Hydrogen sulfide (H2S), the gas with a """"""""rotten egg"""""""" smell, is a colorless highly neurotoxic gas. It is an environmental pollutant and an occupational hazard in several industries including the oil and gas industry, intensive animal farming operations, sewer and wastewater treatment plants, pulp and paper, and gas storage facilities, among others. There is also a significant concern about the use H2S as a weapon of mass destruction, particularly in confined spaces such as underground transit facilities. Catastrophic industrial accidents are also a concern. Hydrogen sulfide has the potential to cause mass civilian casualties under these circumstances. Symptoms in acutely exposed individuals include seizures, respiratory distress, and death. Lingering neurological sequelae include neurobehavioral and cognitive deficits, hearing impairment, and permanent vegetative states, among others. Currently, recommended treatment for H2S poisoning includes intravenous injections of nitrites, and the administration of hyperbaric oxygen. However, none of these treatment modalities is suitable for field treatment of mass casualties. Besides, the efficacy of nitrites is both debatable and associated with major side effects such as hypotension. Treatment of mass victims of H2S poisoning in the field requires medications that can be given by intramuscular (IM) injections, similar to the EpiPen(R) or ComboPen(R). Cobinamide is a novel drug and our preliminary investigations have shown that it is efficacious for treatment of H2S-induced neurotoxicity in the C57 Black mouse animal model. Cobinamide has a significant advantage over current therapies in that it is stable and can be given IM. The objective of the proposed study is to investigate the efficacy of cobinamide as an antidote to H2S poisoning. The proposed study has two Specific Aims.
In Specific Aim #1 we will fully characterize our mouse model of H2S-induced neurotoxicity.
In Specific Aim #2 we will conduct a series of experiments to evaluate the efficacy of cobinamide to prevent and treat H2S-induced neurotoxicity. Results of this study will be used for development of competitive grant applications for future support under the NIH CounterAct and other relevant funding programs.

Public Health Relevance

Hydrogen sulfide (H2S) is a highly neurotoxic gas commonly encountered in industrial, agricultural, and occupational settings. Because it has previously been used as a chemical weapon, there is concern about its potential misuse as a weapon of mass destruction. Currently there is no ideal antidote to H2S poisoning. This study will investigate the efficacy of cobinamide as an antidote to neurological sequelae of H2S poisoning in humans using a novel animal model, the mouse.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1-MDCN-B (55))
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Yeung, David
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Iowa State University
Veterinary Sciences
Schools of Veterinary Medicine
United States
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Anantharam, Poojya; Whitley, Elizabeth M; Mahama, Belinda et al. (2017) Characterizing a mouse model for evaluation of countermeasures against hydrogen sulfide-induced neurotoxicity and neurological sequelae. Ann N Y Acad Sci 1400:46-64
Anantharam, Poojya; Whitley, Elizabeth M; Mahama, Belinda et al. (2017) Cobinamide is effective for treatment of hydrogen sulfide-induced neurological sequelae in a mouse model. Ann N Y Acad Sci 1408:61-78
Rumbeiha, Wilson; Whitley, Elizabeth; Anantharam, Poojya et al. (2016) Acute hydrogen sulfide-induced neuropathology and neurological sequelae: challenges for translational neuroprotective research. Ann N Y Acad Sci 1378:5-16