RESUMEN
BACKGROUND AND PURPOSE: Cyclophosphamide induces urotoxicity characterized by the development of cystitis, which involves bladder overactivity and inflammation. Here, we investigated the roles of chemokine receptor 2 (CXCR2) and transient receptor potential vanilloid 1 (TRPV1) channels in a rat model of cyclophosphamide-induced cystitis. EXPERIMENTAL APPROACH: Cystitis induced by cyclophosphamide in rats was assessed by gross morphology, histology and immunohistochemistry of bladder tissue. mRNA for CXCR2 and TRPV1 channels were measured by RT-PCR. Nociceptive responses in paw and abdomen, along with cystometric measures were recorded. KEY RESULTS: Cyclophosphamide, i.p., induced pain behaviour, bladder inflammation and voiding dysfunction. The CXCR2 antagonist, SB225002, the TRPV1 channel antagonist, SB366791 or their combination reduced the mechanical hypersensitivity of paw and abdominal area and nociceptive behaviour after cyclophosphamide. Cyclophosphamide-induced cystitis was characterized by haemorrhage, oedema, neutrophil infiltration and other inflammatory changes, which were markedly decreased by the antagonists. Up-regulation of CXCR2 and TRPV1 mRNA in the bladder after cyclophosphamide was inhibited by SB225002, SB366791 or their combination. Expression of CXCR2 and TRPV1 channels was increased in the urothelium after cyclophosphamide. Bladder dysfunction was shown by increased number of non-voiding contractions (NVCs) and bladder pressures and a reduction in bladder capacity (BC), voided volume (VV) and voiding efficiency (VE). SB225002 or its combination with SB366791 reduced bladder pressures, whereas SB225002, SB366791 or their combination increased BC, VV and VE, and also reduced the number of NVCs. CONCLUSIONS AND IMPLICATIONS: CXCR2 and TRPV1 channels play important roles in cyclophosphamide-induced cystitis in rats and could provide potential therapeutic targets for cystitis.
Asunto(s)
Antineoplásicos Alquilantes , Conducta Animal/efectos de los fármacos , Ciclofosfamida , Cistitis/patología , Trastornos Hemorrágicos/patología , Inflamación/patología , Receptores de Interleucina-8B/metabolismo , Canales Catiónicos TRPV/metabolismo , Animales , Cistitis/inducido químicamente , Cistitis/tratamiento farmacológico , Citocinas/metabolismo , Femenino , Trastornos Hemorrágicos/inducido químicamente , Trastornos Hemorrágicos/tratamiento farmacológico , Hiperalgesia/inducido químicamente , Hiperalgesia/psicología , Inmunohistoquímica , Neutrófilos/metabolismo , Tamaño de los Órganos/efectos de los fármacos , Dimensión del Dolor/efectos de los fármacos , Peroxidasa/metabolismo , Ratas , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores de Interleucina-8B/antagonistas & inhibidores , Canales Catiónicos TRPV/antagonistas & inhibidores , Vejiga Urinaria/patologíaRESUMEN
BACKGROUND: Kinin B1 receptors are inducible molecules up-regulated after inflammatory stimuli. This study evaluated the relevance of kinin B1 receptors in a mouse depression behavior model. METHODS: Mice were exposed to a 5-min swimming session, and 30 min later they were injected with E. coli lipopolysaccharide (LPS). Depression-like behavior was assessed by determining immobility time in a tail suspension test. Different brain structures were collected for molecular and immunohistochemical studies. Anhedonia was assessed by means of a sucrose intake test. RESULTS: Our protocol elicited an increase in depression-like behavior in CF1 mice, as assessed by the tail-suspension test, at 24 h. This behavior was significantly reduced by treatment with the selective B1 receptor antagonists R-715 and SSR240612. Administration of SSR240612 also prevented an increase in number of activated microglial cells in mouse hippocampus, but did not affect a reduction in expression of mRNA for brain-derived neurotrophic factor. The increased immobility time following LPS treatment was preceded by an enhancement of hippocampal and cortical B1 receptor mRNA expression (which were maximal at 1 h), and a marked production of TNFα in serum, brain and cerebrospinal fluid (between 1 and 6 h). The depression-like behavior was virtually abolished in TNFα p55 receptor-knockout mice, and increased B1 receptor mRNA expression was completely absent in this mouse strain. Furthermore, treatment with SSR240612 was also effective in preventing anhedonia in LPS-treated mice, as assessed using a sucrose preference test. CONCLUSION: Our data show, for the first time, involvement of kinin B1 receptors in depressive behavioral responses, in a process likely associated with microglial activation and TNFα production. Thus, selective and orally active B1 receptor antagonists might well represent promising pharmacological tools for depression therapy.
Asunto(s)
Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Depresión/fisiopatología , Lipopolisacáridos/farmacología , Receptor de Bradiquinina B1/metabolismo , Estrés Psicológico , Animales , Encéfalo/citología , Encéfalo/metabolismo , Humanos , Cininas , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microglía/citología , Microglía/metabolismo , Receptor de Bradiquinina B1/genética , Receptores Tipo I de Factores de Necrosis Tumoral/genética , Receptores Tipo I de Factores de Necrosis Tumoral/metabolismo , Receptores Señuelo del Factor de Necrosis Tumoral/genética , Receptores Señuelo del Factor de Necrosis Tumoral/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
It has been demonstrated that kinin B(1) receptors are highly up-regulated under several stressful stimuli, such as infection. However, there is no evidence indicating whether Porphyromonas gingivalis lipopolysaccharide (Pg-LPS) might lead to B(1) receptor up-regulation. In this study, we demonstrate that Pg-LPS injection into the rat paw resulted in a marked functional up-regulation of B(1) receptors (as measured by an increase of B(1) receptor-induced edema), which was preceded by a rapid rise in B(1) receptor mRNA expression. The local administration of Pg-LPS also resulted in a prominent production of the proinflammatory cytokine tumor necrosis factor alpha (TNF-alpha), followed by an increase of neutrophil influx; both events were observed at periods before B(1) receptor induction. The functional and molecular Pg-LPS-elicited B(1) receptor up-regulation was significantly reduced by the glucocorticoid dexamethasone (0.5 mg/kg s.c.), and to a lesser extent by the chimeric anti-TNF-alpha antibody infliximab (1 mg/kg s.c.). Of high relevance, we show for the first time that a single administration of the proresolution lipid mediator (5S,12R,18R)-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid (resolvin E1; 300 ng/rat i.p.) was able to markedly down-regulate Pg-LPS-driven B(1) receptor expression, probably by inhibiting TNF-alpha production and neutrophil migration. Collectively, the present findings clearly suggest that Pg-LPS is able to induce the up-regulation of B(1) receptors through mechanisms involving TNF-alpha release and neutrophil influx, which are largely sensitive to resolvin E1. It is tempting to suggest that kinin B(1) receptors might well represent a pivotal pathway for the inflammatory responses evoked by P. gingivalis and its virulence factors.