In addition, neurosteroids confer robust neuroprotection by reducing neuronal injury and neuroinflammation. Neurosteroids that activate both extrasynaptic and synaptic GABA-A receptors have the potential to stop SE more effectively and safely than benzodiazepines. In 2008, our group was among the first to identify the potential of neurosteroids for SE. We have discovered neurosteroids as next-generation anticonvulsants superior to midazolam for the treatment of OP poisoning. Thus, there is an urgent need for new, mechanism-based antidotes for OP intoxication. The loss of inhibitory interneurons creates a self-sustaining seizure circuit and refractory status epilepticus. OP exposure downregulates critical inhibitory GABA-A receptors, kills neurons, and causes massive neuroinflammation that induce more neuronal death, which raises the problem of too few benzodiazepine receptors. We uncovered why current therapies are not able to stop the OP-induced seizures, status epilepticus (SE), and brain cell death, as well as what type of drug may be more effective. Recent mechanistic studies of benzodiazepine-resistant seizures have key consequences for victims of OP pesticide and nerve agent attacks. This article describes current pursuits for developing novel antidotes for organophosphate (OP) intoxication. Overall, our findings show that MDZ is a promising drug for reducing H2S-induced acute mortality, neurotoxicity, and neurological sequelae. MDZ also significantly prevented H2S-induced neurological sequelae, including weight loss, behavior deficits, neuroinflammation, and histopathologic lesions (p < 0.01). MDZ significantly reduced H2S-induced lethality, seizures, knockdown, and behavioral deficits (p < 0.01). Endpoints monitored included assessment of clinical signs, mortality, behavioral changes, and brain histopathological changes. A separate experiment tested whether MDZ pre-treatment prevented neurological sequelae. MDZ (4 mg/kg) was administered IM in mice, 5 min pre-exposure to a high concentration of H2S at 1000 ppm or 12 min post-exposure to 1000 ppm H2S followed by 30 min of continuous exposure. This proof-of-concept study had two objectives: to determine whether MDZ prevents/reduces H2S-induced mortality and to test whether MDZ prevents H2S-induced neurological sequelae. In this study, we tested the hypothesis that MDZ is effective in preventing/treating acute H2S-induced neurotoxicity. Midazolam (MDZ), an anti-convulsant drug recommended for treatment of nerve agent intoxications, could also be of value in treating acute H2S intoxication. Currently, there is no suitable antidote for treatment of acute H2S-induced neurotoxicity. Acute high-dose H2S exposure causes death, while survivors may develop neurological sequelae. It is not only an occupational and environmental hazard but also of concern to the Department of Homeland Security for potential nefarious use.
Hydrogen sulfide (H2S) is a colorless, highly neurotoxic gas. However, benzodiazepines are less effective at terminating seizures when given 30 min or later after OP exposure or seizure onset, likely because of internalization or downregulation of synaptic, but not extrasynaptic, GABAA receptors, which can lead to diminished potency and seizure recurrence.
Versed antidote trial#
Clinical studies such as the recent Rapid Anticonvulsant Medication Prior to Arrival Trial (RAMPART) trial have confirmed the anticonvulsant efficacy of midazolam in SE in prehospital settings.SignificanceIn experimental models, midazolam is effective when given at the onset of seizures caused by nerve agents. Due to its favorable pharmacokinetic features, midazolam is being considered as a replacement anticonvulsant for diazepam in the antidote kit for nerve agents. Midazolam is administered intravenously or intramuscularly to control acute seizures and SE. It potentiates GABAergic inhibition and thereby controls hyperexcitability and seizures. Midazolam is a positive allosteric modulator of synaptic γ-aminobutyric acid (GABA)A receptors in the brain. Midazolam is a benzodiazepine hypnotic with a rapid onset and short duration of action.ResultsMidazolam is considered the new drug of choice for persistent acute seizures and SE, including those caused by neurotoxic OPs and nerve agents.
This review summarizes the therapeutic potential of midazolam as an anticonvulsant antidote for organophosphate (OP) intoxication.Methodsīenzodiazepines are widely used to treat acute seizures and status epilepticus (SE), a neurologic emergency of persistent seizures that can lead to severe neuronal damage or death.