ROLE OF MINOCYCLINE IN MYOCARDIAL ISCHEMIA-REPERFUSION INJURY: AN OLD DRUG WITH NEW IMPLICATIONS
Tiziano M. Scarabelli, M.D., Ph.D., St John Hospital & Medical Center/Wayne State University SOM, USA
Minocycline is a semisynthetic second -generation tetracycline with proven safety, which is used in humans for the treatment of acne and urethritis. The drug is also considered for the treatment of severe chronic inflammatory diseases, such as rheumatoid arthritis, as it exerts anti-inflammatory effects that are completely separate and distinct from its antimicrobial action. It has been shown that minocycline protects the brain in rodent models of global and focal cerebral ischaemia as well as in patients with acute stroke. The significant neuroprotection was attributed to decreased expression of caspase-1 and cyclooxygenase 2 (COX-2), as well as inhibition of the inducible form of nitric oxide synthase (iNOS). Minocycline was also shown to inhibit mitochondrial leakage of cytochrome c and delay progression of amyotrophic lateral sclerosis in a transgenic mouse model of the disease. Protective effects of minocycline during ischemia/reperfusion (I/R) injury to a new target organ, the heart, have also been recently documented. Minocycline significantly reduced the post-ischemic occurrence of necrotic and apoptotic cell death, with normalization of developed and diastolic pressure. In regard to its antiapoptotic mechanism of action, minocycline reduced the expression level of initiator caspases, increased the ratio of XIAP to Smac/DIABLO at both the mRNA and protein level, and prevented the mitochondria-mediated release of cytochrome c and Smac/DIABLO. These synergetic actions dramatically prevented the post-ischemic induction of caspase activity associated with cardiac I/R injury. Owing to its safety record and multiple novel mechanisms of action, minocycline may be clinically useful not only to supply neuroprotection, but as cardioprotective agent, to ameliorate the cardiac dysfunction and cell loss associated with I/R injury.