The ability of five organophosphorus
nerve agents (
tabun,
sarin,
soman, GF, and
VX) to produce brain
seizures and the effectiveness of
atropine as an
anticonvulsant treatment against these
nerve agents were studied in two different animal models--the rat and guinea pig. All animals were implanted with cortical
electrodes for EEG recordings. Five minutes after the start of
nerve agent-induced EEG
seizures, animals were treated intramuscularly (IM) with different doses of
atropine sulfate and observed for seizure termination. The
anticonvulsant ED50 of
atropine sulfate for termination of
seizures induced by each
nerve agent was calculated and compared. In the rat model, selected
oximes were administered either before, concurrent with, or following challenge with a 1.6 x LD50 dose of a given
nerve agent to maximize seizure development with certain agent/
oxime combinations. The choice and the timing of
oxime administration significantly effected the incidence of seizure development by different
nerve agents. When
oxime administration did not effect seizure development (
tabun,
soman) the
anticonvulsant ED50 for
atropine sulfate was the same, regardless of the
nerve agent used to elicit the seizure. When
oxime administration reduced the incidence of seizure occurrence (
sarin, GF,
VX), the
anticonvulsant ED50 dose of
atropine sulfate for a
nerve agent was lower. In the guinea pig model, animals were pretreated with
pyridostigmine prior to challenge with 2 x LD50 of a given agent, and treated 1 min later with
atropine sulfate (2 mg/kg) and
2-PAM (25 mg/kg). Under these conditions, the incidence, latency of seizure development, and
anticonvulsant ED50s of
atropine for
soman-,
tabun-, and GF-elicited
seizures were virtually identical. With
sarin, although the latency of seizure development was the same as with
soman,
tabun, and GF,
seizures occurred with a lower incidence, and the
anticonvulsant ED50 of
atropine was lower. With
VX, the latency of seizure development was notably longer, while the incidence of seizure development and
anticonvulsant ED50 of
atropine were significantly lower than with
soman,
tabun, or GF. In both models, a lower incidence of seizure development predicted a lower
anticonvulsant dose of
atropine. In the rat, the incidence of seizure development and the
anticonvulsant effectiveness of
atropine was highly dependent on the
oxime used. In the guinea pig, higher doses of
atropine sulfate were required to control
soman-,
tabun-, or GF-induced
seizures, perhaps reflecting the lower
cholinesterase reactivating ability of
2-PAM against these agents.