Midazolam Efficacy Against Acute Hydrogen Sulfide-Induced Mortality and Neurotoxicity

Hydrogen sulfide (H₂S) 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 H₂S exposure causes death, while survivors may develop neurological sequelae. Currently, there is no suitable antidote for treatment of 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. In this study, we tested the hypothesis that MDZ is effective in preventing/treating acute H₂S-induced neurotoxicity. 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. 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. 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 H₂S-induced lethality, seizures, knockdown, and behavioral deficits (p < 0.01). MDZ also significantly prevented H₂S-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 H₂S-induced acute mortality, neurotoxicity, and neurological sequelae.