Chemical warfare nerve agents (CWNA) such as soman (GD) are highly toxic organophosphorus cholinesterase inhibitors and pose a significant threat to both military and civilian populations. CWNA exposure causes seizure activity, which progresses to self-sustaining status epilepticus (SE) and becomes refractory to anticonvulsant treatment. SE is accompanied by neuropathology and functional behavioral impairments. Seizure activity is initiated through excessive stimulation of acetylcholine receptors and maintained by excessive glutamatergic stimulation, which causes pro-convulsive neuroplastic changes and excitotoxic damage. As these two neurotransmitter systems are crucial to the initiation and maintenance of CWNA-induced seizure activity, we hypothesized that multifunctional drugs with combined anticholinergic and antiglutamatergic activity could terminate seizure activity, and thereby prevent neuropathology and behavioral deficits. To test this hypothesis, we selected two drugs to be used as adjunct treatment in a rat GD-exposure model: caramiphen, an anticholinergic with antiglutamatergic activity, and ketamine, an antiglutamatergic with anticholinergic activity. Rats were exposed to 1.2 LD50 GD and treated with one of the test drugs in association with standard antidotal therapy consisting of atropine to block overactivation of muscarinic receptors, an oxime to reactivate GD-inhibited cholinesterase, and a benzodiazepine (midazolam or diazepam) to suppress acute convulsions. Subsequently, rats were subjected to a series of behavioral tests to assess vestibular-motor, locomotor, and sensorimotor function, as well as spatial learning and memory retention, fear memory, response inhibition, and interval timing behavior. Continuous EEG recordings were used to measure seizure activity. Brain tissue was assessed for neuropathological injury at the conclusion of each experiment. Results presented here demonstrate that the association of standard antidotal therapy with caramiphen within the first 10 min following seizure onset effectively attenuates the acute seizures, prevents the acute neurodegeneration, and mitigates most of the delayed neurological deficits that develop following the exposure to GD. They also reveal that administration of ketamine or a higher dose of caramiphen in combination with a benzodiazepine 30-40 min after onset of seizures counters the acute and most of the delayed neurotoxic effects of GD. In both cases, GD-exposed rats treated with caramiphen or ketamine in addition to the standard antidotal therapy had less neurological damage than those treated only with the standard therapy. It is noteworthy, however, that neither ketamine nor caramiphen fully attenuated the GD-induced impairments in vestibular-motor, locomotor, and sensorimotor tests. In sum, treatment of CWNA-induced seizure with a benzodiazepine and a multifunctional compound possessing both antiglutamatergic and anticholinergic properties is a viable strategy to terminate seizure, prevent neuropathology, and preserve many neurological functions.
|Advisor:||Mong, Jessica A.|
|Commitee:||Elmer, Gregory I., Krueger, Bruce K., Lange, Lucille A., Pereira-Albuquerque, Edna F.|
|School:||University of Maryland, Baltimore|
|School Location:||United States -- Maryland|
|Source:||DAI-B 76/12(E), Dissertation Abstracts International|
|Keywords:||Anticonvulsant, Behavior, Nerve agent, Neuroprotection, Rats, Seizure|
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