Midazolam Efficacy Against Acute Hydrogen Sulfide-Induced Mortality and Neurotoxicity

Hydrogen sulfide (H(2)S) is a colorless, highly neurotoxic gas. It is not only an occupational and environmental hazard but also of concern to the Department of Homeland Security for potential nefarious use. Acute high-dose H(2)S exposure causes death, while survivors may develop neurological sequelae. Currently, there is no suitable antidote for treatment of acute H(2)S-induced neurotoxicity. Midazolam (MDZ), an anti-convulsant drug recommended for treatment of nerve agent intoxications, could also be of value in treating acute H(2)S intoxication. In this study, we tested the hypothesis that MDZ is effective in preventing/treating acute H(2)S-induced neurotoxicity. This proof-of-concept study had two objectives: to determine whether MDZ prevents/reduces H(2)S-induced mortality and to test whether MDZ prevents H(2)S-induced neurological sequelae. MDZ (4 mg/kg) was administered IM in mice, 5 min pre-exposure to a high concentration of H(2)S at 1000 ppm or 12 min post-exposure to 1000 ppm H(2)S followed by 30 min of continuous exposure. A separate experiment tested whether MDZ pre-treatment prevented neurological sequelae. Endpoints monitored included assessment of clinical signs, mortality, behavioral changes, and brain histopathological changes. MDZ significantly reduced H(2)S-induced lethality, seizures, knockdown, and behavioral deficits (p < 0.01). MDZ also significantly prevented H(2)S-induced neurological sequelae, including weight loss, behavior deficits, neuroinflammation, and histopathologic lesions (p < 0.01). Overall, our findings show that MDZ is a promising drug for reducing H(2)S-induced acute mortality, neurotoxicity, and neurological sequelae.