Abstracts

Rationale: Organophosphate (OP) pesticides such as monochrotopos and diisopropylfluorophosphate (DFP) cause cholinergic crisis characterized by lethal convulsions and brain injury. DFP is an irreversible cholinesterase inhibitor and thereby cause prolonged seizures, status epilepticus (SE), and brain injury. Benzodiazepines such as diazepam and lorazepam are the first-line drugs for the treatment of SE, but there is evidence for partial or complete resistance, a condition known as refractory SE. In this study, we investigated the efficacy of the standard benzodiazepine diazepam the in DFP model of OP intoxication in rats. Methods: Acute OP intoxication was induced in rats by exposure to DFP (1-4 mg/kg, SC). Two standard antidotes atropine and pralidoxime are administered to increase the survival. Diazepam was given 10, 60 or 120 min after DFP. The progression of seizures was monitored by video-EEG recordings for 24 h. The onset and termination of seizure activity was based on EEG recordings. Animals were perfused for determination of neuronal damage. Brain damage was assessed by FJB neuropathology and quantifications of principal cells and interneurons by unbiased stereology. Results: Rats exhibited cholinergic signs and convulsions within ~10 min after DFP and seizures progressed into SE lasting for several hours. OP intoxication caused massive neuronal loss in brain regions such as hippocampus and amygdala. Diazepam (5-10 mg/kg) controlled seizures when given at 10 min, but it was partly or completely ineffective when given at 60 or 120 min after DFP--a profile indicative of refractoriness to benzodiazepines. Delayed diazepam therapy was not associated with any neuroprotection. Conclusions: DFP model replicates several features of OP nerve intoxication, including seizures, neuronal injury and neurodegeneration. The DFP-induced seizures and neuronal injury are progressively resistant to delayed treatment with diazepam, confirming the benzodiazepine refractoriness of DFP-induced neurological dysfunction. Supported by NIH CounterACT grants NS076426 & NS083460 (to DSR).