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Tóth KF, Ádám D, Arany J, Ramirez YA, Bíró T, Drake JI, O'Mahony A, Szöllősi AG, Póliska S, Kilić A, Soeberdt M, Abels C, Oláh A. Fluoxetine exerts anti-inflammatory effects on human epidermal keratinocytes and suppresses their endothelin release. Exp Dermatol 2024; 33:e14988. [PMID: 38284184 DOI: 10.1111/exd.14988] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 11/08/2023] [Accepted: 11/22/2023] [Indexed: 01/30/2024]
Abstract
Fluoxetine is a safe antidepressant with remarkable anti-inflammatory actions; therefore, we aimed to investigate its effects on immortalized (HaCaT) as well as primary human epidermal keratinocytes in a polyinosinic-polycytidylic acid (p(I:C))-induced inflammatory model. We found that a non-cytotoxic concentration (MTT-assay, CyQUANT-assay) of fluoxetine significantly suppressed p(I:C)-induced expression and release of several pro-inflammatory cytokines (Q-PCR, cytokine array, ELISA), and it decreased the release of the itch mediator endothelins (ELISA). These effects were not mediated by the inhibition of the NF-κB or p38 MAPK pathways (western blot), or by the suppression of the p(I:C)-induced elevation of mitochondrial ROS production (MitoSOX Red labeling). Instead, unbiased activity profiling revealed that they were most likely mediated via the inhibition of the phosphoinositide 3-kinase (PI3K) pathway. Importantly, the PI3K-inhibitor GDC0941 fully mimicked the effects of fluoxetine (Q-PCR, ELISA). Although fluoxetine was able to occupy the binding site of GDC0941 (in silico molecular docking), and exerted direct inhibitory effect on PI3K (cell-free PI3K activity assay), it exhibited much lower potency and efficacy as compared to GDC0941. Finally, RNA-Seq analysis revealed that fluoxetine deeply influenced the transcriptional alterations induced by p(I:C)-treatment, and exerted an overall anti-inflammatory activity. Collectively, our findings demonstrate that fluoxetine exerts potent anti-inflammatory effects, and suppresses the release of the endogenous itch mediator endothelins in human keratinocytes, most likely via interfering with the PI3K pathway. Thus, clinical studies are encouraged to explore whether the currently reported beneficial effects translate in vivo following its topical administration in inflammatory and pruritic dermatoses.
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Affiliation(s)
- Kinga Fanni Tóth
- Department of Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
- University of Debrecen, Doctoral School of Molecular Medicine, Debrecen, Hungary
| | - Dorottya Ádám
- Department of Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
- University of Debrecen, Doctoral School of Molecular Medicine, Debrecen, Hungary
| | - József Arany
- Department of Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
- University of Debrecen, Doctoral School of Molecular Medicine, Debrecen, Hungary
| | - Yesid A Ramirez
- Design and Applied Sciences, School of Applied Sciences and Sustainable Industry, Department of Pharmaceutical and Chemical Sciences, Faculty of Engineering, Universidad Icesi, Cali, Valle del Cauca, Colombia
- Cannaflos-Gesellschaft für medizinisches Cannabis mbH, Köln, Germany
| | - Tamás Bíró
- Department of Immunology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | | | - Alison O'Mahony
- Eurofins Discovery, St. Charles, Missouri, USA
- Recursion, Salt Lake City, Utah, USA
| | - Attila Gábor Szöllősi
- Department of Immunology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Szilárd Póliska
- Genomic Medicine and Bioinformatics Core Facility, Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Ana Kilić
- Dr. August Wolff GmbH & Co. KG Arzneimittel, Bielefeld, Germany
| | - Michael Soeberdt
- Dr. August Wolff GmbH & Co. KG Arzneimittel, Bielefeld, Germany
- Bionorica SE, Neumarkt, Germany
| | - Christoph Abels
- Dr. August Wolff GmbH & Co. KG Arzneimittel, Bielefeld, Germany
- Bionorica SE, Neumarkt, Germany
| | - Attila Oláh
- Department of Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
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Asfour HZ, Alhakamy NA, Ahmed OAA, Fahmy UA, El-moselhy MA, Rizg WY, Alghaith AF, Eid BG, Abdel-Naim AB. Amitriptyline-Based Biodegradable PEG-PLGA Self-Assembled Nanoparticles Accelerate Cutaneous Wound Healing in Diabetic Rats. Pharmaceutics 2022; 14:1792. [PMID: 36145540 PMCID: PMC9503070 DOI: 10.3390/pharmaceutics14091792] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 08/16/2022] [Accepted: 08/22/2022] [Indexed: 11/17/2022] Open
Abstract
The aim of this work was to study the healing activity of amitriptyline (Amitrip) in rat diabetic wounds. A nanoformula of the drug was prepared as Amitrip-based biodegradable PEG-PLGA self-assembled nanoparticles (Amitrip-NPs) with a mean particle size of 67.4 nm. An in vivo investigation was conducted to evaluate the wound-healing process of Amitrip-NPs in streptozotocin-induced diabetic rats. Wound contraction was accelerated in rats treated with Amitrip-NPs. Histological examinations confirmed these findings, with expedited remodeling and collagen deposition in the NPs-treated animals. The formula showed anti-inflammatory activities as demonstrated by inhibition of interleukin-6 (IL-6) expression and tumor necrosis factor-α (TNF-α) expression, as well as enhanced expression of interleukin-10 (IL-10). In addition, Amitrip-NPs protected against malondialdehyde (MDA) buildup and superoxide dismutase (SOD) and glutathione peroxidase (GPx) enzymatic exhaustion. The pro-collagen activity of Amitrip-NPs was confirmed by the observed enhancement of hydroxyproline wounded skin content, upregulation of Col 1A1 mRNA expression and immune expression of collagen type IV expression. Further, Amitrip-NPs significantly increased expression transforming growth factor-β1 (TGF-β1), vascular endothelial growth factor-A (VEGF-A), platelet-derived growth factor-B (PDGF-B) and cluster of differentiation 31 (CD31). In conclusion, the developed Amitrip-NPs expedited wound healing in diabetic rats. This involves anti-inflammatory, antioxidant, pro-collagen and angiogenic activities of the prepared NPs. This opens the gate for evaluating the usefulness of other structurally related tricyclic antidepressants in diabetic wounds.
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Affiliation(s)
- Hani Z. Asfour
- Department of Medical Microbiology and Parasitology, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Nabil A. Alhakamy
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Center of Excellence for Drug Research and Pharmaceutical Industries, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Mohamed Saeed Tamer for Pharmaceutical Industries, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Osama A. A. Ahmed
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Center of Excellence for Drug Research and Pharmaceutical Industries, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Mohamed Saeed Tamer for Pharmaceutical Industries, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Usama A. Fahmy
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Mohamed A. El-moselhy
- Department of Clinical Pharmacy and Pharmacology, Ibn Sina National College for Medical Studies, Jeddah 22413, Saudi Arabia
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, Minia 61519, Egypt
| | - Waleed Y. Rizg
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Adel F. Alghaith
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Basma G. Eid
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Ashraf B. Abdel-Naim
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia
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Abstract
Patients with inflammatory bowel disease can present with a wide variety of symptoms. Most are related to disease activity and should be managed with appropriate medical therapy for inflammatory bowel disease. However, some patients may develop symptoms due to the side effects of the medications, or due to immunosuppression. In these cases, the offending medications should be discontinued until resolution of the symptoms and a few may be able to restart therapy. Symptoms can also occur as an extraintestinal manifestation of the disease or due to concomitant autoimmune-mediated disorders. Regardless of the etiology, symptoms should be addressed promptly with immediate evaluation and appropriate therapy, as a delay may lead to permanent sequela.
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Affiliation(s)
- Bincy P Abraham
- Houston Methodist Hospital, 6550 Fannin St., Smith Tower, Suite 1001 Houston, TX 77030 USA
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Srinath A, Young E, Szigethy E. Pain management in patients with inflammatory bowel disease: translational approaches from bench to bedside. Inflamm Bowel Dis 2014; 20:2433-49. [PMID: 25208108 DOI: 10.1097/mib.0000000000000170] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Abdominal pain is a common symptom in patients with inflammatory bowel disease (IBD) that negatively affects quality of life and can lead to increased health-seeking behavior. Although abdominal pain has been traditionally attributed to inflammation, there is growing literature demonstrating the existence of functional abdominal pain in patients with IBD, of which there are a variety of potential causes. Thus, when approaching a patient with IBD who has abdominal pain, in addition to IBD-related complications (e.g., inflammation/stricture), it is important to screen for related contributors, including peripheral factors (visceral hypersensitivity, bacterial overgrowth, and bowel dysmotility) and centrally mediated neurobiological and psychosocial underpinnings. These central factors include psychological symptoms/diagnoses, sleep disturbance, and stress. Opioid-induced hyperalgesia (e.g., narcotic bowel syndrome) is also growing in recognition as a potential central source of abdominal pain. This review draws from clinical studies and animal models of colitis and abdominal pain to consider how knowledge of these potential etiologies can be used to individualize treatment of abdominal pain in patients with IBD, including consideration of potential novel treatment modalities for the future. Accurate assessment of the source(s) of pain in patients with IBD can help guide appropriate diagnostic workup and use of disease-modifying therapy.
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Affiliation(s)
- Arvind Srinath
- *Department of Pediatric Gastroenterology, Children's Hospital of UPMC, Pittsburgh, Pennsylvania; †Department of Anesthesiology, University of Pittsburgh, Pittsburgh, Pennsylvania; and ‡Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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Filipovic BR, Filipovic BF. Psychiatric comorbidity in the treatment of patients with inflammatory bowel disease. World J Gastroenterol 2014; 20:3552-3563. [PMID: 24707138 PMCID: PMC3974522 DOI: 10.3748/wjg.v20.i13.3552] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2013] [Revised: 12/20/2013] [Accepted: 01/20/2014] [Indexed: 02/06/2023] Open
Abstract
Ulcerative colitis and Crohn’s disease, commonly known as inflammatory bowel disease (IBD), draw attention from specialists of various disorders, including gastroenterology, psychiatry, and radiology. The involvement of a cortical influence in the brain-gut axis as well as the interaction of the hypothalamic-pituitary-adrenal axis and the peripheral nervous system provide an initial explanation of the psychological symptoms associated with IBD. The involvement of structures the limbic system, such as the anterior cingulate cortex, the prefrontal cortex, and the amygdala, paves the way for the discovery of the mechanisms underlying depression depression, anxiety, alexithymia, personality traits, and other psychological impairments following the onset of IBD. Psychiatric therapy in IBD patients is almost as important as the gastroenterological approach and consists of pharmacological treatment and psychotherapy. Neither of the available psychiatric treatment methods is considered the golden standard because both methods have side effects, and psychotropic medication can provoke the worsening of IBD symptoms. Thus, both approaches must be applied with awareness of the possibility of side effects. We suggest that psychiatrists and gastroenterologists work together to reach a consensus on IBD therapy to ensure success and to reduce side effects and relapse to the lowest possible rates.
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Valera E, Ubhi K, Mante M, Rockenstein E, Masliah E. Antidepressants reduce neuroinflammatory responses and astroglial alpha-synuclein accumulation in a transgenic mouse model of multiple system atrophy. Glia 2013; 62:317-37. [PMID: 24310907 DOI: 10.1002/glia.22610] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2013] [Revised: 11/01/2013] [Accepted: 11/14/2013] [Indexed: 12/13/2022]
Abstract
Multiple system atrophy (MSA) is a neurodegenerative disease characterized by the pathological accumulation of alpha-synuclein (α-syn) within oligodendroglial cells. This accumulation is accompanied by neuroinflammation with astrogliosis and microgliosis, that leads to neuronal death and subsequent parkinsonism and dysautonomia. Antidepressants have been explored as neuroprotective agents as they normalize neurotrophic factor levels, increase neurogenesis and reduce neurodegeneration, but their anti-inflammatory properties have not been fully characterized. We analyzed the anti-inflammatory profiles of three different antidepressants (fluoxetine, olanzapine and amitriptyline) in the MBP1-hα-syn transgenic (tg) mouse model of MSA. We observed that antidepressant treatment decreased the number of α-syn-positive cells in the basal ganglia of 11-month-old tg animals. This reduction was accompanied with a similar decrease in the colocalization of α-syn with astrocyte markers in this brain structure. Consistent with these results, antidepressants reduced astrogliosis in the hippocampus and basal ganglia of the MBP1-hα-syn tg mice, and modulated the expression levels of key cytokines that were dysregulated in the tg mouse model, such as IL-1β. In vitro experiments in the astroglial cell line C6 confirmed that antidepressants inhibited NF-κB translocation to the nucleus and reduced IL-1β protein levels. We conclude that the anti-inflammatory properties of antidepressants in the MBP1-hα-syn tg mouse model of MSA might be related to their ability to inhibit α-syn propagation from oligodendrocytes to astroglia and to regulate transcription factors involved in cytokine expression. Our results suggest that antidepressants might be of interest as anti-inflammatory and α-syn-reducing agents for MSA and other α-synucleinopathies.
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Affiliation(s)
- Elvira Valera
- Department of Neurosciences, University of California, San Diego, La Jolla, California
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Gurgel JA, Lima-Júnior RCP, Rabelo CO, Pessoa BBGP, Brito GAC, Ribeiro RA. Amitriptyline, clomipramine, and maprotiline attenuate the inflammatory response by inhibiting neutrophil migration and mast cell degranulation. BRAZILIAN JOURNAL OF PSYCHIATRY 2013; 35:387-92. [DOI: 10.1590/1516-4446-2012-0977] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/27/2012] [Accepted: 01/07/2013] [Indexed: 11/22/2022]
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Rahimi HR, Shiri M, Razmi A. Antidepressants can treat inflammatory bowel disease through regulation of the nuclear factor-κB/nitric oxide pathway and inhibition of cytokine production: A hypothesis. World J Gastrointest Pharmacol Ther 2012; 3:83-5. [PMID: 23494719 PMCID: PMC3596516 DOI: 10.4292/wjgpt.v3.i6.83] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2012] [Revised: 11/06/2012] [Accepted: 11/20/2012] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a group of inflammatory disorders mainly affecting the colon and small intestine. The main types of IBD are Crohn’s disease (CD) and ulcerative colitis (UC). UC is restricted to the large intestine whereas CD can affect any part of the gastrointestinal tract. Treating this disorder depends on the form and level of severity. Common treatment involves an anti-inflammatory drug, such as mesalazine, and an immunosuppressant, such as prednisone. Several signaling pathways, including nuclear factor (NF)-κB and nitric oxide (NO), and genetic and environmental factors are believed to play an important role in IBD. Amitriptyline is a commonly used antidepressant with known anti-inflammatory activities. Amitriptyline also acts on the NF-κB/NO pathway or cytokine production. Therefore, we hypothesize that antidepressants like amitriptyline can be pioneered and considered effective as an innovative and effective therapeutic in the treatment and attenuation of development of IBD in adjusted doses.
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Affiliation(s)
- Hamid Reza Rahimi
- Hamid Reza Rahimi, Mahdi Shiri, Department of Toxicology and Pharmacology, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran 15614, Iran
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Mischoulon D, Alpert JE, Arning E, Bottiglieri T, Fava M, Papakostas GI. Bioavailability of S-adenosyl methionine and impact on response in a randomized, double-blind, placebo-controlled trial in major depressive disorder. J Clin Psychiatry 2012; 73:843-8. [PMID: 22687580 PMCID: PMC4156851 DOI: 10.4088/jcp.11m07139] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2011] [Accepted: 08/19/2011] [Indexed: 01/22/2023]
Abstract
OBJECTIVE To characterize the impact of S-adenosyl methionine (SAMe) on homocysteine and potential risk of adverse cardiovascular effects by examining plasma levels of SAMe, S-adenosyl homocysteine (SAH), total homocysteine (tHCY), methionine (MET), and 5-methyltetrahydrofolate (5-MTHF) in 35 of 73 patients from a 6-week randomized double-blind, placebo-controlled trial of SAMe augmentation in serotonin reuptake inhibitor partial responders with DSM-IV major depressive disorder (MDD), published in 2010. METHOD Subjects were randomized from June 4, 2004, until August 8, 2008, to adjunctive placebo or SAMe 800-1600 mg/d for 6 weeks. Primary outcome measures included changes in one-carbon cycle intermediates within each treatment arm (by paired t test) and between treatment arms (by independent samples t test). Univariate analysis of variance and Fisher Protected Least Significant Difference were carried out to compare posttreatment levels of each one-carbon cycle intermediate. Secondary outcome measures included associations between clinical improvement and change in plasma intermediate levels, examined by linear regression (for change in Hamilton Depression Rating Scale scores) and logistic regression (for response or remission). RESULTS We found significant differences in pretreatment plasma levels of tHCY (P = .03) between the SAMe and placebo arms. Following 6 weeks of treatment, plasma SAMe (P = .002) and SAH (P < .0001) levels increased significantly in the SAMe arm; no intermediates in the placebo group changed significantly. Posttreatment plasma SAMe (P = .0035), SAH (P < .0001), and tHCY (P = .0016) levels differed significantly between the SAMe and placebo groups. No significant associations were found between plasma intermediate levels and clinical improvement, response, or remission. CONCLUSIONS Despite concerns about the impact that SAMe therapy may have on homocysteine levels and risk of adverse cardiovascular effects, the lack of significant increase in tHCY levels after treatment suggests that no toxic effects from SAMe should be expected. Our findings, however, have some significant limitations and should be interpreted with caution. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT00093847.
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Affiliation(s)
| | - Jonathan E. Alpert
- Depression Clinical and Research Program, Massachusetts General Hospital and Harvard Medical School, Boston, MA
| | - Erland Arning
- Baylor Research Institute, Institute of Metabolic Disease, Dallas, TX
| | | | - Maurizio Fava
- Depression Clinical and Research Program, Massachusetts General Hospital and Harvard Medical School, Boston, MA
| | - George I. Papakostas
- Depression Clinical and Research Program, Massachusetts General Hospital and Harvard Medical School, Boston, MA
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Vismari L, Alves GJ, Muscará MN, Palermo-Neto J. A possible role to nitric oxide in the anti-inflammatory effects of amitriptyline. Immunopharmacol Immunotoxicol 2012; 34:578-85. [PMID: 22208160 DOI: 10.3109/08923973.2011.638305] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Antidepressants are reported to display anti-inflammatory effects. Nitric oxide (NO), in turn, has a key role in inflammation. The objective of the present study was to evaluate the effect of amitriptyline co-administered with L-NAME (a NO synthase inhibitor) on certain parameters of acute inflammatory response in rats, as a form to investigate a possible participation of NO in the anti-inflammatory effects of amitriptyline. For this, two animal models were used: carrageenan-induced paw edema and acute peritonitis. In the last one, peritoneal exudate, adhesion molecules expression by peripheral blood leukocytes and serum cytokines levels were evaluated. In a noninflammatory condition, serum levels of nitrates were determined. L-NAME induced a potentiation of the anti-inflammatory effects of amitriptyline (p < 0.05) in the paw edema model; however, these effects were not abrogated when L-NAME was substituted by L-arginine administration. A decrease in both leukocyte concentration and total number of cells in the peritoneal exudate and a reduction in the total serum levels of nitrates were observed with co-administration of L-NAME and amitriptyline (p < 0.05). No significant differences among groups were found concerning the expression of adhesion molecules by peripheral blood leukocytes (p > 0.05). There was a significant decrease on IL-1β and TNF-α serum levels in the experimental groups when compared to the control animals. Together the present results and the literature suggest that the anti-inflammatory effects of amitriptyline may be due to a decrease in NO production. A decrease in IL-1β/TNF-α serum levels may also be implicated in the results observed.
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Affiliation(s)
- Luciana Vismari
- Department of Pathology, São Paulo University, Av. Prof. Dr. Orlando Marques de Paiva, Cidade Universitária, São Paulo, Brazil
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