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1.
Artigo em Inglês | MEDLINE | ID: mdl-31136852

RESUMO

Copper is a metal that participates in several essential reactions in living organisms, and it has been used as an inflammatory inducing agent in zebrafish larvae. In this study, we evaluated the effect P2X7 receptor and/or pannexin channel 1 (PANX-1) blockage in this inflammation model. To perform the experiments, 7 dpf larvae were exposed to 10 µM of copper and treated with 100 µM probenecid, PANX-1 inhibitor, and/or 300 nM A740003, a P2X7R selective antagonist. Larvae survival was assessed up to 24 h after treatments. The evaluation of larvae behavior was evaluated after acute (4 h) and chronic (24 h) exposure. The parameters of locomotor activity measured were: mobile time, average speed, distance and turn angle. We analyzed the gene expression of the P2X7 receptor, PANX1a and PANX1b channels and interleukins IL-10 and IL-1b after 24 h of treatment. Treatments did not decrease larval survival in the time interval studied. Changes in larvae locomotion were observed after the longest time of exposure to copper and the treatment with probenecid was able to reverse part of the effects caused by copper. No significant difference was observed in the oxidative stress assays and probenecid and copper treatment decrease partially PANX1a gene expression groups. The data presented herein shows the relevance of the blockage of P2X7-PANX-1 in copper-induced inflammation.


Assuntos
Conexinas/genética , Cobre/toxicidade , Inflamação/induzido quimicamente , Receptores Purinérgicos P2X7/genética , Proteínas de Peixe-Zebra/genética , Peixe-Zebra/metabolismo , Acetamidas/farmacologia , Animais , Conexinas/antagonistas & inibidores , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/mortalidade , Interleucina-10/genética , Interleucina-1beta/genética , Larva/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Masculino , Estresse Oxidativo , Probenecid/farmacologia , Antagonistas do Receptor Purinérgico P2X/toxicidade , Quinolinas/farmacologia , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/antagonistas & inibidores
2.
Br J Pharmacol ; 172(3): 924-39, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25298144

RESUMO

BACKGROUND AND PURPOSE: Spinal voltage-gated calcium channels (VGCCs) are pivotal regulators of painful and inflammatory alterations, representing attractive therapeutic targets. We examined the effects of epidural administration of the P/Q- and N-type VGCC blockers Tx3-3 and Phα1ß, respectively, isolated from the spider Phoneutria nigriventer, on symptomatic, inflammatory and functional changes allied to mouse cyclophosphamide (CPA)-induced haemorrhagic cystitis (HC). The effects of P. nigriventer-derived toxins were compared with those displayed by MVIIC and MVIIA, extracted from the cone snail Conus magus. EXPERIMENTAL APPROACH: HC was induced by a single i.p. injection of CPA (300 mg·kg(-1) ). Dose- and time-related effects of spinally administered P/Q and N-type VGCC blockers were assessed on nociceptive behaviour and macroscopic inflammation elicited by CPA. The effects of toxins were also evaluated on cell migration, cytokine production, oxidative stress, functional cystometry alterations and TRPV1, TRPA1 and NK1 receptor mRNA expression. KEY RESULTS: The spinal blockage of P/Q-type VGCC by Tx3-3 and MVIIC or N-type VGCC by Phα1ß attenuated nociceptive and inflammatory events associated with HC, including bladder oxidative stress and cytokine production. CPA produced a slight increase in bladder TRPV1 and TRPA1 mRNA expression, which was reversed by all the toxins tested. Noteworthy, Phα1ß strongly prevented bladder neutrophil migration, besides HC-related functional alterations, and its effects were potentiated by co-injecting the selective NK1 receptor antagonist CP-96345. CONCLUSIONS AND IMPLICATIONS: Our results shed new light on the role of spinal P/Q and N-type VGCC in bladder dysfunctions, pointing out Phα1ß as a promising alternative for treating complications associated with CPA-induced HC.


Assuntos
Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo N/metabolismo , Cistite/tratamento farmacológico , Hemorragia/tratamento farmacológico , Neuropeptídeos/farmacologia , Venenos de Aranha/farmacologia , Animais , Bloqueadores dos Canais de Cálcio/administração & dosagem , Bloqueadores dos Canais de Cálcio/isolamento & purificação , Ciclofosfamida/administração & dosagem , Cistite/induzido quimicamente , Masculino , Camundongos , Neuropeptídeos/administração & dosagem , Neuropeptídeos/isolamento & purificação , Venenos de Aranha/administração & dosagem , Venenos de Aranha/isolamento & purificação , Medula Espinal/efeitos dos fármacos
3.
Neuroscience ; 280: 220-30, 2014 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-25239372

RESUMO

Adenosine triphosphate (ATP) plays a role in cell signaling. It was soon proposed that ATP activates ionotropic P2X receptors, exerting an influence on neurons as well as on glial cells. In addition to the fact that the activation of P2X and P2Y receptors can stimulate or inhibit the release of glutamate from rat hippocampal neurons, the release of ATP has been implicated in hippocampal long-term potentiation (LTP). Through different behavioral paradigms, this study aimed to investigate the participation of P2X7R in genetically modified (knockout (KO)) mice with the suppressed expression of this receptor and in the pharmacological blockage of this receptor in rats, as well as to evaluate the effect of environmental enrichment on potential mnemonic deficits. The results suggest that P2X7R participates in aversive memory processes: pharmacological blockage with the selective P2X7R antagonist, A-740003, in different time frames elicited dose-dependent impairments in memory acquisition, consolidation and retrieval in rats that were submitted to the contextual fear-conditioning (FC) task, and the deletion of P2X7R hampered the aversive memory processes of mice that were subjected to the FC paradigm. Experiments using mice that were subjected to environmental enrichment suggest that this form of stimulation reverses mnemonic impairments that are ascribed to the absence of the P2X7R, suggesting that these receptors do not participate on such a reversal. Finally, no alterations were observed in the habituation memory of P2X7KO mice.


Assuntos
Acetamidas/farmacologia , Memória/efeitos dos fármacos , Memória/fisiologia , Antagonistas do Receptor Purinérgico P2X/farmacologia , Quinolinas/farmacologia , Receptores Purinérgicos P2X7/fisiologia , Animais , Região CA1 Hipocampal/efeitos dos fármacos , Região CA1 Hipocampal/fisiologia , Condicionamento Psicológico/efeitos dos fármacos , Condicionamento Psicológico/fisiologia , Relação Dose-Resposta a Droga , Meio Ambiente , Medo/efeitos dos fármacos , Medo/fisiologia , Habituação Psicofisiológica/efeitos dos fármacos , Habituação Psicofisiológica/fisiologia , Abrigo para Animais , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Limiar da Dor/efeitos dos fármacos , Limiar da Dor/fisiologia , Distribuição Aleatória , Ratos Wistar , Receptores Purinérgicos P2X7/genética
4.
Invest New Drugs ; 31(4): 812-22, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23224295

RESUMO

Kinins and their receptors have been recently implicated in cancer. Using functional and molecular approaches, we investigated the relevance of kinin B1 and B2 receptors in bladder cancer. Functional studies were conducted using bladder cancer cell lines, and human biopsies were employed for molecular studies. Both B1 des-Arg(9)-BK and B2 BK receptor agonists stimulated the proliferation of grade 3-derived T24 bladder cancer cells. Furthermore, treatment with B1 and B2 receptor antagonists (SSR240612 and HOE140) markedly inhibited the proliferation of T24 cells. Only higher concentrations of BK increased the proliferation of the grade 1 bladder cancer cell line RT4, while des-Arg(9)-BK completely failed to induce its proliferation. Real-time PCR revealed that the mRNA expression of kinin receptors, particularly B1 receptors, was increased in T24 cells relative to RT4 cells. Data from bladder cancer human biopsies revealed that B1 receptor expression was increased in all tumor samples and under conditions of chronic inflammation. We also show novel evidence demonstrating that the pharmacological inhibition of PI3Kγ (phosphatidylinositol 3-kinase) with AS252424, concentration-dependently reduced T24 cell proliferation induced by BK or des-Arg(9)-BK. Finally, the incubation of T24 cells with kinin agonists led to a marked activation of the PI3K/AKT and ERK 1/2 signaling pathways, whereas p38 MAP kinase remained unaffected. Kinin receptors, especially B1 receptors, appear to be implicated in bladder cancer progression. It is tempting to suggest that selective kinin antagonists might represent potential alternative therapies for bladder cancer.


Assuntos
Fosfatidilinositol 3-Quinases/metabolismo , Receptor B1 da Bradicinina/metabolismo , Receptor B2 da Bradicinina/metabolismo , Neoplasias da Bexiga Urinária/enzimologia , Idoso , Idoso de 80 Anos ou mais , Biópsia , Antagonistas de Receptor B1 da Bradicinina , Antagonistas de Receptor B2 da Bradicinina , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Sistema de Sinalização das MAP Quinases , Pessoa de Meia-Idade , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor B1 da Bradicinina/agonistas , Receptor B1 da Bradicinina/genética , Receptor B2 da Bradicinina/agonistas , Receptor B2 da Bradicinina/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Tiazolidinedionas/farmacologia , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/enzimologia , Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia
5.
Br J Pharmacol ; 165(1): 183-96, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21675966

RESUMO

BACKGROUND AND PURPOSE: ATP is released in response to cellular damage, and P2X7 receptors have an essential role in the onset and maintenance of pathological changes. Haemorrhagic cystitis (HC) is a well-known adverse effect of therapy with cyclophosphamide used for the treatment of many solid tumours and autoimmune conditions. Here we have evaluated the role of P2X7 receptors in a model of HC induced by cyclophosphamide. EXPERIMENTAL APPROACH: Effects of pharmacological antagonism or genetic deletion of P2X7 receptor on cyclophosphamide-induced HC in mice was assessed by nociceptive and inflammatory measures. In addition, the presence of immunoreactive P2X7 receptors was assessed by immunohistochemistry. KEY RESULTS: Pretreatment with the selective P2X7 receptor antagonist A-438079 or genetic ablation of P2X7 receptors reduced nociceptive behaviour scores in the HC model. The same strategies decreased both oedema and haemorrhage indices, on macroscopic or histological evaluation. Treatment with A-438079 decreased the staining for c-Fos in the lumbar spinal cord and brain cortical areas. Treatment with A-438079 also prevented the increase of urinary bladder myeloperoxidase activity and macrophage migration induced by cyclophosphamide and reduced the tissue levels of IL-1ß and TNF-α. Finally, P2X7 receptors were markedly up-regulated in the bladders of mice with cyclophosphamide-induced HC. CONCLUSIONS AND IMPLICATIONS: P2X7 receptors were significantly involved in a model of HC induced by cyclophosphamide. Pharmacological inhibition of these receptors might represent a new therapeutic option for this pathological condition.


Assuntos
Ciclofosfamida/toxicidade , Cistite/induzido quimicamente , Hemorragia/induzido quimicamente , Inflamação/metabolismo , Nociceptividade/fisiologia , Receptores Purinérgicos P2X7/metabolismo , Animais , Movimento Celular , Cistite/metabolismo , Cistite/patologia , Citocinas/genética , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica , Genes fos , Hemorragia/metabolismo , Macrófagos/fisiologia , Masculino , Mesna/farmacologia , Camundongos , Camundongos Knockout , Antagonistas do Receptor Purinérgico P2X/farmacologia , Piridinas/administração & dosagem , Piridinas/farmacologia , Receptores Purinérgicos P2X7/genética , Tetrazóis/administração & dosagem , Tetrazóis/farmacologia , Bexiga Urinária/metabolismo
6.
Br J Pharmacol ; 158(4): 1104-11, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19422380

RESUMO

BACKGROUND AND PURPOSE: The effects of systemic treatment with indomethacin-loaded nanocapsules (IndOH-NC) were compared with those of free indomethacin (IndOH) in rat models of acute and chronic oedema. EXPERIMENTAL APPROACH: The following models of inflammation were employed: carrageenan-induced acute oedema (measured between 30 min and 4 h), sub-chronic oedema induced by complete Freund's adjuvant (CFA) (determined between 2 h and 72 h), and CFA-induced arthritis (oedema measured between 14 and 21 days). KEY RESULTS: IndOH or IndOH-NC produced equal inhibition of carrageenan-elicited oedema. However, IndOH-NC was more effective in both the sub-chronic (33 +/- 4% inhibition) and the arthritis (35 +/- 2% inhibition) model of oedema evoked by CFA, when compared with IndOH (21 +/- 2% and 14 +/- 3% inhibition respectively) (P < 0.01). In the CFA arthritis model, treatment with IndOH-NC markedly inhibited the serum levels of the pro-inflammatory cytokines tumour necrosis factor alpha and IL-6 (by 83 +/- 8% and 84 +/- 11% respectively), while the levels of the anti-inflammatory cytokine IL-10 were significantly increased (196 +/- 55%). The indices of gastrointestinal damage in IndOH-NC-treated animals were significantly less that those after IndOH treatment (58 +/- 16%, 72 +/- 6% and 69 +/- 2%, for duodenum, jejunum and ileum respectively). CONCLUSIONS AND IMPLICATIONS: IndOH-NC produced an increased anti-inflammatory efficacy in long-term models of inflammation, allied to an improved gastrointestinal safety. This formulation might represent a promising alternative for treating chronic inflammatory diseases, with reduced undesirable effects.


Assuntos
Anti-Inflamatórios/uso terapêutico , Artrite Experimental/tratamento farmacológico , Indometacina/uso terapêutico , Inflamação/tratamento farmacológico , Nanocápsulas/uso terapêutico , Animais , Anti-Inflamatórios/efeitos adversos , Avaliação Pré-Clínica de Medicamentos , Indometacina/efeitos adversos , Masculino , Ratos , Ratos Wistar
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