Chemical Warfare Nerve Agent Soman Research Articles

The Cu- and Zn-complex-catalyzed methanolysis of the chemical warfare nerve agents soman, sarin, and VX

The catalytic methanolysis of the chemical warfare nerve agents soman, sarin, and VX was investigated by using Cu or Zn complexes. Although VX withstood decontamination, the decomposition yield being around 96%, the soman and sarin deposited on different surfaces were almost fully destroyed under ambient conditions. The catalytic tests performed on a wide range of contaminated surfaces confirm the activity of the investigated catalytic systems, these complexes being suitable, from an economical point of view, for use in the formulation of a possible decomposition kit with military or civilian applicability. La méthanolyse catalytique des agents neurotoxiques de guerre chimique soman, sarin et VX a été étudiée en utilisant des complexes du Cu ou du Zn. Bien que VX résiste à la décontamination, le rendement de décomposition étant d'environ 96%, le soman et le sarin déposés sur différentes surfaces ont été presque entièrement détruits dans les conditions ambiantes. Les essais catalytiques effectués sur une large gamme de surfaces contaminées confirment l'activité des systèmes catalytiques étudiés, ces complexes étant appropriés d'un point de vue économique pour être utilisés dans la formulation d'un éventuel kit de décomposition militaire ou civil.

Anticonvulsant efficacy of antihistamine cyproheptadine in rats exposed to the chemical warfare nerve agent soman

Organophosphate compounds, such as soman and sarin, are highly toxic chemical warfare nerve agents that cause a build-up of acetylcholine in synapses and neuromuscular junctions. Current therapies aim to prevent seizures and protect against brain injury following exposure. The present study was designed to evaluate the effectiveness of the antihistamine cyproheptadine in improving survival and controlling seizures in rats exposed to soman. Rats were pretreated with the oxime reactivator HI-6 (125mg/kg, ip) 30min prior to soman exposure (225μg/kg, sc) and then treated with atropine methylnitrate (AMN, 2.0mg/kg, im) 1min after soman. Cyproheptadine (10, 13, 16 or 20mg/kg, ip) was given at one of three time points: 1min after soman intoxication, at the onset of soman-induced seizures or 5min after seizure onset. Control animals were exposed to soman and given an equivalent volume of sterile water instead of cyproheptadine. The incidence of seizures, mortality, neuron counts, neuropathology and apoptosis in specific regions of the brain were evaluated. In animals given HI-6 and AMN the incidence of soman-induced seizure and mortality rate within the first 24h were 100%. When cyproheptadine was given at a dose of 13 or 20mg/kg 1min after soman exposure, the incidence of seizures was reduced from 100% to 13% and 30%, respectively. In addition, cyproheptadine given at 1min after soman exposure increased the survival rate to 100% regardless of dose. When cyproheptadine was administered at seizure onset, seizures were terminated in 100% of the animals at doses above 10mg/kg. The survival rate with cyproheptadine treatment at the onset of seizure was ≥83%. Seizures terminated in ≥75% of the animals that received cyproheptadine 5min after soman-induced seizure onset. When given at 5min after seizure onset the survival rate was 100% at all tested doses of cyproheptadine. The neuropathology scores and the number of TUNEL positive cells in the brain regions examined decreased at all time points and cyproheptadine doses tested. These observations indicate that cyproheptadine treatment can effectively control seizures, improve survival, reduce seizure duration and reduce the number of dying cells in the brain following soman exposure.

Neuroprotective effects of imidazenil against chemical warfare nerve agent soman toxicity in guinea pigs

The chemical warfare nerve agent, soman irreversibly inhibits acetylcholinesterase (AChE) leading to hypercholinergy and seizures which trigger glutamate toxicity and status epilepticus ultimately resulting in neuropathology and neurobehavioral deficits. The standard emergency treatment comprising of anticholinergic, AChE reactivator and anticonvulsant does not completely protect against soman toxicity. We have evaluated imidazenil, a new anticonvulsant imidazo benzodiazepine with high affinity and intrinsic efficacy at α5-, α2-, and α3- but low intrinsic efficacy at α1-containing GABAA receptors and is devoid of cardiorespiratory depression, sedative/hypnoitc and amnestic actions and does not elicit tolerance and dependence liabilities unlike diazepam, for protection against soman toxicity. Guinea pigs implanted with bipotential radiotelemetry probes for recording EEG and ECG were administered with 26μg/kg pyridostigmine bromide 30min prior to 2× LD50 soman exposure and 1min later treated with a combination of 2mg/kg atropine sulfate and 25mg/kg 2-pralidoxime and various doses of imidazenil. Intramuscular administration of imidazenil, dose-dependently protected against 2× LD50 of soman toxicity up to 1mg/kg. Further increase in the dose of imidazenil to 2.5mg/kg was less effective than 1mg/kg probably due to non-specific actions at sites other than GABAA receptors. Compared to vehicle group, 1mg/kg imidazenil treatment showed optimal increase in survival rate, reduction in behavioral manifestations and high power of EEG spectrum as well as neuronal necrosis. These data suggest that imidazenil is an effective anticonvulsant for medical countermeasure against soman-induced toxicity.

Acute respiratory toxicity following inhalation exposure to soman in guinea pigs

Respiratory toxicity and lung injury following inhalation exposure to chemical warfare nerve agent soman was examined in guinea pigs without therapeutics to improve survival. A microinstillation inhalation exposure technique that aerosolizes the agent in the trachea was used to administer soman to anesthetized age and weight matched male guinea pigs. Animals were exposed to 280, 561, 841, and 1121 mg/m 3 concentrations of soman for 4 min. Survival data showed that all saline controls and animals exposed to 280 and 561 mg/m 3 soman survived, while animals exposed to 841, and 1121 mg/m 3 resulted in 38% and 13% survival, respectively. The microinstillation inhalation exposure LCt 50 for soman determined by probit analysis was 827.2 mg/m 3. A majority of the animals that died at 1121 mg/m 3 developed seizures and died within 15–30 min post-exposure. There was a dose-dependent decrease in pulse rate and blood oxygen saturation of animals exposed to soman at 5–6.5 min post-exposure. Body weight loss increased with the dose of soman exposure. Bronchoalveolar lavage (BAL) fluid and blood acetylcholinesterase and butyrylcholinesterase activity was inhibited dose-dependently in soman treated groups at 24 h. BAL cells showed a dose-dependent increase in cell death and total cell counts following soman exposure. Edema by wet/dry weight ratio of the accessory lung lobe and trachea was increased slightly in soman exposed animals. An increase in total bronchoalveolar lavage fluid protein was observed in soman exposed animals at all doses. Differential cell counts of BAL and blood showed an increase in total lymphocyte counts and percentage of neutrophils. These results indicate that microinstillation inhalation exposure to soman causes respiratory toxicity and acute lung injury in guinea pigs.

Assessment of low level whole-body soman vapor exposure in rats

We evaluated biochemical and behavioral effects of single, low-level exposures to the chemical warfare nerve agent soman (GD). Male Sprague-Dawley rats were trained on a variable-interval, 56-sec schedule of food reinforcement (VI56). The schedule specifies that a single lever press, following an average interval of 56 s, produces food reinforcement (i.e., a single food pellet). After training, rats received a single 60 min exposure to soman vapor at concentrations of 1.0–7.0 mg/m 3, or air control ( n = 8 for each treatment condition). Blood was sampled before and after the exposure. Following exposures, performance on the VI56 was evaluated for approximately 11 weeks. Additionally, the acquisition and maintenance of a radial-arm maze (RAM) spatial memory task were evaluated in the same subjects during the same 11-week period. Soman exposures produced miosis in all subjects but were otherwise essentially asymptomatic. That is, no convulsions or major signs of toxicity were observed in any subjects, a result consistent with a low-level concentration. Soman exposures produced significant and concentration-dependent decreases in circulating acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activity. Soman exposures also produced concentration-dependent levels of regenerated soman in plasma and red blood cell fractions that served to verify the systemic exposure and estimate the total body burden. Soman exposure did not disrupt performance on the VI56 schedule as responding was maintained at pre-exposure levels throughout the 11-week period in all treatment groups. All subjects acquired, and maintained, performance on the RAM task and no significant differences were observed as a result of soman exposure. That is, soman-exposed rats learned the RAM task at the same general rate and to the same general level of accuracy as air-control rats. No delayed effects from exposures were observed. These results demonstrate that, in rats, single exposures to soman vapors at levels that produce substantial AChE and BChE inhibition, but below those producing convulsions and other severe clinical signs of toxicity, may not produce observable effects on the performance of a previously learned task or the acquisition of a new task.

Pathology of nerve agents: Perspectives on medical management

Recent investigations at several institutes have demonstrated extensive acute brain pathology in experimental animals exposed to single subcutaneous doses of the chemical warfare nerve agents soman or sarin. Lesions include neuronal and neurophil degeneration, necrosis, and in animals that survive for several weeks, a degenerative encephalopathy characterized by mineralization, encephalomalacia, atrophy, and hydrocephalus. The cerebral cortex, amygdaloid complex, hippocampus, and multiple thalamic nuclei are consistently affected. This pattern of injury resembles that described for epilepsy and ischemic brain injury. Some animals have cardiac lesions characterized by acute necrosis with subsequent mild inflammation and fibrosis. Anticonvulsants protect experimental animals from lesion development. In rats, this encephalopathy causes long-range behavioral changes characterized by hyperactivity during routine handling and variances in traditional behavioral tests. The histopathologic features and distribution of lesions in nerve agent-poisoned animals support the hypothesis that epileptiform seizure activity is a major factor in nerve agent pathology. Other localized insults such as ischemia and hypoxia probably contribute to the pathogenesis.