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Eur J Pharm Sci ; 47(3): 604-14, 2012 Oct 09.
Artículo en Inglés | MEDLINE | ID: mdl-22564708


The development of diabetic cardiomyopathy is accompanied with a high membrane-bound protein kinase C (PKC) levels. Curcumin is a naturally occurring compound which is known to inhibit PKC activity. However, the effects of curcumin on ameliorating diabetic cardiomyopathy are still undefined. We evaluated whether curcumin treatment is associated with the modulation of PKC-α and -ß2-mitogen-activated protein kinase (MAPK) pathway in experimental diabetic cardiomyopathy. Diabetes was induced in male Sprague-Dawley rats by streptozotocin (STZ). Curcumin (100mg/kg/day) was started three weeks after STZ injection and was given for 8 weeks. We demonstrate that curcumin significantly prevented diabetes-induced translocation of PKC-α and -ß2 to membranous fraction and diabetes-induced increased phosphorylation of p38MAPK and extracellular regulated-signal kinase (ERK)1/2 in left ventricular tissues of diabetic rats. Curcumin treatment also markedly decreased NAD(P)H oxidase subunits (p67phox, p22phox, gp91phox), growth factors (transforming growth factor-ß, osteopontin) and myocyte enhancer factor-2 protein expression as well as inhibited NF-κB activity at nuclear level. Furthermore, curcumin decreased the mRNA expression of transcriptional coactivator p300 and atrial natriuretic peptide, decreased accumulation of ECM protein and reversed the increment of superoxide production in left ventricular tissues, as evidenced by dihydroethidium staining. It is also significantly lowered plasma glucose and attenuated oxidative stress, as determined by lipid peroxidation and activity of anti-oxidant enzyme, and as a result attenuated cardiomyocyte hypertrophy, myocardial fibrosis and left ventricular dysfunction. Taken together, it is suggested that curcumin by inhibiting PKC-α and -ß2-MAPK pathway may be useful as an adjuvant therapy for the prevention of diabetic cardiomyopathy.

Curcumina/uso terapéutico , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Cardiomiopatías Diabéticas/prevención & control , Inhibidores de Proteínas Quinasas/uso terapéutico , Animales , Curcumina/farmacología , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patología , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/patología , Fibrosis/tratamiento farmacológico , Fibrosis/patología , Glutatión Peroxidasa/metabolismo , Ventrículos Cardíacos/efectos de los fármacos , Ventrículos Cardíacos/patología , Ventrículos Cardíacos/fisiopatología , Hemodinámica , Hiperglucemia/tratamiento farmacológico , Peroxidación de Lípido/efectos de los fármacos , Masculino , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/patología , Estrés Oxidativo/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas/metabolismo , Ratas , Ratas Sprague-Dawley
Mol Nutr Food Res ; 55(11): 1655-65, 2011 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-22045654


SCOPE: We hypothesized that curcumin, a potent anti-oxidant, might be beneficial in ameliorating the development of diabetic nephropathy through inhibition of PKC-α and PKC-ß1 activity-ERK1/2 pathway. METHODS AND RESULTS: Diabetes was induced by a single intraperitoneal injection of streptozotocin (STZ) (55 mg/kg) in rats. Three weeks after STZ injection, rats were divided into three groups, namely, normal, diabetic and diabetic treated with curcumin at 100 mg/kg/day, p.o., for 8 wk. At 11 wk after STZ injection, diabetic rats exhibited renal dysfunction, as evidenced by reduced creatinine clearance, increased blood urea nitrogen (BUN) and proteinuria, marked increases in lipid peroxidation, NOX4 and p67phox and decrease in anti-oxidant enzyme. All of these abnormalities were significantly reversed by curcumin. Furthermore, the high-glucose-induced PKC-α and PKC-ß1 activities and phosphorylated ERK1/2 was significantly diminished by curcumin. Curcumin also attenuated the expression of TGF-ß1, CTGF, osteopontin, p300 and ECM proteins such as fibronectin and type IV collagen. The high-glucose-induced expression of VEGF and its receptor VEGF receptor II (flk-1) was also ameliorated by curcumin. CONCLUSION: These results prove that curcumin produces dual blockade of both PKC-α and PKC-ß1 activities, which suggests that curcumin is a potential adjuvant therapy for the prevention and treatment of diabetic nephropathy.

Curcumina/uso terapéutico , Diabetes Mellitus Tipo 1/complicaciones , Nefropatías Diabéticas/prevención & control , Riñón/efectos de los fármacos , Proteína Quinasa C-alfa/antagonistas & inhibidores , Proteína Quinasa C/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/uso terapéutico , Animales , Antioxidantes/uso terapéutico , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/patología , Nefropatías Diabéticas/fisiopatología , Proteínas de la Matriz Extracelular/genética , Proteínas de la Matriz Extracelular/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Isoenzimas/antagonistas & inhibidores , Isoenzimas/metabolismo , Riñón/metabolismo , Riñón/patología , Riñón/fisiopatología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , NADPH Oxidasa 4 , NADPH Oxidasas/metabolismo , Estrés Oxidativo/efectos de los fármacos , Fosfoproteínas/metabolismo , Proteína Quinasa C/metabolismo , Proteína Quinasa C beta , Proteína Quinasa C-alfa/metabolismo , ARN Mensajero/metabolismo , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Estreptozocina
Drug Discov Today ; 15(19-20): 826-41, 2010 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-20708094


Arginine vasopressin (AVP) attracted attention as a potentially important neurohormonal mediator of the heart failure (HF) syndrome and hyponatremic states in humans because AVP influences renal handling of free water, vasoconstriction and myocyte biology through activation of V2 and V1(a) receptors. Current research is exploring V2- and dual V1(a)/V2 receptor antagonism for the treatment of hyponatremia, as well as for the congestion and edema associated with chronic HF, because vasopressin receptor antagonists might offer benefits in comparison with conventional loop diuretics. The purpose of this review is to update the current status of experimental and clinical studies with available vasopressin receptor antagonists (conivaptan and tolvaptan) and their potential role in the treatment of HF and hyponatremia of multiple causes.

Antagonistas de los Receptores de Hormonas Antidiuréticas , Benzazepinas/farmacología , Insuficiencia Cardíaca/tratamiento farmacológico , Hiponatremia/tratamiento farmacológico , Arginina Vasopresina/metabolismo , Benzazepinas/uso terapéutico , Ensayos Clínicos como Asunto , Evaluación Preclínica de Medicamentos , Humanos , Hiponatremia/etiología , Receptores de Vasopresinas/metabolismo , Inhibidores del Simportador de Cloruro Sódico y Cloruro Potásico/farmacología , Tolvaptán