RESUMO
Cardiovascular disorders constitute the principal cause of deaths worldwide and will continue as the major disease-burden by the year 2060. A significant proportion of heart failures occur because of use and misuse of drugs and most of the investigational agents fail to achieve any clinical relevance. Here, we investigated rosuvastatin and retinoic acid for their "pharmacological pleiotropy" against high dose ß-adrenergic agonist (isoproterenol)-induced acute myocardial insult. Rats were pretreated with rosuvastatin and/or retinoic acid for seven days and the myocardial injury was induced by administering isoproterenol on the seventh and eighth day. After induction, rats were anaesthetized for electrocardiography, then sacrificed and different samples were collected/stored for various downstream assays. Myocardial injury with isoproterenol resulted in increased cardiac mass, decreased R-wave amplitude, increased QRS and QT durations; elevated levels of cardiac markers like cTnI, CK-MB, ALT and AST; increased lipid peroxidation, protein carbonylation and tissue nitric oxide levels; decreased endogenous antioxidants like SOD, CAT, GR, GST, GPx and total antioxidant activity; increased inflammatory markers like TNF-α and IL-6; decreased the mRNA expression of Nrf2 and Bcl-2; increased the mRNA expression of Bax, eNOS and iNOS genes. Pretreatment with rosuvastatin and/or retinoic acid mitigated many of the above biochemical and pathological alterations. Our results demonstrate that rosuvastatin and retinoic acid exert cardioprotective effects and may act as potential agents in the prevention of ß-adrenergic agonist-induced acute myocardial injury in rats. Cardioprotective potential of rosuvastatin and retinoic acid could be attributed to their influence on the redox pathways, immunomodulation, membrane stability, Nrf2 preservation, iNOS and Bax expression levels. Thus, they may act directly or indirectly at various steps, the breakpoints, in the pathophysiological cascade responsible for cardiac injury. Our study gives insights about the pharmacological pleiotropism of rosuvastatin and retinoic acid.
Assuntos
Isoproterenol/toxicidade , Infarto do Miocárdio/induzido quimicamente , Infarto do Miocárdio/prevenção & controle , Rosuvastatina Cálcica/farmacologia , Transdução de Sinais/efeitos dos fármacos , Tretinoína/farmacologia , Agonistas Adrenérgicos beta/toxicidade , Animais , Anticolesterolemiantes/farmacologia , Antineoplásicos/uso terapêutico , Peso Corporal/efeitos dos fármacos , Coração/anatomia & histologia , Coração/efeitos dos fármacos , Masculino , Tamanho do Órgão , Distribuição Aleatória , Ratos , Ratos WistarRESUMO
Nanoparticles have higher frequency of being exposed to cells or tissue, and are thus more likely to gain access into cytoplasm or nuclei to modulate molecular events due to significantly larger surface area to volume ratio. As a result, they present amplified response or even different physiochemical and biomedical properties from bigger particles. Deferoxamine accelerates wound healing in diabetic rats by increased neovascularization, reduced inflammation and improved maturation of wound. We investigated the wound healing potential of deferoxamine-nanoparticles in diabetic rats. Lecithin based nanoparticles of deferoxamine were prepared and characterized. The diabetic rats were divided into five Groups, of which Group I was treated with pluronic-gel f-127 (25%), Group II with deferoxamine 0.1% and Group III, IV and V were treated with deferoxamine-nanoparticles incorporated in pluronic-gel f-127 25% at 0.03% (0.01% deferoxamine), 0.1% (0.03% deferoxamine) and 0.3% (0.1% deferoxamine) w/v respectively. The wound closure was significantly accelerated in group V as compared to control groups. HIF-1α, VEGF, SDF-1α, TGF-ß1, and IL-10 protein levels were significantly higher in group V. The collagen deposition and neovascularization was greater in deferoxamine-nanoparticle treated rats. In contrast, TNF-α level was lowest in group V. In summary, the deferoxamine-nanoparticle formulation we developed, when applied topically on diabetic wounds results in faster wound healing as compared to simple deferoxamine formulation. This formulation may prove to be an effective therapy for treatment of diabetic wounds.