到 80%和 90%。此外，惊厥迅速而永久地得到抑制，毒性体征、体温过低和心动过缓在 48 小时内恢复，并且没有明显的神经病理学变化。我们的研究结果证实，ENBA 是一种有效的 A/N 辅助治疗剂，可用于延迟治疗 NA 暴露。
