Therapeutic hypothermia The therapeutic effect of hypothermia is not confined to metabolism and membrane stability. Hypothermia can also 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 patient's inflammatory immune responses during reperfusion. Beyond this, reperfusion also increases free radical production. Hypothermia too has been shown to minimize a patient's 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.
Remote ischemic conditioning Causing repeated, temporary cessation of blood flow to a limb to create
ischemia (lack of
oxygen and
glucose) in the tissue appears to protect against ischemic and reperfusion injury in animals. Although noted to have some benefits in experimental models in animals, this is still an experimental procedure in humans and initial evidence from small studies have not been replicated in larger clinical trials. Successive clinical trials have failed to identify evidence supporting a protective role in humans as of 2015. Two large human studies completed in 2023 had re-ignited interest in this technique with positive results.
Edaravone Edaravone is approved as an adjuvant treatment for
stroke in Japan. It appears to improve outcomes when added to reperfusion therapy. It is known to reduce reperfusion injury in animal models and presumably it also helps human patients by reducing reperfusion injury. It can be taken intravenously or by mouth. Edaravone is combined with dextro-
borneol (dexborneol) in
edaravone/dexborneol, a drug approved in China for stroke. It is approved in intravenous (2021) and sublingual (2025) forms. The intravenous combination was approved on the basis of trials showing it to be superior to edavarone alone.
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. Reperfusion leads to biochemical imbalances within the cell that lead to
cell death and increased infarct size. More specifically,
calcium overload and excessive production of
reactive oxygen species in the first few minutes after reperfusion set off a cascade of biochemical changes that result in the opening of the so-called
mitochondrial permeability transition pore (MPT pore) in the mitochondrial membrane of cardiac cells. The opening of the MPT pore leads to the inrush of water into the mitochondria, resulting in mitochondrial dysfunction and collapse. Upon collapse, the calcium is then released to overwhelm the next mitochondria in a cascading series of events that cause mitochondrial energy production supporting the cell to be reduced or stopped completely. The cessation of energy production results in cellular death. Protecting mitochondria is a viable cardioprotective strategy. In 2008, an editorial in the New England Journal of Medicine called for more studies to determine if cyclosporin can become a treatment to ameliorate reperfusion injury by protecting mitochondria.
TRO40303 TRO40303 is a new cardioprotective compound that was shown to inhibit the MPT pore and reduce infarct size after ischemia-reperfusion. It was developed by
Trophos company and currently is in
Phase I clinical trial.
Stem cell therapy Recent investigations suggest a possible beneficial effect of
mesenchymal stem cells on heart and kidney reperfusion injury.
Superoxide dismutase Superoxide dismutase is an effective anti-oxidant enzyme which converts superoxide anions to water and hydrogen peroxide. Recent researches have shown significant therapeutic effects on pre-clinical models of reperfusion injury after ischemic stroke.
Metformin A series of 2009 studies published in the Journal of Cardiovascular Pharmacology suggest that
Metformin may prevent cardiac reperfusion injury by inhibition of
Mitochondrial Complex I and the opening of MPT pore and in rats.
Riboflavin In neonatal in vivo model of brain ischemia/reperfusion, tissue injury can be alleviated by the administration of FMN precursor, riboflavin that prevents inactivation of mitochondrial complex I.
Cannabinoids A study published in 2012 show that the
synthetic analogue of the
phytocannabinoid Tetrahydrocannabivarin (THCV), Δ8-Tetrahydrocannabivarin (Δ8-THCV) and its
metabolite 11-OH-Δ8-THCV, prevent
hepatic ischaemia/reperfusion injury by decreasing
oxidative stress and
inflammatory responses through cannabinoid
CB2 receptors and thereby decrease tissue injury and inflammation with a protective effect against liver damage. Pretreatment with a CB2
receptor antagonist attenuated the protective effects of Δ8-THCV, while a
CB1 antagonist tended to enhance it. An earlier study published in 2011 found, that
Cannabidiol (CBD) also protects against hepatic ischemia/reperfusion injury by attenuating inflammatory signaling and response of oxidative and
nitrative stress, and thereby
cell death and
tissue injury, but independent from classical CB1 and CB2 receptors. ==Reperfusion protection in obligate hibernators==