Anticonvulsant and antilethal effects of the phencyclidine derivative TCP in soman poisoning.
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.
Carpentier
P
P
Centre de Recherches du Service de Santé des Armées, Unité de Neurotoxicologie, La Tronche, France.
Foquin-Tarricone
A
A
Bodjarian
N
N
Rondouin
G
G
Lerner-Natoli
M
M
Kamenka
J M
JM
Blanchet
G
G
Denoyer
M
M
Lallement
G
G
D000818:Animals; D000927:Anticonvulsants; D001285:Atropine / Q000633:toxicity; D004569:Electroencephalography / Q000187:drug effects; D006168:Guinea Pigs; D007928:Lethal Dose 50; D008297:Male; D010622:Phencyclidine / Q000031:analogs & derivatives / Q000633:toxicity*; D011729:Pyridostigmine Bromide / Q000633:toxicity; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D012999:Soman / Q000633:toxicity*
D000927:Anticonvulsants; D016194:Receptors, N-Methyl-D-Aspartate; D001285:Atropine; D012999:Soman; D010622:Phencyclidine; D011729:Pyridostigmine Bromide