Activated endothelial cells produce more reactive oxygen species but less nitric oxide following reperfusion, and the imbalance results in a subsequent inflammatory response.

Repeated bouts of ischemia and reperfusion injury also are thought to be a factor leading to the formation and failure to heal of chronic wounds such as pressure sores and diabetic foot ulcer.

[4] The main reason for the acute phase of ischemia-reperfusion injury is oxygen deprivation and, therefore, arrest of generation of ATP (cellular energy currency) by mitochondria oxidative phosphorylation.

[5] It was found that lack of oxygen leads to conditions in which mitochondrial complex I loses its natural cofactor, flavin mononucleotide (FMN) and become inactive.

[6] When oxygen is present the enzyme catalyzes a physiological reaction of NADH oxidation by ubiquinone, supplying electrons downstream of the respiratory chain (complexes III and IV).

[8] 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.

[13] 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.

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.

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.

[18] 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.

[23][24] 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.

[25][26] 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.

In addition, the increase in lipid metabolism generates ketone bodies and activates peroxisome proliferating-activated receptors (PPARs), both of which have been shown to be protective against I/R injury.