Carpentier P, Foquin-Tarricone A, Bodjarian N, Rondouin G, Lerner-Natoli M, Kamenka J M, Blanchet G, Denoyer M, Lallement G
Centre de Recherches du Service de Santé des Armées, Unité de Neurotoxicologie, La Tronche, France.
Neurotoxicology. 1994 Winter;15(4):837-51.
The protection afforded by TCP (thienylcylohexylpiperidine), a non-competitive blocker of N-methyl-D-aspartate (NMDA) receptors, against the seizures and lethality produced by 2 x LD50 of soman (62 micrograms/kg, sc), an irreversible inhibitor of cholinesterase, was studied in guinea-pigs. In the presence of additional anticholinergic medication (pyridostigmine: 0.2 mg/kg, sc, 30min prior to soman; atropine sulphate: 5mg/kg, im, 1 min post-soman), TCP pretreatment (2.5mg/kg, im, 30 or 15 min prior to soman) did not generally prevent the appearance of soman-induced status epilepticus but did arrest it after 30-40 min in 80% (TCP-30min) or 100% (TCP-15min) of the convulsing subjects. Moreover, in all subjects treated curatively, TCP was able to interrupt ongoing status epilepticus in approximately 20, 10 or 8 min when it was administered 5, 30 or 60min respectively after the onset of epileptiform tracings on EEG. All of these curatively administered animals survived and recovered remarkably well. On every criteria examined (latency-to-seizure arrest, 24hr-survival rate, clinical recovery), injection of 2.5mg/kg TCP after 90min of seizures appeared slightly less efficient compared to earlier curative administration. Therefore, our study (a) establishes that the previously reported capacity of MK-801 (dibenzocyclohepneimine) to counteract soman toxicity is not unique and could be extended to other non-competitive inhibitors of NMDA receptors; (b) shows that TCP could easily prevent and, above all, interrupt soman-induced seizures; furthermore, TCP appears the first compound ever tested on soman poisoning that still displays satisfactory anticonvulsant activity after such a long duration of initial status epilepticus (90min); therefore, TCP might be of special value for the delayed therapy for soman poisoning; (c) confirms that NMDA receptors are involved in the maintenance of seizures and play an important role in other processes implicated in the overall toxicity (including the lethal respiratory effects) of soman poisoning.
在豚鼠中研究了N-甲基-D-天冬氨酸（NMDA）受体的非竞争性阻滞剂TCP（噻吩环己基哌啶）对由2倍半数致死剂量的梭曼（62微克/千克，皮下注射）所产生的惊厥和致死作用的保护作用，梭曼是一种不可逆的胆碱酯酶抑制剂。在使用额外的抗胆碱能药物（吡啶斯的明：0.2毫克/千克，皮下注射，在注射梭曼前30分钟；硫酸阿托品：5毫克/千克，肌肉注射，在注射梭曼后1分钟）的情况下，TCP预处理（2.5毫克/千克，肌肉注射，在注射梭曼前30或15分钟）通常不能预防梭曼诱导的癫痫持续状态的出现，但在30 - 40分钟后能使80%（TCP - 30分钟组）或100%（TCP - 15分钟组）正在惊厥的动物停止惊厥。此外，在所有接受治疗的动物中，当在脑电图上出现癫痫样放电后分别于5、30或60分钟给予TCP时，它能够在大约20、10或8分钟内中断正在进行的癫痫持续状态。所有这些接受治疗的动物都存活下来并且恢复得非常好。在每一项检查标准（惊厥停止潜伏期、24小时存活率、临床恢复情况）方面，与早期治疗给药相比，在惊厥发作90分钟后注射2.5毫克/千克TCP的效果似乎稍差。因此，我们的研究（a）证实了先前报道的MK - 801（二苯并环庚烯亚胺）对抗梭曼毒性的能力并非独一无二，并且可以扩展到其他NMDA受体的非竞争性抑制剂；（b）表明TCP能够轻易预防，最重要的是能够中断梭曼诱导的惊厥；此外，TCP似乎是有史以来在梭曼中毒实验中测试的第一种在如此长时间的初始癫痫持续状态（90分钟）后仍显示出令人满意的抗惊厥活性的化合物；因此，TCP可能对梭曼中毒的延迟治疗具有特殊价值；（c）证实NMDA受体参与惊厥的维持，并且在梭曼中毒的整体毒性（包括致命的呼吸效应）所涉及的其他过程中起重要作用。
