Hydrogen sulfide (H2S) remains a chemical hazard in the gas and farming industry. It is easy to manufacture from common chemicals and thus represents a potential threat for the civilian population. It is also employed as a method of suicide, for which incidence has recently increased in the US. H2S exerts its toxicity through its high affinity with various metallo-proteins (cytochrome C oxidase) and its interactions with the cysteine residues of proteins. The latter has been recently shown to alter ion channels in cardiomyocytes and neurons. Indeed, during severe H2S intoxication, a reduction in cardiac contractility, associated with a coma, develops within minutes or even seconds leading to death by complete electro- mechanical dissociation of the heart. If the level of intoxication is milder, a rapid and spontaneous recovery of the coma occurs as soon as the exposure stops. However, in many instances, a cardiogenic shock will persist along with a risk of developing debilitating motor or cognitive deficits. One of the major challenges impeding our effort to offer an effective treatment against H2S intoxication after exposure is that the pool of free/soluble H2S almost immediately disappears from the body, preventing agents trapping free H2S (cobalt or ferric compounds) to play their protective role. We found that methylene blue (MB) appears to overcome this challenge: MB drastically decreases the immediate mortality of H2S intoxication-induced cardiogenic shock and improves the long-term neurological outcome. MB appears to counteract the consequences of H2S intoxication related to the persistent pool of protein-bound H2S. The objective of our proposal is twofold. First, we intend to extend our previous findings on the efficacy of MB against H2S intoxication in two animal models (a large mammal -sheep- and unsedated rats), an essential prerequisite under the Animal Rule, in conditions (inhaled H2S) more faithful to human intoxication. The effects of MB on the short and long term outcomes will be established at two different doses administered up to 30 minutes after the end of intoxication. Second, we will continue to explore the mechanisms of action of MB using isolated contracting cardiomyocytes (studies performed by the group of Dr. Joseph Cheung, Temple University), and cortical neurons from acute brain slices in rats (studies performed by the group of Dr. Brady Maher, Lieber Institute for Brain Development, Johns Hopkins University). Since MB has been used for decades for treating methemoglobinemia (1-2 mg/kg iv) in humans, our ultimate goal is to reposition methylene blue, a drug already on the WHO's list of essential medications, as a key treatment of H2S intoxication.
Hydrogen sulfide (H2S) is an extremely toxic gas, which causes fatal intoxication and can produce long-term neurological deficits; it is used as a method of suicide and remains a potential chemical threat for the civilian population, with no established treatment. We have recently found that administration of methylene blue, which is in the WHO's list of essential medications, dramatically increases survival in H2S induced coma by rapidly restoring the cardiac function depressed by H2S and improves the short and long-term neurological outcomes. These findings have prompted us to develop this proposal which will 1- extend our findings in larger mammals and in unsedated animals exposed to H2S intoxication by inhalation, 2- describe the mechanisms for the action of methylene blue on isolated cardiac cells and on neurons, the main targets of H2S toxicity. Our ultimate objective is to reposition methylene blue as a treatment of acute H2S intoxication.
|Cheung, Joseph Y; Wang, JuFang; Zhang, Xue-Qian et al. (2018) Methylene Blue Counteracts H2S-Induced Cardiac Ion Channel Dysfunction and ATP Reduction. Cardiovasc Toxicol 18:407-419|
|Imamura, Fumiaki; Cooper, Timothy K; Hasegawa-Ishii, Sanae et al. (2017) Hydrogen Sulfide Specifically Alters NAD(P)H Quinone Dehydrogenase 1 (NQO1) Olfactory Neurons in the Rat. Neuroscience 366:105-112|
|Sonobe, Takashi; Haouzi, Philippe (2016) H2S concentrations in the heart after acute H2S administration: methodological and physiological considerations. Am J Physiol Heart Circ Physiol 311:H1445-H1458|