Ischemia leads to dramatic increase of succinate level. In the presence of succinate mitochondria catalyze reverse electron transfer so that fraction of electrons from succinate is directed upstream to FMN of complex I. Reverse electron transfer results in a reduction of complex I FMN, increased generation of ROS, followed by a loss of the reduced cofactor (FMNH2) and impairment of mitochondria energy production. The FMN loss by complex I and I/R injury can be alleviated by the administration of FMN precursor, riboflavin.Reperfusion can cause hyperkalemia.Reperfusion injury is a primary concern in liver transplantation surgery. Treatment
Therapeutic hypothermia
However, the therapeutic effect of hypothermia does not confine itself to metabolism and membrane stability. Another school of thought focuses on hypothermias ability to prevent the injuries that occur after circulation returns to the brain, or what is termed reperfusion injuries. In fact an individual suffering from an ischemic insult continues suffering injuries well after circulation is restored. In rats it has been shown that neurons often die a full 24 hours after blood flow returns. Some theorize that this delayed reaction derives from the various inflammatory immune responses that occur during reperfusion. These inflammatory responses cause intracranial pressure, pressure which leads to cell injury and in some situations cell death. Hypothermia has been shown to help moderate intracranial pressure and therefore to minimize the harmful effect of a patients inflammatory immune responses during reperfusion. Beyond this, reperfusion also increases free radical production. Hypothermia too has been shown to minimize a patients production of deadly free radicals during reperfusion.
Many now suspect it is because hypothermia reduces both intracranial pressure and free radical production that hypothermia improves patient outcome following a blockage of blood flow to the brain. Hydrogen sulfide treatment
There are some preliminary studies in mice that seem to indicate that treatment with hydrogen sulfide (H2S) can have a protective effect against reperfusion injury. Cyclosporin
In addition to its well-known immunosuppressive capabilities, the one-time administration of cyclosporin at the time of percutaneous coronary intervention (PCI) has been found to deliver a 40 percent reduction in infarct size in a small group proof of concept study of human patients with reperfusion injury published in The New England Journal of Medicine in 2008.Cyclosporin has been confirmed in studies to inhibit the actions of cyclophilin D, a protein which is induced by excessive intracellular calcium flow to interact with other pore components and help open the MPT pore. Inhibiting cyclophilin D has been shown to prevent the opening of the MPT pore and protect the mitochondria and cellular energy production from excessive calcium inflows.However, the studies CIRCUS and CYCLE (published in September 2015 and February 2016 respectively) looked at the use of cyclosporin as a one time IV dose given right before perfusion therapy (PCI). Both studies found there is no statistical difference in outcome with cyclosporin administration.Reperfusion leads to biochemical imbalances within the cell that lead to cell death and increased infarct size.