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Publications (85)

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    [Show abstract] [Hide abstract] ABSTRACT: This review article focuses on pre-clinical and clinical studies with some selected Brazilian medicinal plants in different areas of interest, conducted by research groups in Brazil and abroad. It also highlights the Brazilian market of herbal products and the efforts of Brazilian scientists to develop new phytomedicines. This review is divided into three sections. The section I describes the Brazilian large biodiversity and some attempts of Brazilian scientists to assess the pharmacological profile of most plant extracts or isolated active principles. Of note, Brazilian scientists have made a great effort to study the Brazilian biodiversity, especially among the higher plants. In fact, more than 10,000 papers were published on plants in international scientific journals between 2011 and 2013. This first part also discussed the main efforts to develop new medicines from plants, highlighting the Brazilian phytomedicines market. Despite the large Brazilian biodiversity, notably with the higher plants, which comprise over 45,000 species (20–22% of the total worldwide), and the substantial number of scientific publications on medicinal plants, only one phytomedicine is found in the top 20 market products. Indeed, this market is still only worth about 261 million American dollars. This represents less than 5% of the global Brazilian medicine market. The section II of this review focus on the use of Brazilian plant extract and/or active principles for some selected diseases, namely: central nervous systems disorders, pain, immune response and inflammation, respiratory diseases, gastrointestinal tract and metabolic diseases. Finally, section III discusses in more details some selected Brazilian medicinal plants including: Cordia verbenacea, Euphorbia tirucalli, Mandevilla velutina, Phyllanthus spp., Euterpe oleracea, Vitis labrusca, Hypericum caprifoliatum and Hypericum polyanthemum, Maytenus ilicifolia, Protium kleinii and Protium heptaphylium and Trichilia catigua. Most of these publications are preliminary and only report the effects of crude extracts, both in vitro and in vivo studies. Only very few studies have been dedicated to investigate the mechanisms of action of isolated compounds. Likewise, studies on safety (toxicology), pharmacokinetic, and especially on well-conducted clinical trials are rare. In conclusion, in spite of the abundant Brazilian biodiversity and the thousands of academic publications on plants in international peer-reviewed scientific journals, few patents and medicines have been derived from such studies. Undoubtedly, great efforts must be made to improve the development of plant-derived medicine market in Brazil, especially by involving the partnership between academia and pharmaceutical companies.
    Full-text available · Article · Jan 2016 · Pharmacological Research
  • Paula J S Pereira · Gustavo D B Machado · Giuliano M Danesi · [...] · Maria M Campos
    [Show abstract] [Hide abstract] ABSTRACT: Significance statement: Itch is the most common symptom of the skin and is related to noncutaneous diseases. It severely impairs patients' quality of life when it becomes chronic and there is no specific or effective available therapy, mainly because itch pathophysiology is not completely elucidated. Our findings indicate that the enzyme PI3Kγ is a key central mediator of itch transmission. Therefore, we suggest PI3Kγ as an attractive target for the development of new anti-pruritic drugs. With this study, we take a step forward in our understanding of the mechanisms underlying the central transmission of itch sensation.
    Article · Dec 2015 · The Journal of Neuroscience
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    Full-text available · Article · Dec 2015 · Current Topics in Pharmacology
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    Raquel D.S. Freitas · Kesiane M Costa · Natália F Nicoletti · [...] · Maria M Campos
    [Show abstract] [Hide abstract] ABSTRACT: This study investigated the effects of the long-term dietary fish oil supplementation or the acute administration of the omega-3 fatty acid docosahexaenoic acid (DHA) in the mouse hemorrhagic cystitis (HC) induced by the anticancer drug cyclophosphamide (CYP). HC was induced in mice by a single CYP injection (300mg/kg ip). Animals received four different diets containing 10% and 20% of corn or fish oil, during 21days. Separated groups received DHA by ip (1μmol/kg) or intrathecal (i.t.; 10μg/site) routes, 1h or 15min before CYP. The behavioral tests (spontaneous nociception and mechanical allodynia) were carried out from 1h to 6h following CYP injection. Bladder inflammatory changes, blood cell counts and serum cytokines were evaluated after euthanasia (at 6h). Immunohistochemistry analysis was performed for assessing spinal astrocyte and microglia activation or GPR40/FFAR1 expression. Either fish oil supplementation or DHA treatment (ip and i.t.) markedly prevented visceral pain, without affecting CYP-evoked bladder inflammatory changes. Moreover, systemic DHA significantly prevented the neutrophilia/lymphopenia caused by CYP, whereas this fatty acid did not significantly affect serum cytokines. DHA also modulated the spinal astrocyte activation and the GPR40/FFAR1 expression. The supplementation with fish oil enriched in omega-3 fatty acids or parenteral DHA might be interesting nutritional approaches for cancer patients under chemotherapy schemes with CYP.
    Full-text available · Article · Oct 2015 · The Journal of nutritional biochemistry
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    [Show abstract] [Hide abstract] ABSTRACT: Glioblastoma multiforme (GBM) is considered the most lethal intracranial tumor and the median survival time is approximately 14 months. Although some glioma cells present radioresistance, radiotherapy has been the mainstay of therapy for patients with malignant glioma. The activation of P2X7 receptor (P2X7R) is responsible for ATP-induced death in various cell types. In this study, we analyzed the importance of ATP-P2X7R pathway in the radiotherapy response P2X7R silenced cell lines, in vivo and human tumor samples. Both glioma cell lines used in this study present a functional P2X7R and the P2X7R silencing reduced P2X7R pore activity by ethidium bromide uptake. Gamma radiation (2 Gy) treatment reduced cell number in a P2X7R-dependent way, since both P2X7R antagonist and P2X7R silencing blocked the cell cytotoxicity caused by irradiation after 24 h. The activation of P2X7R is time-dependent, as EtBr uptake significantly increased after 24 h of irradiation. The radiotherapy plus ATP incubation significantly increased annexin V incorporation, compared with radiotherapy alone, suggesting that ATP acts synergistically with radiotherapy. Of note, GL261 P2X7R silenced-bearing mice failed in respond to radiotherapy (8 Gy) and GL261 WT-bearing mice, that constitutively express P2X7R, presented a significant reduction in tumor volume after radiotherapy, showing in vivo that functional P2X7R expression is essential for an efficient radiotherapy response in gliomas. We also showed that a high P2X7R expression is a good prognostic factor for glioma radiosensitivity and survival probability in humans. Our data revealed the relevance of P2X7R expression in glioma cells to a successful radiotherapy response, and shed new light on this receptor as a useful predictor of the sensitivity of cancer patients to radiotherapy and median survival.
    Full-text available · Article · Sep 2015 · The International Journal of Biochemistry & Cell Biology
  • [Show abstract] [Hide abstract] ABSTRACT: Mephedrone and methedrone are cathinone-related compounds, which act as non-selective substrates for monoamine transporters, facilitating a neurotransmitter release. We compared the acute pharmacological effects of mephedrone and methedrone, attempting to further evaluate the action mechanisms of methedrone by responsibly and ethically using mice under approved procedures. The effects of both compounds were examined from 10 to 60min, in a series of behavioral paradigms, namely open-field, plus-maze, hot-plate and tail suspension tests, whereas neurotransmitter brain tissue levels were determined ex vivo by HPLC. Separate groups were pre-treated with the dopamine (DA) antagonist haloperidol, or the serotonin (5-HT) synthesis inhibitor ρCPA, to further assess the mechanisms underlying methedrone effects. The compounds caused marked hyperlocomotion, displaying dissimilar stereotyped behavior, in an open-field arena. Mephedrone caused anxiolytic-like effects, while methedrone induced anxiogenic-like actions in the elevated plus-maze. Both compounds displayed thermal antinociception, with a reduced immobility time in the tail suspension model. Mephedrone triggered a 2- and 3-fold increment of dopamine and serotonin tissue levels, respectively, in the nucleus accumbens, with a 1.5-fold elevation of tissue dopamine in the frontal cortex. Methedrone caused a 2-fold increment of tissue dopamine in the nucleus accumbens and in the striatum, and a 1.5-fold increment of serotonin tissue levels in the hippocampus and striatum. In vivo methedrone effects were partially inhibited by a pre-treatment with haloperidol or ρCPA. Despite similar actions on locomotion, analgesia, and depression-like behavior, the acute administration of mephedrone and methedrone elicited divergent effects on anxiety-like behavior and stereotyped movements in mice, which might be related to the distinct modulation of brain tissue neurotransmitter levels. Copyright © 2015 Elsevier Inc. All rights reserved.
    Article · Aug 2015 · NeuroToxicology
  • Natália P. Cignachi · João B. Pesquero · Rogério B. Oliveira · [...] · Maria M. Campos
    [Show abstract] [Hide abstract] ABSTRACT: The effects of kinin B1 receptor (B1 R) deletion were examined on femur bone regeneration in streptozotocin (STZ)-type 1 diabetes. Diabetes induction in wild-type C57/BL6 (WTC57BL6) mice led to decrease in body weight and hyperglycemia, compared to the non-diabetic group of the same strain. The lack of B1 R did not affect STZ-elicited body weight loss, but partially prevented hyperglycemia. Diabetic mice had a clear delay in bone regeneration, and displayed large areas of loose connective tissue within the defects, with a reduced expression of the mineralization-related protein osteonectin, when compared to the non-diabetic WTC57/BL6. The non-diabetic and diabetic B1 R knockout (B1 RKO) mice had bone regeneration levels and osteonectin expression comparable to that seen in control WTC57/BL6 mice. WTC57/BL6 STZ-diabetic mice also showed a marked reduction of collagen contents, with increased immunolabelling for the apoptosis marker caspase-3, whereas diabetic B1 RKO had collagen levels and caspase-3 activity comparable to those observed in non-diabetic WTC57/BL6 or B1 RKO mice. No significant difference was detected in the number of tartrate-resistant acid phosphatase (TRAP)-stained cells, or in RANK/RANKL/OPG system immunolabelling throughout the experimental groups. Data bring novel evidence on the relevance of kinin B1 R under type 1 diabetes with regards to its role in bone regeneration. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Article · May 2015 · Journal of Cellular Physiology
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    [Show abstract] [Hide abstract] ABSTRACT: Acute liver injury was induced in male BALB/c mice by coadministering isoniazid and rifampicin. In this work, the effects of resveratrol (1) were investigated in the hepatotoxicity caused by isoniazid-rifampicin in mice. Compound 1 was administered 30 min prior to isoniazid-rifampicin. Serum biochemical tests, liver histopathological examination, oxidative stress, myeloperoxidase activity, cytokine production (TNF-α, IL-12p70, and IL-10), and mRNA expression of SIRT1-7 and PPAR-γ/PGC1-α were evaluated. The administration of 1 significantly decreased aspartate transaminase and alanine aminotransferase levels, myeloperoxidase activity, and cytokine levels. Furthermore, 1 reverted the decrease of catalase and glutathione activities and ameliorated the histopathological alterations associated with antituberculosis drugs. Modulation of SIRT1 and PPAR-γ/PGC1-α expression is likely involved in the protective effects of 1. The results presented herein show that 1 was able to largely prevent the hepatotoxicity induced by isoniazid and rifampicin in mice, mainly by modulating SIRT1 mRNA expression.
    Full-text available · Article · Oct 2014 · Journal of Natural Products
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    [Show abstract] [Hide abstract] ABSTRACT: This work aimed to develop and validate a routine method for the specific determination of Sn2+ 2-methoxy isobutyl isonitrile (MIBI) radiopharmaceutical kits. A voltammetric electrochemical technique was used for the analysis. Screening experiments revealed that 1 mol L-1 HCl electrolyte showed the best results, among all the tested solutions. Stability experiments showed a gradual decline in the current of MIBI, and 23 days after the preparation of the solution, the current corresponding to stannous ion disappeared. To confirm the selectivity of the technique using HCl, we have induced oxidation of SnCl2 that resulted in a proportional decline of the current in the voltammogram. The reliability of the method was observed with the values of precision and accuracy intra-and inter-assay, and also its robustness. We provide novel evidence on the selective detection of Sn2+ in the presence of its oxidized form in radiopharmaceutical kits, by using 1 mol L-1 HCl as electrolyte.
    Full-text available · Article · Sep 2014 · Journal of the Brazilian Chemical Society
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    [Show abstract] [Hide abstract] ABSTRACT: Paraquat (PQ) is an agrochemical agent commonly used worldwide, which is allied to potential risks of intoxication. This herbicide induces the formation of reactive oxygen species (ROS) that ends up compromising various organs, particularly the lungs and the brain. This study evaluated the deleterious effects of paraquat on the central nervous system (CNS) and peripherally, with special attempts to assess the putative protective effects of the selective CXCR2 receptor antagonist SB225002 on these parameters. PQ-toxicity was induced in male Wistar rats, in a total dose of 50 mg/kg, and control animals received saline solution at the same schedule of administration. Separate groups of animals were treated with the selective CXCR2 antagonist SB225002 (1 or 3 mg/kg), administered 30 min before each paraquat injection. The major changes found in paraquat-treated animals were: decreased body weight and hypothermia, nociception behavior, impairment of locomotor and gait capabilities, enhanced TNF-α and IL-1β expression in the striatum, and cell migration to the lungs and blood. Some of these parameters were reversed when the antagonist SB225002 was administered, including recovery of physiological parameters, decreased nociception, improvement of gait abnormalities, modulation of striatal TNF-α and IL-1β expression, and decrease of neutrophil migration to the lungs and blood. Taken together, our results demonstrate that damage to the central and peripheral systems elicited by paraquat can be prevented by the pharmacological inhibition of CXCR2 chemokine receptors. The experimental evidence presented herein extends the comprehension on the toxicodynamic aspects of paraquat, and opens new avenues to treat intoxication induced by this herbicide.
    Full-text available · Article · Aug 2014 · PLoS ONE
  • Izaque S Maciel · Vanessa M Azevedo · Talita C Pereira · [...] · Maria M Campos
    [Show abstract] [Hide abstract] ABSTRACT: The present study investigated the effects of pharmacological spinal inhibition of voltage-gated calcium channels (VGCC) in mouse pruritus. The epidural administration of P/Q-type MVIIC or PhTx3.3, L-type verapamil, T-type NNC 55-0396 or R-type SNX-482 VGCC blockers failed to alter the scratching behavior caused by the PAR-2 activator trypsin, injected into the mouse nape skin. Otherwise, trypsin-elicited pruritus was markedly reduced by the spinal administration of preferential N-type VGCC inhibitors MVIIA and Phα1β. Time-course experiments revealed that C. magus-derived toxin MVIIA displayed significant effects when dosed from 1 to 4 h before trypsin, whilst the anti-pruritic effects of Phα1β from P. nigriventer remained significant for up to 12 h. In addition to reducing trypsin-evoked itching, MVIIA or Phα1β also prevented the itching elicited by intradermal (i.d.) injection of SLIGRL-NH2, compound 48/80 or chloroquine, although they did not affect H2O2-induced scratching behavior. Furthermore, the co-administration of MVIIA or Phα1β markedly inhibited the pruritus caused by the spinal injection of gastrin-releasing peptide (GRP), but not morphine. Notably, the epidural administration of MVIIA or Phα1β greatly prevented the chronic pruritus allied to dry skin model. However, either tested toxin failed to alter the edema formation or neutrophil influx caused by trypsin, whereas they significantly reduced the c-Fos activation in laminas I, II and III of the spinal cord. Our data brings novel evidence on itching transmission mechanisms, pointing out the therapeutic relevance of N-type VGCC inhibitors to control refractory pruritus.
    Article · Aug 2014 · Neuroscience
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    [Show abstract] [Hide abstract] ABSTRACT: Purpose: 5-fluorouracil (5-FU) has been broadly used to treat solid tumors for more than 50 years. One of the major side effects of fluoropyrimidines therapy is oral and intestinal mucositis. Human uridine phosphorylase (hUP) inhibitors have been suggested as modulators of 5-FU toxicity. Therefore, the present study aimed to test the ability of hUP blockers in preventing mucositis induced by 5-FU. Methods: We induced intestinal mucositis in Wistar rats with 5-FU, and the intestinal damage was evaluated in presence or absence of two hUP1 inhibitors previously characterized. We examined the loss of weight and diarrhea following the treatment, the villus integrity, uridine levels in plasma, and the neutrophil migration by MPO activity. Results: We found that one of the compounds, 6-hydroxy-4-methyl-1H-pyridin-2-one-3-carbonitrile was efficient to promote intestinal mucosa protection and to inhibit the hUP1 enzyme, increasing the uridine levels in the plasma of animals. However, the loss of body weight, diarrhea intensity or neutrophil migration remained unaffected. Conclusion: Our results bring support to the hUP1 inhibitor strategy as a novel possibility of prevention and treatment of mucositis during the 5-FU chemotherapy, based on the approach of uridine accumulation in plasma and tissues.
    Full-text available · Article · Jul 2014 · Investigational New Drugs
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    Caroline P Klein · Nathalia D.M. Sperotto · Izaque S Maciel · [...] · Maria M Campos
    [Show abstract] [Hide abstract] ABSTRACT: This study investigated whether the spinal or systemic treatment with the lipid resolution mediators resolvin D1 (RvD1), aspirin-triggered resolvin D1 (AT-RvD1) and resolvin D2 (RvD2) might interfere with behavioral and neurochemical changes in the mouse fibromyalgia-like model induced by reserpine. Acute administration of AT-RvD1 and RvD2 produced a significant inhibition of mechanical allodynia and thermal sensitization in reserpine-treated mice, whereas RvD1 was devoid of effects. A similar antinociceptive effect was obtained by acutely treating animals with the reference drug pregabalin. Noteworthy, the repeated administration of AT-RvD1 and RvD2 also prevented the depressive-like behavior in reserpine-treated animals, according to assessment of immobility time, although the chronic administration of pregabalin failed to affect this parameter. The induction of fibromyalgia by reserpine triggered a marked decrease of dopamine and serotonin (5-HT) levels, as examined in total brain, spinal cord, cortex and thalamus. Reserpine also elicited a reduction of glutamate levels in total brain, and a significant increase in the spinal cord and thalamus. Chronic treatment with RvD2 prevented 5-HT reduction in total brain, and reversed the glutamate increases in total brain and spinal cord. Otherwise, AT-RvD1 led to a recovery of dopamine levels in cortex, and 5-HT in thalamus, whilst it diminished brain glutamate contents. Concerning pregabalin, this drug prevented dopamine reduction in total brain, and inhibited glutamate increase in brain and spinal cord of reserpine-treated animals. Our data provide novel evidence, showing the ability of D-series resolvins AT-RvD1, and mainly RvD2, in reducing painful and depressive symptoms allied to fibromyalgia in mice.
    Full-text available · Article · Jun 2014 · Neuropharmacology
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    [Show abstract] [Hide abstract] ABSTRACT: 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.
    Full-text available · Article · Jan 2014 · British Journal of Pharmacology
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    [Show abstract] [Hide abstract] ABSTRACT: Objective: Mitogen-activated protein kinase (MAPK) p38 inhibitors have entered the clinical phase, although many of them have failed due to high toxicity and lack of efficacy. In the present study we compared the effects of the selective p38 inhibitor ML3403 and the dual p38-PDE4 inhibitor CBS-3595, on inflammatory and nociceptive parameters in a model of polyarthritis in rats. Methods: Male Wistar rats (180-200 g) were used for the complete Freund's adjuvant (CFA)-induced arthritis model and they were evaluated at 14-21 days. We also analysed the effects of these pharmacological tools on liver and gastrointestinal toxicity and on cytokine levels. Results: Repeated CBS-3595 (3 mg/kg) or ML3403 (10 mg/kg) administration produced significant anti-inflammatory actions in the chronic arthritis model induced by CFA. CBS-3595 and ML3403 treatment also markedly reduced the production of the proinflammatory cytokine IL-6 in the paw tissue, whereas it widely increased the levels of the anti-inflammatory cytokine IL-10. Moreover, CBS-3595 produced partial anti-allodynic effects in the CFA model at 4 and 8 days after treatment. Notably, ML3403 and CBS-3595 did not show marked signs of hepatoxicity, as supported by unaltered histological observations in the liver sections. Finally, both compounds were safe in the gastrointestinal tract, according to evaluation of intestinal biopsies. Conclusion: CBS-3595 displayed a superior profile regarding its anti-inflammatory effects. Thus p38 MAPK/PDE4 blocking might well constitute a relevant strategy for the treatment of RA.
    Full-text available · Article · Nov 2013 · Rheumatology (Oxford, England)
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    [Show abstract] [Hide abstract] ABSTRACT: In this work, the antitubercular activity of a pentacyano(isoniazid)ferrate(II) compound (IQG-607) was investigated using a macrophage model of Mycobacterium tuberculosis infection. Importantly, treatment of M.-tuberculosis-infected macrophages with IQG-607 significantly diminished the number of CFU compared with the untreated control group. The antitubercular activity of IQG-607 was similar to that observed for the positive control drugs isoniazid and rifampicin. Nevertheless, higher concentrations of IQG-607 produced a significantly greater reduction in bacterial load compared with the same concentrations of isoniazid. Analysis of the mechanism of action of IQG-607 revealed that the biosynthesis of mycolic acids was blocked. The promising activity of IQG-607 in infected macrophages and the experimental determination of its mechanism of action may help in further studies aimed at the development of a new antimycobacterial agent.
    Full-text available · Article · Oct 2013 · International journal of antimicrobial agents
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    Izaque S Maciel · Rodrigo B M Silva · Fernanda B Morrone · [...] · Maria M Campos
    [Show abstract] [Hide abstract] ABSTRACT: This study was aimed to characterize the depression-like behaviour in the classical model of chronic inflammation induced by Complete Freund's Adjuvant (CFA). Male Swiss mice received an intraplantar ( injection of CFA (50 µl/paw) or vehicle. Behavioural and inflammatory responses were measured at different time-points (1 to 4 weeks), and different pharmacological tools were tested. The brain levels of IL-1β and BDNF, or COX-2 expression were also determined. CFA elicited a time-dependent edema formation and mechanical allodynia, which was accompanied by a significant increase in the immobility time in the tail suspension (TST) or forced-swimming (FST) depression tests. Repeated administration of the antidepressants imipramine (10 mg/kg), fluoxetine (20 mg/kg) and bupropion (30 mg/kg) significantly reversed depression-like behaviour induced by CFA. Predictably, the anti-inflammatory drugs dexamethasone (0.5 mg/kg), indomethacin (10 mg/kg) and celecoxib (30 mg/kg) markedly reduced CFA-induced edema. The oral treatment with the analgesic drugs dipyrone (30 and 300 mg/kg) or pregabalin (30 mg/kg) significantly reversed the mechanical allodyinia induced by CFA. Otherwise, either dipyrone or pregabalin (both 30 mg/kg) did not significantly affect the paw edema or the depressive-like behaviour induced by CFA, whereas the oral treatment with dipyrone (300 mg/kg) was able to reduce the immobility time in TST. Noteworthy, CFA-induced edema was reduced by bupropion (30 mg/kg), and depression behaviour was prevented by celecoxib (30 mg/kg). The co-treatment with bupropion and celecoxib (3 mg/kg each) significantly inhibited both inflammation and depression elicited by CFA. The same combined treatment reduced the brain levels of IL-1β, as well as COX-2 immunopositivity, whilst it failed to affect the reduction of BDNF levels. We provide novel evidence on the relationship between chronic inflammation and depression, suggesting that combination of antidepressant and anti-inflammatory agents bupropion and celecoxib might represent an attractive therapeutic strategy for depression.
    Full-text available · Article · Sep 2013 · PLoS ONE
  • [Show abstract] [Hide abstract] ABSTRACT: This study evaluated the development of periapical lesions in a rat model of type 2 diabetes and assessed the potential actions of the antioxidant agent tempol in this model. Male Wistar rats were used; they received tap water (N = 5) or a 20% glucose solution (N = 15) during a period of 9 weeks. At the sixth week, periapical lesions were induced on the first mandibular molars, and the animals were subdivided into 4 groups. The subgroup 1 was composed of nondiabetic rats orally receiving saline solution (10 mL/kg). Chronically glucose-fed rats were divided into the following subgroups: (2) saline-treated animals (10 mL/kg by oral route), and animals treated with tempol by gavage at doses of (3) 50 mg/kg or (4) 100 mg/kg. The body weight was monitored thoroughly. After 21 days of apical periodontitis induction, the animals were killed, and the mandibles were collected and submitted to radiographic and histologic analysis. The livers were collected to determine free radicals, and the blood plasma was used to measure insulin levels. Type 2 diabetic rats displayed a significant decrease of body weight gain and a slight increase of insulin levels, which were allied to reduced levels of the antioxidant components catalase and reduced glutathione; these alterations were reversed by tempol. Concerning the periapical lesions, neither radiographic nor histologic analysis revealed any significant difference between control and type 2 diabetic rats. In diabetic rats, the apical periodontitis was refractory to tempol treatment. The extent and cellularity of periapical lesions in glucose-fed type 2 diabetic rats were similar to those seen in control rats. Despite affecting other parameters related to diabetes, tempol failed to improve the outcome of endodontic lesions in type 2 diabetic animals.
    Article · May 2013 · Journal of endodontics
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    [Show abstract] [Hide abstract] ABSTRACT: In the present study, we analyzed the role of purinergic P2X7 receptor in Mycobacterium tuberculosis infection and host interaction mechanisms in vitro and in vivo. For experimental procedures, a macrophage murine cell line RAW 264.7, and male Swiss, wild-type C57BL/6 and P2X7 receptor knockout (P2X7R(-/-)) mice were used throughout this study. We have demonstrated that treatment of RAW 264.7 cells with ATP (3 and 5mM) resulted in a statistically significant reduction of M. tuberculosis-colony-forming units. The purinergic P2X7 receptor expression was found significantly augmented in the lungs of mice infected with M. tuberculosis H37Rv. Infected wild-type mice showed a marked increase in the spleen weight, in comparison to non-infected animals. Furthermore, M. tuberculosis-infected P2X7R(-/-) mice showed an increase of M. tuberculosis burden in lung tissue, when compared to infected wild-type mice. In P2X7R(-/-) spleens, we observed a significant decrease in the populations of Treg (CD4(+)Foxp3(+)), T cells (CD4(+), CD8(+)CD25(+) and CD4(+)CD25(+)), dendritic cells (CD11c(+)) and B220(+) cells. However, a significant increase in CD11b(+) cells was observed in P2X7R(-/-) mice, when compared to wild-type animals. In the lungs, P2X7R(-/-)M. tuberculosis-infected mice exhibited pulmonary infiltrates containing an increase of Treg cells (CD4(+)Foxp3(+)), T cells (CD4(+) and CD8(+)) and a decrease in the B220(+) cells, when compared with wild-type M. tuberculosis-infected mice. The findings observed in the present study provide novel evidence on the role of P2X7 receptors in the pathogenesis of tuberculosis.
    Full-text available · Article · Mar 2013 · Immunobiology
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    [Show abstract] [Hide abstract] ABSTRACT: Irritant contact dermatitis (ICD) is an inflammatory reaction caused by chemical toxicity on the skin. The P2X7 receptor (P2X7R) is a key mediator of cytokine release, which recruits immune cells to sites of inflammation. We investigated the role of P2X7R in croton oil (CrO)-induced ICD using in vitro and in vivo approaches. ICD was induced in vivo by CrO application on the mouse ear and in vitro by incubation of murine macrophages and dendritic cells (DCs) with CrO and ATP. Infiltrating cells were identified by flow cytometry, histology and myeloperoxidase (MPO) determination. Effects of the ATP scavenger apyrase were assessed to investigate further the role of P2X7R in ICD. Animals were also treated with N-1330, a caspase-1 inhibitor, or with clodronate, which induces macrophage apoptosis. CrO application induced severe inflammatory Gr1(+) cell infiltration and increased MPO levels in the mouse ear. Selective P2X7R antagonism with A438079 or genetic P2X7R deletion reduced the neutrophil infiltration. Clodronate administration significantly reduced Gr1(+) cell infiltration and local IL-1β levels. In vitro experiments confirmed that A438079 or apyrase treatment prevented the increase in IL-1β that was evoked by macrophage and DC incubation with CrO and ATP. These data support a key role for P2X7 in ICD-mediated inflammation via modulation of inflammatory cells. It is tempting to suggest that P2X7R inhibition might be an alternative ICD treatment.
    Full-text available · Article · Mar 2013 · Experimental Dermatology