Cardiac Uptake of Minocycline and Mechanisms for In Vivo Cardioprotection

Abstract

Objectives The ability of minocycline to be transported into cardiac cells, concentrate in normal and ischemic myocardium and act as in vivo cardioprotector was examined. We also determined minocycline's capacity to act as a reducer of myocardial oxidative stress and matrix metalloproteinase (MMP) activity. Background The identification of compounds with the potential to reduce myocardial ischemic injury is of great interest. Tetracyclines (TTCs) are antibiotics with pleiotropic cytoprotective properties that accumulate in normal and diseased tissues. Minocycline is highly lipophilic and has shown promise as a possible cardioprotector. However, minocycline's potential as an in vivo cardioprotector as well as the means by which this action is attained are not well understood. Methods Rats were subjected to 45 min of ischemia and 48 h of reperfusion. Animals were treated 48 h before and 48 h after thoracotomy with either vehicle or 50 mg/kg/day minocycline. Tissue samples were used for biochemical assays and cultured cardiac cells for minocycline uptake experiments. Results Minocycline significantly reduced infarct size (∼33%), tissue MMP-9 activity and oxidative stress. Minocycline was concentrated ∼24-fold in normal (0.5 mM) and ∼50-fold in ischemic regions (1.1 mM) vs. blood. Neonatal rat cardiac fibroblasts, myocytes and adult fibroblasts demonstrate a time- and temperature-dependent uptake of minocycline to levels that approximate those of normal myocardium. Conclusions Given the high intracellular levels observed and results from the assessment of in vitro antioxidant and MMP inhibitor capacities, it is likely that minocycline acts to limit myocardial ischemic injury via mass action effects.

Minocycline is More Potent Than Tetracycline and Doxycycline in Inhibiting MMP-9 in Vitro

“…In our study, minocycline showed the highest potency in MMP-9 inhibition, which is in accordance with previous reports that introduced minocycline as an effective MMP inhibitor in pathological states, such as ischemic cardiac events, cerebral neurologic damage, and arthritis (28). As a result of accumulation and concentration in cardiac cells, minocycline provides cardio protection at lower doses (29). In addition, due to its lipophilicity, minocycline can pass through the bloodbrain barrier and provide neuroprotection at a high potency (low IC50) in comparison to other tetracyclines (18).…”

Matrix Metalloproteinase (MMP)-9, but Not MMP-2, Is Involved in the Development and Progression of C Protein-Induced Myocarditis and Subsequent Dilated Cardiomyopathy

“…The effective use of minocycline in brain diseases such as encephalomyelitis (16,31) and stroke (21) has been demonstrated, but this is the first report to demonstrate the effectiveness of minocycline in heart inflammation. In addition to down-regulation of MMPs, minocycline has several functions, including antiapoptotic and antioxidant actions (32,33). Therefore, it is possible that carioprotection may be also exerted by these mechanisms other than MMP suppression.…”

Death, near death, and an antibiotic

“…Expanding from neuroprotection to possible cardioprotection, several preclinical studies administered minocycline in cardioplegia and in ischemia/reperfusion injury models and found beneficial results. 17,18 Further studies investigated mechanisms and found that minocycline reduces/inhibits several important mediators of inflammation and apoptosis including high mobility group box 1 protein (HMGB1) an early mediator of inflammation and poly(ADP-ribose) polymerase-1 (PARP-1) extensively activated in ischemic tissue where it releases apoptotic-inducing factors. 19,20 In this current study, the investigators used micro-SPECT/CT imaging to demonstrate lower uptake of GSAO in risk regions of minocycline-treated rabbits compared to saline-treated control rabbits.…”