RESUMEN
BACKGROUND: Radical prostatectomy induces some degree of cavernous nerve injury (CNI) and causes denervation-induced pathologic changes in cavernous vasculature, regardless of the advances in surgical techniques and robotic procedures. The precursor for nerve growth factor (proNGF) is known to be involved in neuronal cell apoptosis and microvascular dysfunction through its receptor p75NTR . OBJECTIVES: To determine the expression of proNGF/p75NTR and the efficacy of proNGF neutralizing antibody (anti-proNGF-Ab) in a mouse model of ED induced by CNI. MATERIALS AND METHODS: Age-matched 12-week-old C57BL/6 mice were distributed into three groups: sham group and bilateral CNI group treated with intracavernous injections of PBS (20 µL) or of anti-proNGF-Ab (20 µg in 20 µL of PBS) on days -3 and 0. Two weeks after treatment, erectile function was measured by electrical stimulation of cavernous nerve. Penis tissues from a separate group of animals were harvested for further analysis. We also determined the efficacy of anti-proNGF-Ab on neural preservation in major pelvic ganglion (MPG) ex vivo. RESULTS: We observed increased penile expression of proNGF and p75NTR after CNI. Intracavernous administration of anti-proNGF-Ab increased nNOS and neurofilament expression probably by enhancing the production of neurotrophic factors, such as neurotrophin-3, NGF, and brain-derived neurotrophic factor. Anti-proNGF-Ab preserved the integrity of cavernous sinusoids, such as pericytes, endothelial cells, and endothelial cell-to-cell junctions, possibly by controlling angiogenic factors (angiopoietin-1, angiopoietin-2, and vascular endothelial growth factor) and induced endogenous eNOS phosphorylation in CNI mice. And finally, treatment with anti-proNGF-Ab rescued erectile function in CNI mice. Anti-proNGF-Ab also enhanced neurite sprouting from MPG exposed to lipopolysaccharide. DISCUSSION AND CONCLUSION: The preservation of damaged cavernous neurovasculature through inhibition of the proNGF/p75NTR pathway may be a novel strategy to treat radical prostatectomy-induced erectile dysfunction.
Asunto(s)
Anticuerpos Neutralizantes/uso terapéutico , Disfunción Eréctil/tratamiento farmacológico , Factor de Crecimiento Nervioso/antagonistas & inhibidores , Pene/efectos de los fármacos , Traumatismos de los Nervios Periféricos/tratamiento farmacológico , Precursores de Proteínas/antagonistas & inhibidores , Proteínas Angiogénicas/metabolismo , Animales , Anticuerpos Neutralizantes/farmacología , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Disfunción Eréctil/etiología , Masculino , Ratones Endogámicos C57BL , Factor de Crecimiento Nervioso/metabolismo , Pene/inervación , Pene/metabolismo , Traumatismos de los Nervios Periféricos/metabolismo , Prostatectomía/efectos adversos , Precursores de Proteínas/metabolismo , Receptores de Factor de Crecimiento Nervioso/metabolismoRESUMEN
OBJECTIVES: To investigate the antioxidant activity of Korean red ginseng (KRG) and its effect on erectile function in non-insulin-dependent diabetes mellitus (NIDDM) rats. Oxidative stress is an important factor in vascular complications of diabetes. METHODS: A total of 84 male Sprague-Dawley rats were included in this study. NIDDM was induced by an intraperitoneal injection of 90 mg/kg of streptozotocin on day 2 after birth. According to the diabetic period, they were classified as either short-term (22 weeks, n = 32) or long-term (38 weeks, n = 32) diabetics. Of those, 20 (10 short-term and 10 long-term) were fed 30 mg/kg of KRG three times weekly for 1 month. The remaining diabetic rats (22 short-term and 22 long-term) and their age-matched controls (n = 10 each for each group) were fed a normal diet. Erectile function was measured after electrostimulation of the cavernous nerve. The total cavernous malondialdehyde and glutathione levels were measured using a spectrophotometric assay. RESULTS: The intracavernous pressure after nerve stimulation and cavernous glutathione level were significantly lower in the long-term than the short-term diabetics with a normal diet and were markedly decreased compared with their age-matched controls (P <0.01 and P <0.05, respectively). The malondialdehyde content was markedly increased in the short-term diabetics compared with the controls (P <0.05). In contrast, erectile function was not impaired in the diabetic group treated with KRG. Furthermore, both glutathione and malondialdehyde levels in those treated with KRG were comparable to their age-matched controls. CONCLUSIONS: Oxidative stress to cavernous tissue may be a contributory factor in erectile dysfunction in diabetics. KRG may preserve potency in the NIDDM rats through its antioxidant activity.
Asunto(s)
Antioxidantes/uso terapéutico , Complicaciones de la Diabetes/tratamiento farmacológico , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Disfunción Eréctil/tratamiento farmacológico , Disfunción Eréctil/etiología , Panax , Fitoterapia , Preparaciones de Plantas/uso terapéutico , Animales , Diabetes Mellitus Experimental , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
Transforming growth factor (TGF) beta1 has been suggested to have an important role in cavernous fibrosis and resultant erectile dysfunction. For further elucidation of TGFbeta1 signaling in association with cavernous fibrosis, we developed a rat model of cavernous fibrosis using TGFbeta1-producing NIH 3T3 fibroblasts (NIH 3T3-TGFbeta1). The NIH 3T3-TGFbeta1 cells were injected into male Sprague-Dawley rats intracavernously. Masson trichrome staining at 20 days postinjection showed multiple fibrous scars in the rats injected with the NIH 3T3-TGFbeta1 cells (group 3), whereas no histological evidence of cavernous fibrosis was found in the control rats (group 1) or the recombinant human TGFbeta1 protein-injected rats (group 2). Immunohistochemical staining revealed a higher expression of TGFbeta1 and its type II receptor in group 3 than in groups 1 and 2. Electrostimulation of the cavernous nerve revealed that the maximal intracavernous pressure was significantly lower in group 3 than in groups 1 and 2 (P < 0.01). The expression of transgenic TGFbeta1 mRNA continued to 10 days after injection of the cells. The NIH 3T3-TGFbeta1 cells sufficiently induced relatively long-lasting cavernous fibrosis. This novel animal model may contribute to future investigations of the pathogenesis of penile fibrosis associated with TGFbeta1 signaling and the development of new therapeutics targeting this pathway.