Seizure suppression and neuroprotection in soman-exposed rats following delayed intramuscular treatment of adenosine A1 receptor agonist as an adjunct to standard medical treatment

IF 4.3 3区 材料科学 Q1 ENGINEERING, ELECTRICAL & ELECTRONIC ACS Applied Electronic Materials Pub Date : 2024-05-20 DOI:10.1016/j.taap.2024.116970
Zora-Maya Keith, Crystal Munoz, Cindy Acon-Chen, Tsung-Ming Shih
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Abstract

Soman produces excitotoxic effects by inhibiting acetylcholinesterase in the cholinergic synapses and neuromuscular junctions, resulting in soman-induced sustained status epilepticus (SSE). Our previous work showed delayed intramuscular (i.m.) treatment with A1 adenosine receptor agonist N-bicyclo-[2.2.1]-hept-2-yl-5′-chloro-5′-deoxyadenosine (ENBA) alone suppressed soman-induced SSE and prevented neuropathology. Using this same rat soman seizure model, we tested if delayed therapy with ENBA (60 mg/kg, i.m.) would terminate seizure, protect neuropathology, and aid in survival when given in conjunction with current standard medical countermeasures (MCMs): atropine sulfate, 2-PAM, and midazolam (MDZ). Either 15- or 30-min following soman-induced SSE onset, male rats received atropine and 2-PAM plus either MDZ or MDZ + ENBA. Electroencephalographic (EEG) activity, physiologic parameters, and motor function were recorded. Either 2- or 14-days following exposure surviving rats were euthanized and perfused for histology. All animals treated with MDZ + ENBA at both time points had 100% EEG seizure termination and reduced total neuropathology compared to animals treated with MDZ (2-day, p = 0.015 for 15-min, p = 0.002 for 30-min; 14-day, p < 0.001 for 15-min, p = 0.006 for 30-min), showing ENBA enhanced MDZ's anticonvulsant and neuroprotectant efficacy. However, combined MDZ + ENBA treatment, when compared to MDZ treatment groups, had a reduction in the 14-day survival rate regardless of treatment time, indicating possible enhancement of MDZ's neuronal inhibitory effects by ENBA. Based on our findings, ENBA shows promise as an anticonvulsant and neuroprotectant in a combined treatment regimen following soman exposure; when given as an adjunct to standard MCMs, the dose of ENBA needs to be adjusted.

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将腺苷 A1 受体激动剂作为标准药物治疗的辅助手段进行延迟肌肉注射后,可抑制索曼暴露大鼠的癫痫发作并保护其神经系统。
索曼通过抑制胆碱能突触和神经肌肉接头处的乙酰胆碱酯酶产生兴奋毒性作用,导致索曼诱发的癫痫持续状态(SSE)。我们之前的研究表明,单独使用 A1 腺苷受体激动剂 N-双环-[2.2.1]-庚-2-基-5'-氯-5'-脱氧腺苷(ENBA)进行延迟肌肉注射(i.m.)治疗可抑制索曼诱导的癫痫持续状态,并防止神经病理学的发生。使用相同的大鼠索曼癫痫模型,我们测试了ENBA(60 毫克/千克,i.m.)延迟治疗是否能终止癫痫发作、保护神经病理学,以及在与目前的标准医疗对策(MCMs)(硫酸阿托品、2-PAM 和咪达唑仑(MDZ))同时使用时帮助患者存活。在索曼诱导的 SSE 发作后 15 或 30 分钟,雄性大鼠接受阿托品和 2-PAM 以及 MDZ 或 MDZ + ENBA。记录脑电图(EEG)活动、生理参数和运动功能。暴露后 2 天或 14 天,将存活的大鼠安乐死并灌注组织学。与接受 MDZ 治疗的动物相比,所有接受 MDZ + ENBA 治疗的动物在这两个时间点的脑电图发作终止率均为 100%,总的神经病理变化也有所减少(2 天,15 分钟的 p = 0.015,30 分钟的 p = 0.002;14 天,p = 0.015,30 分钟的 p = 0.002)。
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CiteScore
7.20
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4.30%
发文量
567
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