Melatonin delivery in solid lipid nanoparticles: prevention of cyclosporine A induced cardiac damage.
Melatonin is a potent antioxidant molecule with a capacity to protect tissues from damage caused by oxidative stress. It reduces cyclosporine A (CsA)-induced cardiotoxicity; this improvement required melatonin's binding to its membrane receptors. This experimental study examined whether melatonin is a useful tool for counteracting CsA-induced apoptosis in the heart of rats. We investigated melatonin's antiapoptotic efficacy in protecting the heart and tested whether this effect was totally dependent on its binding to membrane receptors or also involved radical scavenging. In some animals, solid lipid nanoparticles (SLN) as a melatonin delivery system were used. In one group of rats, melatonin (1 mg/kg/day i.p.) was given concurrently with CsA (15 mg/kg/day s.c.; CsA-MT) for 21 days. In other animals, melatonin loaded in SLN was injected with CsA (CsA-MTSLN). Oxidative stress in heart tissue was estimated using the evaluation of lipid peroxidation and the expression of the isoform of inducible nitric oxide (iNOS). The antiapoptotic effect of melatonin was evaluated using TUNEL staining and Bcl-2 protein family expression. CsA administration produced morphological and biochemical changes in the heart of rats, while melatonin reversed the changes. In particular, since the antiapoptotic melatonin's efficacy is mainly observed when it is loaded in SLN, we suggest that MT1/MT2 pathway is not sufficient for apoptosis antagonism and the additional intracellular effects may be required. Finally, we show that, (i) melatonin significantly reduces CsA cardiotoxicity acting also on apoptotic processes, and (ii) the reduction in CsA-induced cardiotoxicity is mediated mainly by its antioxidant effect.
Rezzani
Rita
R
Division of Human Anatomy, Department of Biomedical Sciences and Biotechnology, University of Brescia, Brescia, Italy. rezzani@med.unibs.it
Rodella
Luigi Fabrizio
LF
Fraschini
Franco
F
Gasco
Maria Rosa
MR
Demartini
Germana
G
Musicanti
Claudia
C
Reiter
Russel J
RJ
D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016572:Cyclosporine / Q000633:toxicity*; D004337:Drug Carriers; D006331:Heart Diseases / Q000139:chemically induced* / Q000517:prevention & control*; D007166:Immunosuppressive Agents / Q000633:toxicity*; D020287:In Situ Nick-End Labeling; D015227:Lipid Peroxidation / Q000187:drug effects; D008055:Lipids / Q000008:administration & dosage / Q000627:therapeutic use; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D008550:Melatonin / Q000008:administration & dosage* / Q000378:metabolism / Q000627:therapeutic use; D009206:Myocardium / Q000648:ultrastructure; D053758:Nanoparticles / Q000008:administration & dosage* / Q000627:therapeutic use; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D004337:Drug Carriers; D007166:Immunosuppressive Agents; D008055:Lipids; D019253:Proto-Oncogene Proteins c-bcl-2; D008315:Malondialdehyde; D016572:Cyclosporine; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D008550:Melatonin