Methylene Blue, A Novel Treatment of H2S Poisoning-induced Brain Injury

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 DESCRIPTION (provided by applicant): The epidemiological features of hydrogen sulfide (H2S) intoxication have changed over the last few years. While H2S still poses a persistent risk as a chemical hazard for workers in gas or oil industry, H2S poisoning has become a new method of suicide with an incidence which has increased at an alarming rate in many countries including the US. H2S toxicity results from the combination of a direct inhibition of the mitochondrial activity of neurons and the consequences of the cardio-respiratory failure (apnea and shock) on oxygen delivery. H2S is lethal within minutes at a concentration of less than 0.1 %; at lower concentrations, H2S produces an acute coma leading to memory and cognitive deficits in the surviving patients. Our recent findings of the very fast disappearance of free/soluble H2S following hydrogen sulfide exposure represents a major limitation for using, after the intoxication, metallo-compounds, i.e. the only family of antidotes with a proven efficacy during H2S exposure. Indeed, the benefit of Fe3+or Co2+ compounds currently proposed against H2S toxicity relies on their ability to trap free/soluble H2S in the blood, as for instance with methemoglobin, or inside cells, with Hydroxocobalamin (HyCo). However, these agents have a limited action against the pool of H2S combined on proteins and have no effect against the ischemic consequences of H2S-induced circulatory failure. Based on our preliminary data on the effects of Methylene Blue (MB) during H2S poisoning and the remarkable protective effects of MB on post-anoxic or post-toxic brain injury, we are proposing to use MB for the treatment of H2S poisoning. This approach represents a novel paradigm as it specifically counteracts the cellular and mitochondrial dysfunctions induced by H2S. In this project we will determine the ability of MB to prevent the short and long-term effects of H2S- induced brain injury, when administered after an acute H2S intoxication in a rat model of reversible coma. We have developed this model to mimic the most common type of non-lethal form of H2S poisoning in humans. The short-term effects (first 12 hours) of MB following H2S-induced coma will be evaluated by physiological and clinical parameters of post-anoxic injury and brain markers of hypoxia or apoptosis. In a separate group of rats, the long-term effects on memory and cognitive functions will be evaluated in non-anesthetized animals trained to perform tests in a Morris Water Maze after acute or repetitive administrations of MB following an episode of sulfide poisoning-induced coma. MB will be administered alone or combined with HyCo to determine the potential synergy of these 2 antidotes against H2S poisoning. The results of these studies will lead to a novel strategy using an agent counteracting the direct consequences of H2S poisoning. Since MB appears to be also effective against other forms of mitochondrial poisoning, these results may have implications beyond the treatment of H2S intoxication.