Development of mouse models of hydrogen sulfide-induced neurotoxicity for the evaluation of neuroprotective strategies

Anantharam, Poojya
Major Professor
Wilson K. Rumbeiha
Committee Member
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Veterinary Diagnostic and Production Animal Medicine

H2S is a colorless gas with a strong “rotten egg” odor. While at physiological concentrations, H2S is a vital gasotransmitter; exposure to high concentrations can result in extreme intoxication, leading to acute death within minutes. H2S poisoning is a leading cause of occupational deaths. Among toxic gases, H2S follows only carbon monoxide poisoning as a leading cause of death. There is also concern for this chemical to weaponized as it is easy to make from household chemicals found in local general stores. H2S can cause severe neurodegeneration and neurological sequelae post exposure. There is no ideal treatment for acute H2S-intoxication in humans. Our laboratory has characterized two translational mouse (C57) models to evaluate potential drugs for prevention and treatment of H2S-induced toxicity, and potentially elucidate the molecular mechanisms involved in the pathophysiology of H2S poisoning. We observed that H2S consistently induced seizures and knockdown in the mice, and induced motor deficits, neurochemical alterations, neuroinflammation, oxidative stress and neuropathology. Our data demonstrated that Cobinamide dose and time dependently reduced the behavioral deficits, neuroinflammation, neurochemical changes, oxidative stress and the histopathological changes induced by H2S. Additionally, our studies show promise for Midazolam as an antidote for treatment of H2S-induced neurotoxicity as it reduced H2S-induced mortality by 90% when given prior H2S exposure, and reduced mortality induced by H2S by 50% when given during the exposure. Midazolam administered pre-exposure prevented clinical signs, motor deficits, and histopathological lesions induced by H2S. Collectively, we have validated and characterized a translational mouse model of H2S-induced neurotoxicity, and used the model to demonstrate efficacy of cobinamide and midazolam as countermeasures against H2S-induced neurotoxicity.