Effects of combinational prophylactics composed of physostigmine and procyclidine on soman-induced lethality, seizures and brain injuries

The antidotal, anticonvulsant and neuroprotective effects of physostigmine (PhS) and procyclidine (PC), the combinational prophylactics for organophosphate poisoning, were evaluated. For the investigation of dose-response relationship in rats and guinea pigs, various doses (0-6 mg/kg) of PC in combination with a fixed dose (0.1 mg/kg) of PhS were pretreated subcutaneously 30 min prior to subcutaneous poisoning with soman. Procyclidine in combination with PhS exhibited remarkable synergistic effects in a dose-dependent manner, leading to 1.92-5.07 folds of protection ratio in rats and 3.00-4.70 folds in guinea pigs. On the other hand, a low effect (1.65 fold) was achieved with the traditional antidotes atropine (17.4 mg/kg) plus 2-pralidoxime (30 mg/kg) treated immediately after soman poisoning, compared with a marked protection (5.50 fold) with atropine (17.4 mg/kg) plus HI-6 (125 mg/kg) in unpretreated rats. Noteworthy, the combinational prophylactics greatly potentiated the effect of atropine plus 2-pralidoxime to 6.13 or 12.27 folds and that of atropine plus HI-6 to 12.00 or 21.50 folds with 1.0 or 3.0 mg/kg of PC, respectively. A high dose (100 μg/kg, 1.3×LD(50)) of soman induced severe epileptiform seizures in rats pretreated with HI-6 (125 mg/kg), resulting in brain injuries in discrete brain regions under histopathological examination in 24 h. Interestingly, such seizures and excitotoxic brain injuries were fully prevented by pretreatment with PhS (0.1 mg/kg) and PC (1 mg/kg). Taken together, it is proposed that the prophylactics composed of PhS and PC could be a promising regimen for the prevention of lethality, seizures and brain injuries induced by soman poisoning.