RESUMO
This work presents a model of rats fed a high-cholesterol diet, receiving a long-term oral administration of cilostazol, a PDE3-inhibitor. The aim of this study was to evaluate the molecular mechanisms by which cilostazol interferes with platelets signaling pathways to avoid atherosclerosis early development. Male Wistar rats were divided into 3 groups: Control group received standard rat chow (C), hypercholesterolemic group (HCD), and HCD+CIL (cilostazol group) received hypercholesterolemic diet for 45 days. HCD+CIL group received cilostazol (30 mg/kg/p.o.) once daily in the last 15 days. Platelet aggregation, lipid profile, lipid peroxidation, and cytokine serum levels were assessed. Expression of P-selectin, CD40L, PKC-α, IkB-α, and iNOS and activation of AMPK, NF-κB, and eNOS in the platelets were assessed using Western blot analysis. Cilostazol reduced the levels of total cholesterol (361.0 ± 12.8 vs. 111.5 ± 1.6 mg/dL), triglycerides (186.9 ± 17.7 vs. 55.4 ±3.1 mg/dL), cLDL (330.9 ± 9.7 vs. 61.5 ± 3.5 mg/dL), cVLDL (45.0 ± 4.6 vs. 11.1 ± 0.6 mg/dL), and malondialdehyde (9.4 ± 0.5 vs. 3.2 ± 0.3 nmol/mL) compared to the HCD group. Cilostazol presented antiplatelet properties and decreased inflammatory markers levels. These effects seem to be related to AMPK activation, NF-kB inhibition, and eNOS activation.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Anti-Inflamatórios/farmacologia , Hipercolesterolemia/metabolismo , NF-kappa B/metabolismo , Inibidores da Agregação Plaquetária/farmacologia , Tetrazóis/farmacologia , Animais , Anti-Inflamatórios/uso terapêutico , Cilostazol , Relação Dose-Resposta a Droga , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/fisiologia , Hipercolesterolemia/tratamento farmacológico , Masculino , NF-kappa B/antagonistas & inibidores , Inibidores da Agregação Plaquetária/uso terapêutico , Ratos , Ratos Wistar , Tetrazóis/uso terapêutico , Resultado do TratamentoAssuntos
HDL-Colesterol/sangue , Talidomida/análogos & derivados , Talidomida/farmacologia , Triglicerídeos/sangue , Fator de Necrose Tumoral alfa/sangue , Animais , HDL-Colesterol/antagonistas & inibidores , Relação Dose-Resposta a Droga , Hipercolesterolemia/sangue , Hipercolesterolemia/tratamento farmacológico , Masculino , Ratos , Ratos Wistar , Talidomida/uso terapêutico , Triglicerídeos/antagonistas & inibidores , Fator de Necrose Tumoral alfa/antagonistas & inibidoresRESUMO
The compound LASSBio-788 (N-Allyl (2-thienylidene) 3,4-methylenedioxybenzoylhydrazine) is a thienylacylhydrazone derivative shown to have antiplatelet, vasodilatory, and anti-inflammatory properties in vitro. We hypothesize that LASSBio-788 may exert beneficial effects on atherosclerosis. Male wistar rats were divided into 4 groups: Control group received standard rat chow, hypercholesterolemic group (HC) and HC+788 (compound LASSBio-788 group) received hypercholesterolemic diet for 45 days. HC+788 group received compound LASSBio-788 (100 µmol/kg) once daily in the last 15 days. LASSBio-788 reduced the levels of total cholesterol (109.1 ± 4.3 vs. 361.0 ± 12.8 mg/dl), triglycerides (66.1 ± 1.1 vs. 186.9 ± 17.7 mg/dl), LDLc (63.2 ± 6.1 vs. 330.9 ± 9.7 mg/dl), VLDLc (9.8 ± 1.1 vs. 45.0 ± 4.6 mg/dl) and malondialdehyde (4.8 ± 0.3 vs. 9.4 ± 0.5 nmol/ml) compared to the HC group. LASSBio-788 presented antiplatelet properties and decreased inflammatory markers levels. LASSBio-788 promoted a decrease in contractile response to phenylephrine and an improvement in endothelium-dependent vasorelaxant response by increasing two-fold the expression of nitric oxide synthase (eNOS). Our results suggest that the compound LASSBio-788 represents a new multi-targeted drug candidate for the treatment of atherosclerosis.
