Editing Reperfusion injury (section)

===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.<ref>{{cite journal |last1=Piot |first1=Christophe |last2=Croisille |first2=Pierre |last3=Staat |first3=Patrick |last4=Thibault |first4=Hélène |last5=Rioufol |first5=Gilles |last6=Mewton |first6=Nathan |last7=Elbelghiti |first7=Rachid |last8=Cung |first8=Thien Tri |last9=Bonnefoy |first9=Eric |last10=Angoulvant |first10=Denis |last11=Macia |first11=Christophe |last12=Raczka |first12=Franck |last13=Sportouch |first13=Catherine |last14=Gahide |first14=Gerald |last15=Finet |first15=Gérard |last16=André-Fouët |first16=Xavier |last17=Revel |first17=Didier |last18=Kirkorian |first18=Gilbert |last19=Monassier |first19=Jean-Pierre |last20=Derumeaux |first20=Geneviève |last21=Ovize |first21=Michel |title=Effect of Cyclosporine on Reperfusion Injury in Acute Myocardial Infarction |journal=New England Journal of Medicine |date=31 July 2008 |volume=359 |issue=5 |pages=473–481 |doi=10.1056/NEJMoa071142 |pmid=18669426 |doi-access=free }}</ref>

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.<ref name="Javadov S. 2007" />

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.<ref name="pmid26321103">{{cite journal |last1=Cung |first1=Thien-Tri |last2=Morel |first2=Olivier |last3=Cayla |first3=Guillaume |last4=Rioufol |first4=Gilles |last5=Garcia-Dorado |first5=David |last6=Angoulvant |first6=Denis |last7=Bonnefoy-Cudraz |first7=Eric |last8=Guérin |first8=Patrice |last9=Elbaz |first9=Meier |last10=Delarche |first10=Nicolas |last11=Coste |first11=Pierre |last12=Vanzetto |first12=Gerald |last13=Metge |first13=Marc |last14=Aupetit |first14=Jean-François |last15=Jouve |first15=Bernard |last16=Motreff |first16=Pascal |last17=Tron |first17=Christophe |last18=Labeque |first18=Jean-Noel |last19=Steg |first19=Philippe Gabriel |last20=Cottin |first20=Yves |last21=Range |first21=Grégoire |last22=Clerc |first22=Jérome |last23=Claeys |first23=Marc J. |last24=Coussement |first24=Patrick |last25=Prunier |first25=Fabrice |last26=Moulin |first26=Frédéric |last27=Roth |first27=Olivier |last28=Belle |first28=Loïc |last29=Dubois |first29=Philippe |last30=Barragan |first30=Paul |last31=Gilard |first31=Martine |last32=Piot |first32=Christophe |last33=Colin |first33=Patrice |last34=De Poli |first34=Fabien |last35=Morice |first35=Marie-Claude |last36=Ider |first36=Omar |last37=Dubois-Randé |first37=Jean-Luc |last38=Unterseeh |first38=Thierry |last39=Le Breton |first39=Hervé |last40=Béard |first40=Thierry |last41=Blanchard |first41=Didier |last42=Grollier |first42=Gilles |last43=Malquarti |first43=Vincent |last44=Staat |first44=Patrick |last45=Sudre |first45=Arnaud |last46=Elmer |first46=Eskil |last47=Hansson |first47=Magnus J. |last48=Bergerot |first48=Cyrille |last49=Boussaha |first49=Inesse |last50=Jossan |first50=Claire |last51=Derumeaux |first51=Geneviève |last52=Mewton |first52=Nathan |last53=Ovize |first53=Michel |title=Cyclosporine before PCI in Patients with Acute Myocardial Infarction |journal=New England Journal of Medicine |date=10 September 2015 |volume=373 |issue=11 |pages=1021–1031 |doi=10.1056/NEJMoa1505489 |pmid=26321103 |hdl=10044/1/41761 |doi-access=free |hdl-access=free }}</ref><ref name="pmid26821623">{{cite journal |last1=Ottani |first1=Filippo |last2=Latini |first2=Roberto |last3=Staszewsky |first3=Lidia |last4=La Vecchia |first4=Luigi |last5=Locuratolo |first5=Nicola |last6=Sicuro |first6=Marco |last7=Masson |first7=Serge |last8=Barlera |first8=Simona |last9=Milani |first9=Valentina |last10=Lombardi |first10=Mario |last11=Costalunga |first11=Alessandra |last12=Mollichelli |first12=Nadia |last13=Santarelli |first13=Andrea |last14=De Cesare |first14=Nicoletta |last15=Sganzerla |first15=Paolo |last16=Boi |first16=Alberto |last17=Maggioni |first17=Aldo Pietro |last18=Limbruno |first18=Ugo |title=Cyclosporine A in Reperfused Myocardial Infarction |journal=Journal of the American College of Cardiology |date=February 2016 |volume=67 |issue=4 |pages=365–374 |doi=10.1016/j.jacc.2015.10.081 |pmid=26821623 |s2cid=205575155 |doi-access=free }}</ref>

Reperfusion leads to biochemical imbalances within the cell that lead to [[cellular death|cell death]] and increased infarct size. More specifically, [[Hypercalcaemia|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.<ref name="Javadov S. 2007">{{cite journal |last1=Javadov |first1=Sabzali |last2=Karmazyn |first2=Morris |title=Mitochondrial Permeability Transition Pore Opening as an Endpoint to Initiate Cell Death and as a Putative Target for Cardioprotection |journal=Cellular Physiology and Biochemistry |date=2007 |volume=20 |issue=1–4 |pages=1–22 |doi=10.1159/000103747 |pmid=17595511 |s2cid=1949575 |doi-access=free }}</ref>

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.<ref name="Hausenloy D 2008">{{cite journal |last1=Hausenloy |first1=Derek J. |last2=Yellon |first2=Derek M. |title=Time to Take Myocardial Reperfusion Injury Seriously |journal=New England Journal of Medicine |date=31 July 2008 |volume=359 |issue=5 |pages=518–520 |doi=10.1056/NEJMe0803746 |pmid=18669431 }}</ref>

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.<ref name="Hausenloy D 2008" /> To that end, in 2011 the researchers involved in the original 2008 NEJM study initiated a phase III clinical study of reperfusion injury in 1000 myocardial infarction patients in centers throughout Europe. Results of that study were announced in 2015 and indicated that "intravenous cyclosporine did not result in better clinical outcomes than those with placebo and did not prevent adverse left ventricular remodeling at 1 year."<ref name="pmid26321103"/>
This same process of mitochondrial destruction through the opening of the MPT pore is implicated in making [[traumatic brain injuries]] much worse.<ref name="pmid21142667">{{cite journal |last1=Sullivan |first1=Patrick G. |last2=Sebastian |first2=Andrea H. |last3=Hall |first3=Edward D. |title=Therapeutic Window Analysis of the Neuroprotective Effects of Cyclosporine A after Traumatic Brain Injury |journal=Journal of Neurotrauma |date=February 2011 |volume=28 |issue=2 |pages=311–318 |doi=10.1089/neu.2010.1646 |pmid=21142667 |pmc=3037811 }}</ref>