Cyclosporine A, a Potential Therapy of Ischemic Reperfusion Injury. A Common History for Heart and Brain

Abstract

Background: Ischemic stroke (IS) and acute myocardial infarction require emergency reperfusion tissue in order to improve functional outcome. Intra-arterial thrombectomy recently showed very encouraging improvement in IS patients' outcome. However, endovascular methods enhancing reperfusion may expose patients to increase in ischemic reperfusion injury. Experimental evidence indicates that brain ischemic reperfusion injury may be attenuated by ischemic pre- and postconditioning. The opening of mitochondrial permeability transition pore plays a critical role in the onset of reperfusion damage. This mechanism can be inhibited by immunosuppressive drugs like cyclosporine A (CsA). Summary: In this review, we present existing experimental and clinical data suggesting that conditioning interventions may prevent brain ischemic reperfusion injury and future challenge for neuroprotection by CsA in acute IS. Key Messages: The concept of conditioning has been recently investigated clinically but to a lesser extent in the realm of IS. Recent experimental and phase II clinical research has suggested potential neuroprotective properties of cyclosporine; however, further larger clinical trials are needed to demonstrate that CsA improves clinical outcome in acute IS patients.

Protective effect of cyclosporine A in the treatment of severe hydronephrosis in a rabbit renal pelvic perfusion model

“…In addition, a study found that the inhibition of cyclophilin D attenuated calcium transfer from the endoplasmic reticulum to the mitochondria in ischemiareperfusion injury [29], as accumulated cytosolic calcium can enhance the sensitivity of the mPTP. Moreover, the protection effect of CsA in ischemia injury was also found to be associated with inhibiting the translocation of the nuclear factor of activated T cells or preventing the dephosphorylation of NOS [9,30,31]; however, the specific mechanism remains unknown and further investigation is needed.…”

Treatment with dietary cyclosporine has no direct effect on myocardial fibrosis and hypertension in mice

“…27 Based on these findings, we propose that there may be a better option to improve cardiac remodeling and outcomes in patient if cyclosporine is orally administered daily after myocardial infarction and during the progression of heart failure. 25,28…”

Edaravone and cyclosporine A as neuroprotective agents for acute ischemic stroke

“…However, in patients with proximal cerebral artery occlusion and efficient recanalization, the infarct volume was significantly smaller than the placebo group. Although effectiveness was not confirmed as class I evidence, the study provided hope for larger clinical trials in the future as effectiveness was confirmed in some individuals with stroke …”

“…There are several neuroprotective agents considered to follow edaravone. Cyclosporine A (CsA), an immunosuppressive agent, is attracting attention as a drug that suppresses mitochondrial dysfunction resulting from the formation of ROS . Like edaravone, CsA's use as a neuroprotective agent has been studied by many Japanese researchers.…”