RESUMEN
Bleomycin is a well-recognized antineoplastic drug. However, pulmonary fibrosis (PF) is considered to be the principal drawback that greatly limits its use. Here, we sought to investigate ability of the neurokinin receptor 1 blocker, aprepitant, to prevent PF caused by bleomycin. Male adult Wistar rat groups were given a single intratracheal injection of bleomycin, either alone or in combination with aprepitant therapy for 3 or 14 days. Collagen deposition and a rise in transforming growth factor beta (TGF-ß) immunoreactivity in lung tissue serve as evidence of bleomycin-induced PF. The serum levels of lactate dehydrogenase, alkaline phosphatase, and total antioxidant improved after aprepitant therapy.Additionally, it reduced the protein expressions of interferon alpha, tumor necrosis factor alpha, and lung lipid peroxidation. Moreover, aprepitant treatment led to an increase in the antioxidant indices glutathione, glutathione peroxidase, and catalase. Aprepitant is postulated to protect against bleomycin-induced PF by decreasing TGF-ß, phosphorylating Smad3, and increasing interleukin 37, an anti-fibrotic cytokine, and G Protein-coupled Receptor Kinase 2. Aprepitant for 14 days considerably exceeded aprepitant for 3 days in terms of improving lung damage and having an anti-fibrotic impact. In conclusion, aprepitant treatment for 14 days may be used as an adjuvant to bleomycin therapy to prevent PF, mostly through inhibiting the TGF-/p-Smad3 fibrotic pathway.
Asunto(s)
Bleomicina , Fibrosis Pulmonar , Fosfatasa Alcalina/metabolismo , Animales , Antioxidantes/metabolismo , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Aprepitant/efectos adversos , Bleomicina/toxicidad , Catalasa/metabolismo , Colágeno/metabolismo , Citocinas/metabolismo , Glutatión/metabolismo , Glutatión Peroxidasa/metabolismo , Interferón-alfa/efectos adversos , Interleucinas/metabolismo , Lactato Deshidrogenasas/metabolismo , Pulmón , Masculino , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/tratamiento farmacológico , Fibrosis Pulmonar/prevención & control , Ratas , Ratas Wistar , Receptores Acoplados a Proteínas G/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
AIMS: Male infertility prevalence is higher in diabetic patients. Those patients exhibit testicular oxidative damage due to sustained hyperglycemia and inflammation. The study has investigated the efficacy of cilostazol, a phosphodiesterase 3 inhibitor, on testicular damage of diabetic rats. MAIN METHODS: Streptozotocin-induced diabetes in rats was used as a model. Six control male rats and 24 diabetic male rats were divided into the following: diabetic, cilostazol at low dose, cilostazol at high dose, and sildenafil treated rat groups. Treatment period was 4â¯weeks. Then, serum testosterone, testicular oxidative parameters, and testicular oxidant defenses were assayed. Real time PCR was done for quantification of Phosphoinositide 3-kinase (PI3K), Akt, and nuclear factor (NF)-κB mRNA. Expression of testicular inducible nitric oxide synthase (iNOS) was assessed. KEY FINDINGS: Diabetes negatively affected the testicular tissue as evident by biochemical analysis and histopathology. Four weeks of cilostazol or sildenafil treatment improved anti-oxidative capacity, ameliorated lipid peroxidation and the pro-inflammatory iNOS expression in testicular tissue. Testosterone level and the spermatogenesis showed marked improvement. Quantitative mRNA expression showed an elevation in PI3K and Akt by cilostazol with decreasing in NF-κB level by both drugs. SIGNIFICANCE: Our findings suggest the beneficial role of cilostazol and sildenafil in diabetic testicular damage dependent on anti-inflammatory and anti-oxidant effects.