Mechanism of RDX-Induced Seizures in Rats
Abstract
RDX is found in soil and ground water in and surrounding training ranges, creating potential hazards to human health. Oral RDX over-exposure causes seizure in rats and humans, the mechanism of which is unknown. In this study rats were dosed orally at 75 mgkg RDX to induce seizure. The brain concentration of RDX was determined in samples taken from rats euthanized at the time of seizure onset: brain acetylchohnesterase was also measured. Also. RDX was screened for affinity to a library of brain receptors to determine if RDX affected any seizure-related targets. Brain concentration: of RDX were greater than S ug/g wet wt. in the animals that seized RDX was found to bind exclusively to the convulsant site on the GABAa receptor with an IC50 of 22 microM. The mechanism of RDX-induced seizure is likely due to dis-inhibition of excitatory neurons by blockage of the GABA-niediated inhibitory chloride current. This valuable information contributes mode of action insights that can be used in the physiologically-based pharmacokinetic modeling to extrapolate rat data to human.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2009
- Accession Number
- ADA511072
Entities
People
- Desmond I Bannon
- Larry R. Williams
Organizations
- United States Army Center for Health Promotion and Preventive Medicine