ReviewHydrogen sulfide: Therapeutic or injurious in ischemic stroke?
Section snippets
Background
Stroke remains one of the leading causes of mortality worldwide. Notably, in the United States a stroke occurs every forty seconds and death due to stroke occurs every four minutes. In addition to high mortality, stroke is also a well-known cause of disability, particularly in those above the age of 65. Strokes can be classified as ischemic or hemorrhagic based on the mode of cerebral artery damage. Ischemic stroke, characterized by an occlusion of vessels supplying the brain, accounts for ∼87%
Stroke, ion channels, and role of H2S
Glucose and oxygen deprivation is detrimental to the brain as a result of ATP depletion that occurs during the ischemic period [2]; glycolysis is a major contributor of reducing equivalents in the ATP-generating oxidative phosphorylation (OXPHOS) pathway. Loss of ATP leads to ion homeostasis imbalance in the cells due to the failure of ATPases, or ATP dependent-ion transporters [34] that regulate the influx of calcium and sodium. This also results in an efflux of potassium due to subsequent ATP
Brain edema
A common characteristic in the pathology of brain ischemia is edema. As mentioned in the previous section, alterations in ion channels results in ion imbalance, stimulating influx of water to maintain osmolarity resulting in edema. Edema increases infarct volume and loss of neurological function, indirectly contributing to stroke-induced disabilities. Water is not freely permeable across the plasma membrane and requires channel proteins called aquaporins (AQP). Aquaporin 4 (AQP4) has been
H2S-dependent signal transduction
(see Fig. 2 for a reference to signaling and Fig. 3 for astrocyte and neuronal specific signaling detailed in this section)
Conclusion
The toxicity and therapeutic value of hydrogen sulfide depends on the concentration, with lower concentrations playing a physiologic role and very high concentrations causing death [81]. While hydrogen sulfide is widely considered a gasotransmitter, there is uncertainty about the total concentration of this volatile gas or the highly reactive anionic species (SH−) in both plasma and tissues [82]. Adding to the complexity, polysulfides, a recently characterized addition to sulfide biology, are
Acknowledgements
This work was supported by an American Heart Association grant (15SDG25710038 to C.B.P.), an intramural Malcolm Feist Post-doctoral Fellowship (B.S.), and the Department of Defense (W81XWH-11-1-0577 to J.S.A.). Research reported in this publication was also supported by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under grant number P20GM121307.
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