Acute hydrogen sulfide–induced neuropathology and neurological sequelae: challenges for translational neuroprotective research

Abstract

Hydrogen sulfide (H2S), the gas with the odor of rotten eggs, was formally discovered in 1777, over 239 years ago. For many years, it was considered an environmental pollutant and a health concern only in occupational settings. Recently, however, it was discovered that H2S is produced endogenously and plays critical physiological roles as a gasotransmitter. Although at low physiological concentrations it is physiologically beneficial, exposure to high concentrations of H2S is known to cause brain damage, leading to neurodegeneration and long-term neurological sequelae or death. Neurological sequelae include motor, behavioral, and cognitive deficits, which are incapacitating. Currently, there are concerns about accidental or malicious acute mass civilian exposure to H2S. There is a major unmet need for an ideal neuroprotective treatment, for use in the field, in the event of mass civilian exposure to high H2S concentrations. This review focuses on the neuropathology of high acute H2S exposure, knowledge gaps, and the challenges associated with development of effective neuroprotective therapy to counteract H2S-induced neurodegeneration.

Cobinamide is effective for treatment of hydrogen sulfide–induced neurological sequelae in a mouse model

“…The advantage of the mouse model used in this study is that the route of exposure—inhalation—is representative of the most common route of human H 2 S exposure. The model also recapitulates lesions found in human survivors of acute H 2 S intoxication . However, we acknowledge that the inhalation mouse model of H 2 S poisoning used here is quite different from human exposure to H 2 S. In particular, the short‐term acute repeated H 2 S exposure used above is atypical of human exposure scenarios.…”

“…Of survivors discharged from the hospital with apparent recovery, many return 3–7 days postexposure complaining of neurological complications . These neurological sequelae include movement disorders, persistent migraines, memory loss, cognitive dysfunction and learning impairment, fatigue, hearing impairment, blindness, and seizures . Typically, neurological sequelae occur in victims who have suffered a knockdown and have been unconscious for at least 5 minutes …”

Characterizing a mouse model for evaluation of countermeasures against hydrogen sulfide–induced neurotoxicity and neurological sequelae

“…This exposure paradigm is ideal for assessment of countermeasures against H 2 S‐induced neurodegeneration with minimal numbers of mice to achieve meaningful statistical significance. Because the molecular mechanisms leading to cell death have yet to be defined, the window of opportunity for efficacy of such drugs is not known . From our observations in this study, neurodegeneration becomes morphologically manifested at least 3 days after H 2 S exposure, suggesting a wider intervention time for the treatment of neurodegeneration.…”

“…The mechanisms underlying acute toxicity and continued neurodegeneration of victims of H 2 S toxicity are not well understood, but cytochrome c oxidase inhibition, ATP depletion, and ischemia/hypoxia are often cited as causal to H 2 S‐induced neurodegeneration . H 2 S exposure has been known to cause a wide array of neurological clinical effects, including persistent headaches, nausea, lethargy, seizures, dizziness, abnormal reflexes, sleeping disorders, hearing impairment, movement disorders, and loss of consciousness, sometimes leading to permanent vegetative states .…”

Environmental toxicology of hydrogen sulfide

“…Interestingly, discounting minor symptoms like dizziness and headaches that resolve themselves, no long-term neurological (or other) effects were evident in any of the 221 cases documented in the Canadian study[112]. A satisfactory animal model of human H 2 S exposure reproducibly leading to neurological sequelae following a single toxicant dose remains elusive [119]. Thus, there is a nagging suspicion that most of the reported neurological consequences of H 2 S exposures in humans necessitating treatment might be due to other factors such as brain anoxia, or head injury sustained during knockdown, rather than any more direct effect of the toxicant.…”