Intramuscularly administered A1 adenosine receptor agonists as delayed treatment for organophosphorus nerve agent-induced Status Epilepticus.
Intramuscularly administered A1 adenosine receptor agonists as delayed treatment for organophosphorus nerve agent-induced Status Epilepticus.
复制标题
肌肉注射 A1 腺苷受体激动剂作为有机磷神经毒剂诱发的癫痫持续状态的延迟治疗。
DOI：
10.1016/j.taap.2021.115515
复制
发表时间：
2021
影响因子：
3.8
通讯作者：
Shih,Tsung-Ming
中科院分区：
文献类型：
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作者：
Loughery,TaraN;Whitten,KimberlyA;Acon-Chen,Cindy;Shih,Tsung-Ming
有机磷类神经毒剂（NAs）如沙林（GB）和梭曼（GD）暴露可导致持续性癫痫发作或癫痫持续状态（SE）。先前的研究表明，A1腺苷受体（A1 ARs）的激活可以抑制神经元的兴奋性，这可能有助于SE终止。两种A1 AR激动剂，2-氯-N6-环戊基腺苷（CCPA）和N-双环（2.2.1）庚基-2-基-5 ′-氯-5 ′-脱氧腺苷（ENBA），通过腹腔注射（IP）有效终止GD诱导的大鼠SE。然而，IP注射不是临床相关的给药途径。本研究评价了这些激动剂通过肌内（IM）途径给药时终止NA诱导SE的疗效。将成年雄性大鼠皮下（SC）暴露于GB（150 μg/kg）或GD（90 μg/kg），并在癫痫发作后15、30或60 min用ENBA或CCPA处理或不处理。暴露后7天，对深度麻醉的大鼠实施安乐死，并取出灌注的脑用于神经病理学的组织学评估（即，神经元损伤）。通过将6个区域的评分相加，确定每只大鼠的总神经病变评分（0-24）。总分越高，神经病理学越严重。对于GB模型和60分钟治疗延迟，ENBA治疗的大鼠经历了78.6%的癫痫终止（N=14）和减少的神经病理学（11.6 ± 2.6，N =5），CCPA治疗组大鼠的癫痫发作终止率为85.7%（N=14），神经病理学改变轻微减轻（20.7 ± 1.8，N =6），而未治疗组大鼠无癫痫发作终止（N=13）和严重的神经病理（22.3 ± 1.0，N =4）。对于GD模型和60分钟治疗延迟，ENBA治疗的大鼠经历了92.9%的癫痫发作终止（N=14）和减少的神经病理学（13.96 ± 1.8，N = 9），CCPA治疗组大鼠的癫痫发作终止率为78.6%（N=14），神经病理学改变轻微减轻（22.0 ± 0.9，N =10）;未治疗组大鼠癫痫发作终止率为16.7%（N=12），神经病理改变严重（22.0 ± 1.8，N =5）。虽然ENBA和CCPA在癫痫发作后长达60分钟给药时都表现出明显的终止SE的能力，但ENBA提供了更多的神经保护，使其成为NA诱导SE的有希望的候选者。
Exposure to organophosphorus nerve agents (NAs) like sarin (GB) and soman (GD) can lead to sustained seizure activity, orstatus epilepticus(SE). Previous research has shown that activation of A1 adenosine receptors (A1ARs) can inhibit neuronal excitability, which could aid in SE termination. Two A1AR agonists, 2-Chloro-N6-cyclopentyladenosine (CCPA) and N-Bicyclo(2.2.1)hept-2-yl-5′-chloro-5′-deoxyadenosine (ENBA), were effective in terminating GD-induced SE in rats when administered via intraperitoneal (IP) injection. However, IP injection is not a clinically relevant route of administration. This study evaluated the efficacy of these agonists in terminating NA-induced SE when administered via intramuscular (IM) route. Adult male rats were exposed subcutaneously (SC) to either GB (150 μg/kg) or GD (90 μg/kg) and were treated with ENBA or CCPA at 15, 30, or 60 min after seizure onset or left untreated. Up to 7 days after exposure, deeply anesthetized rats were euthanized and perfused brains were removed for histologic assessment of neuropathology (i.e., neuronal damage) in six brain regions (amygdala, cerebral cortex, piriform cortex, thalamus, dorsal hippocampus, and ventral hippocampus). A total neuropathy score (0–24) was determined for each rat by adding the scores from each of the six regions. The higher the total score the more severe the neuropathology. With the GB model and 60 min treatment delay, ENBA-treated rats experienced 78.6% seizure termination (N=14) and reduced neuropathology (11.6 ± 2.6,N=5), CCPA-treated rats experienced 85.7% seizure termination (N=14) and slightly reduced neuropathology (20.7 ± 1.8,N=6), and untreated rats experienced no seizure termination (N=13) and severe neuropathology (22.3 ± 1.0,N=4). With the GD model and 60 min treatment delay, ENBA-treated rats experienced 92.9% seizure termination (N=14) and reduced neuropathology (13.96 ± 1.8,N= 9), CCPA-treated rats experienced 78.6% seizure termination (N=14) and slightly reduced neuropathology (22.0 ± 0.9,N=10); and untreated rats experienced 16.7% seizure termination (N=12) and severe neuropathology (22.0 ± 1.8,N=5). While ENBA and CCPA both demonstrate a clear ability to terminate SE when administered up to 60 min after seizure onset, ENBA offers more neuroprotection, making it a promising candidate for NA-induced SE.