Beneficial effects of melatonin in protecting against cyclosporine A‐induced cardiotoxicity are receptor mediated

Abstract

Melatonin, the chief product secreted by pineal gland, is capable of reducing free radical damage by acting directly as a free radical scavenger, and indirectly, by stimulating of antioxidant enzymes. Cyclosporine A (CsA) is the most widely used immunosuppressive drug, but its therapeutic use has several side effects including, i.e. nephrotoxicity and cardiotoxicity. This study was designed to examine the beneficial effects of melatonin in preventing CsA-induced cardiotoxicity. Additionally, we investigated the ability of melatonin to protect the rat heart via melatonin receptor. In one group of Wistar rats, melatonin (1 mg/kg/day i.p.) was administered concurrently with CsA (15 mg/kg/day s.c.) for 21 days. In another group of animals, melatonin was injected with CsA and luzindole, an antagonist of melatonin receptors. Oxidative stress in heart tissue homogenates was estimated using thiobarbituric acid reactive substances (TBARS), reduced glutathione levels and antioxidant enzyme activities including catalase and superoxide dismutase. CsA administration for 21 days produced elevated levels of TBARS, marked depletion of cardiac antioxidant enzymes and caused morphological alterations in myocardial fibers. Melatonin markedly reduced TBARS levels, increased the antioxidant enzyme levels and normalized altered cardiac morphology. The protective effects of melatonin were lost when the animals received the melatonin receptor antagonist. In conclusion our study shows that, (a) melatonin significantly reduces CsA cardiotoxicity, and (b) the reduction in CsA-induced cardiotoxicity was mediated by the binding of melatonin to its membrane receptors.

Melatonin attenuates lung injury in a hind limb ischemia–reperfusion rat model

“…4 Melatonin and its metabolites have been shown to have antioxidant properties in in vitro and in vivo systems, both in cells and body fluids. 22---24 Furthermore, melatonin plays an important role in activating antioxidant defences, 25,26 and protects cells from oxidative loads and apoptosis induced by mitochondrial DNA deletion. 27 Both effects allow melatonin to reduce the extent of reactive oxygen species, improving the outcomes of oxidative related pathologies such as ischemia 35 and prevention of aging.…”

Hepatoprotective actions of melatonin: Possible mediation by melatonin receptors

“…These results point to the possibility that although beneficial, the radical scavenging capacity of melatonin may not be necessary for its protective actions. This hypothesis is supported by the observation that in other organ systems, the protective potential of melatonin may also be antagonized by luzindole: this antagonist has been reported to abolish the protective capacity of melatonin after myocardial ischemia/reperfusion injury [177] , after cyclosporine-A cardiotoxicity [178] , in a model of neonatal brain injury [179] , and with respect to stressinduced gastric lesions [180] .…”

Melatonin receptors mediate improvements of liver function but not of hepatic perfusion and integrity after hemorrhagic shock in rats*

“…Besides melatonin receptors type 1 and 2 (MT 1 , MT 2 ), melatonin may exhibit protective potential via various intracellular binding sites (16). Melatonin receptor antagonist luzindole has been shown to antagonize melatonin's beneficial effects with respect to cardiac injury after ischemia/reperfusion (17) or cyclosporine A-induced cardiotoxicity (18). In a recent study, we were able to demonstrate that treatment with melatonin before hemorrhage and resuscitation improves liver function via receptordependent pathways (19).…”