OBJECTIVE: Schizophrenia is a psychiatric disorder whose mechanisms have remained only partially elucidated. The current proposals regarding its biological basis, such as the dopaminergic hypothesis, do not fully explain the diversity of its symptoms, indicating that other processes may be involved. This paper aims to review evidence supporting the involvement of the endocannabinoid system (ECS), a neurotransmitter group that is the target of Cannabis sativa compounds, in this disorder.
METHODS: A systematic review of original papers, published in English, indexed in PubMed up to April, 2012.
RESULTS: Most studies employed genetics and histological, neuroimaging or neurochemical methods - either in vivo or post-mortem - to investigate whether components of the ECS are compromised in patients. Overall, the data show changes in cannabinoid receptors in certain brain regions as well as altered levels in endocannabinoid levels in cerebrospinal fluid and/or blood.
CONCLUSIONS: Although a dysfunction of the ECS has been described, results are not entirely consistent across studies. Further data are warrant to better define a role of this system in schizophrenia.
Schizophrenia; Cannabis; Endocannabinoids; Antipsychotics.
OBJETIVO: A esquizofrenia é um transtorno psiquiátrico cujos mecanismos permanecem apenas parcialmente elucidados. As atuais propostas relativas à base biológica, tais como a hipótese dopaminérgica, nao explicam por completo a diversidade de seus sintomas, o que indica que outros processos podem estar envolvidos. Este artigo tem como objetivo revisar indícios que sustentem o envolvimento do sistema endocanabinoide (SECB), um grupo de neurotransmissoresalvo dos compostos da Cannabis sativa, nesse transtorno.
MÉTODOS: Revisao sistemática dos artigos originais, publicados em inglês e indexados no PubMed até abril de 2012.
RESULTADOS: A maioria dos estudos empregou métodos neuroquímicos ou de neuroimagem genéticos e histológicos - tanto in vivo quanto post-mortem - para investigar se os componentes do SECB estao comprometidos nos pacientes. De modo geral, os dados mostram mudanças nos receptores canabinoides em determinadas regioes cerebrais, bem como a alteraçao dos níveis de endocanabinoides no líquido cefalorraquidiano e/ou no sangue.
CONCLUSOES: Ainda que a disfunçao do SECB tenha sido descrita, os resultados dos estudos nao sao totalmente consistentes. Sao necessários mais dados para definir melhor o papel desse sistema na esquizofrenia.
Esquizofrenia; Cannabis; Endocanabinoides; Antipsicóticos.
Schizophrenia is a major psychiatric disorder consisting of a diversity of clinical features, which have been grouped as positive, negative and cognitive symptoms.1,2 The pharmacological approach for its treatment is quite limited and consists mainly of antipsychotic compounds, which are not effective in all the dimensions of this disorder . Almost all of these drugs share a common mechanism of action, which is the antagonism of dopamine receptors.3
The biological basis of schizophrenia has been extensively studied and discussed. Based on the mechanisms of antipsychotic medications and other pieces of evidence, the prevalent view is that its symptoms could result from a dysfunction in the dopaminergic neurotransmission, the so called dopaminergic hypothesis.4,5 There are, however, clear limitations for this hypothesis, as it does not properly explain the complexity of symptoms and its clinical heterogeneity. Apart from dopamine, there are other neurotransmitters that are also in focus, such as serotonin and glutamate.6,7
More recently, there has been investigation as to whether the endocannabinoid system (ECS) might be involved in schizophrenia. This neurotransmitter system is named after the herb Cannabis sativa
("marijuana"), known as one of the most consumed drugs of abuse. Its main active compound is delta-9-tetrahydrocannabinol (THC), the prototype of a class of compounds called cannabinoids. Other major natural cannabinoids are cannabidiol (CBD) and cannabinol. The ECS comprises the receptors for the cannabinoids, thus termed cannabinoid type-1 and type-2 receptors (CB1-R and CB2-R); their endogenous ligands, such as arachydonoyl ethanolamide (AEA, also known as anandamide), 2-arachydonoyl glycerol (2-AG), palmitoyl ethanolamide (PEA) and oleoyl ethanolamida (OEA), collectively termed endocannabinoids (eCBs); and the enzymes responsible for their synthesis and catabolism. Anandamide and 2-AG are metabolized by the enzymes fatty acid amide hydrolase (FAAH) and monoacyl glycerol lipase (MAGL), respectively.8,9 A schematic view of the proposed functioning of the ECS is depicted in Figure 1.
Figure 1 A simplified view of the endocannabinoid system, its main components and mechanisms. Endocannabinoids (eCBs), anandamide (arachdonoyl ethanolamide, AEA) and 2-arachydonoyl glycerol (2-AG) are synthesized from the membrane of postsynaptic neurons after calcium influx . They diffuse to the synaptic cleft  and exert their effect mainly through the CB1 receptor at pre-synaptic terminals . eCBs action are limited by uptake processes  to post- or pre-synaptic neurons for AEA and 2-AG, respectively. AEA is broken down to by an enzyme called fatty acid amide hydrolase (FAAH), whereas 2-AG is metabolized by monoacyl glycerol lipase (MAGL) .
The chronic use of cannabis
has been pointed as a possible factor leading to psychosis, more specifically schizophrenia. Other comprehensive reviews have focused on this possible link.10,11,12 The aim of the present paper is to review the literature addressing a putative role of the ECS in the pathophysiology of schizophrenia. METHOD
A search in PubMed database was performed with the terms: "genetic", "central nervous system", "cerebrospinal fluid" (CSF), "serum", "plasma", "blood", "neuroimaging", "PET scan", "fMRI", "post-mortem", individually crossed with "endocannabinoid system", "endocannabinoids", "anandamide", "2-AG", "2-arachidonoyl-glycerol", "cannabinoid receptors", "CNR1", "CB1R", "cannabinoid receptor 2", "CNR2", "CB2R" and "schizophrenia".
The inclusion criteria were: original papers; English language; studying changes of the ECS in schizophrenia (genetic variations in the components of the ECS, changes in cannabinoid receptors in the brain and changes in eCB levels in liquor or blood). ABSTRACTs from scientific meetings were also included. There was no limit for the year of publication, and the search included papers until April, 2012.
The search retrieved 90 articles, from which 22 were included. An Additional 9 articles were included based on references from these articles, totalling 31 articles on which the review was based. The remaining 68 articles were excluded for the following reasons: review papers (n = 19); studies with new radioligands for the cannabinoid receptor (n = 15); studies in animals (n = 7); studies investigating the effects of cannabis
in healthy volunteers or schizophrenic patients (n = 10); studies evaluating the link between Cannabis sativa
use and schizophrenia (n = 3); studies evaluating other outcomes from therapeutic interventions (n = 2); case report (n = 1); comment on an original paper (n = 1); and studies focusing on other disorders and conditions (n = 10). RESULTS
The studies were divided according to three main strategies to approach the ECS in schizophrenia: investigation of polymorphisms, detection of cannabinoid receptors in brain regions and measurement of eCB levels in CSF or blood. Genetic variations in the components of the ECS
Genetic variations related to the components of the ECS have been investigated in several studies. Most of them focused on the relationship between polymorphisms of the CNR1 gene, which encodes for CB1-R, and schizophrenia. This gene is located in the 6q14-q15 chromossomic region, which has been identified as a locus for schizophrenia susceptibility.13
The first studies evaluating the relationship between CNR1 variations and schizophrenia obtained negative results (Table 1). Tsai et al
.14 did not find any link between the (AAT)n triple repeat (AL136096) polymorphism and schizophrenia in a study comparing 127 Chinese patients with schizophrenia and 146 healthy controls. Leroy et al.
15 evaluated a distinct polymorphism from the same gene, 1359 G/A (rs1049353). These authors also did not find any difference in the allele frequency or genotypic distribution between 102 patients with schizophrenia or schizoaffective disorder and 63 controls in a French Caucasian population. Likewise, Zammit et al.16 did not find any relation between this same polymorphism and schizophrenia in 750 patients as compared to 688 controls in a British population. Seifert et al
.17 evaluated the association of three polymorphisms from the CNR1 (1359 G/A (rs1049353), (AAT)n triple repeat (AL136096) and rs6454674) with schizophrenia in 104 patients and 140 controls in a German population, but did not find differences between these groups. There was a tendency towards a lower frequency of the (AAT)10
allele in patients, although the result did not reach statistical significance, possibly due to the low sample size. Hamdani et al
.18 also studied the 1359 G/A (rs1049353) polymorphism and, again, did not find any association with schizophrenia in 133 patients as compared to 141 controls in a French population. Despite the negative result, this work did find a higher frequency of the G allele in patients with refractory schizophrenia, which could mean that the 1359 G/A polymorphism would not be related to vulnerability for this disorder, but rather to a response to antipsychotic drugs. In addition, the differences between three other polymorphisms (rs806368, rs806379 and rs806380) were analysed between patients refractory or responsive to antipsychotic treatment, but no association was found. Finally, Morita et al
.19 investigated a possible relationship between the Pro129Thr (rs324420
) polymorphism of the FAAH gene and schizophrenia. No difference was found in a group of 260 patients with schizophrenia (127 paranoids, 127 hebephrenics and 6 not classified) as compared to 63 controls in a Japanese population, regardless of the disorder subtype.
Contrasting these negative results, other studies point to an association between variations in the CNR1 gene and schizophrenia. Ujike et al
.20 compared 242 patients (110 paranoids and 128 hebephrenics) with 296 healthy controls in a Japanese population, in relation to the (AAT)n triple repeat polymorphism (AL136096), and found a difference in the allelic frequency in hebephrenics versus controls (higher frequency for the (AAT)9
allele and lower for (AAT)17
). In the same study, another group of 116 patients and 137 controls were evaluated for differences in 1359 G/A (rs1049353) polymorphism, but no differences were found. Some of these results were replicated by Martínez-Gras et al
.21 that found a lower frequency of the (AAT)10
allele (allele 4) in 113 patients with schizophrenia in comparison to 111 controls in a Spanish population. Chavarría-Siles et al
.22 compared 244 patients with schizophrenia, without subtype classification, to 66 patients of the hebephrenic subtype and did not find an association between the (AAT)n triple repeat polymorphism (AL136096) and patients with schizophrenia in general, but, similar to Ujike et al
.,20 they observed an effect for patients of the hebephrenic subtype (lower frequency of the (AAT)10
allele). These data reflect the pathophysiologic heterogeneity of schizophrenia and suggest that variations in the CNR1 gene may contribute to the pathogenesis of specific subtypes of this disorder.
Tiwari et al
.23 evaluated 20 polymorphisms of the CNR1 gene in 183 patients with schizophrenia or schizoaffective disorder that were on antipsychotic treatment and found higher allelic frequency (allele T) of the rs806378 polymorphism on those patients that gained more weight while using clozapine or olanzapine, which suggests that this genetic variation relates to susceptibility to antipsychotic-induced weight gain.
Ho et al
.24 evaluated interactions between CNR1 polymorphisms, cannabis
use, cerebral volume and cognitive function in an interesting study. They compared 52 patients with schizophrenia or schizoaffective disorder with cannabis
abuse/dependency and 183 patients without cannabis
use and observed smaller frontotemporal white matter (WM) volumes in those that smoked cannabis
. Besides that, patients with rs12720071 polymorphism (G allele) had lower WM volumes than those with the A allele. Those with the G allele that used cannabis
had even lower WM volumes. Patients with rs7766029 (C allele) and rs9450898 (C allele) had lower WM volumes than those with the T allele. In the cognitive battery, patients with rs12720071 (G allele) had worse results on processing speed/attention and problem-solving tests. Results on problem-solving tests were even worse in those G allele carriers that smoked cannabis
. Those results suggest that the use of cannabis
in association with specific CNR1 genotypes can contribute to alterations in WM and cognitive deficits in a subgroup of schizophrenic patients, which favors the hypothesis that genetic and environmental factors work together to determine the phenotypic expression in schizophrenia.
Only one study focused on variations in the CNR2 gene (which encodes CB2-R) in the pathogenesis of schizophrenia. Ishiguro et al
.25 evaluated differences in the allelic frequencies of five CNR2 polymorphisms (rs9424339, rs2502959, rs2501432 (R63Q), rs2229579 (H316T) and rs12744386), comparing 1920 patients with schizophrenia to 1920 controls in a Japanese population. The authors found an association of the polymorphisms rs2501432 (R63Q) and rs12744386 with the disorder. This result supports the hypothesis that variations in the CNR2 gene may participate in the pathophysiology of schizophrenia.
To summarize, most studies refer to (AAT)n triple repeat (AL136096) and 1359 G/A (rs1049353) polymorphisms of the CNR1 gene. Among the studies evaluating the (AAT)n triple repeat (AL136096) polymorphism, one found an association with schizophrenia,21 two found associations with schizophrenia of the hebephrenic subtype20,22 and two did not find any associations between the polymorphism and the disorder.14,17 Among those evaluating the 1359 G/A (rs1049353)15-18,20 polymorphism, no study found any association. The only study evaluating variations in the CNR2 gene25 observed a relationship between two polymorphisms with schizophrenia. The polymorphisms Pro129Thr (rs324420
) of the FAAH gene; rs6454674 of the CNR1 gene; as well as rs9424339, rs2502959 and rs2229579 (H316T) of the CNR2 gene did not seem to have any association with the disorder. Changes in cannabinoid receptors in the brain
Another strategy employed by several authors to investigate the role of the ECS in the pathophysiology of schizophrenia focuses on the determination of the levels of CB1-R in certain brain regions possibly related to this disorder. This has been performed either in post-mortem
or in vivo
studies evaluated the density of CB1-R through three main methods: radio-ligand binding assays, immunohistochemistry or polymerase chain reaction (PCR), whereas in vivo
studies employed neuroimaging techniques. These studies are summarized in Table 2.
The first post-mortem
study with a radioligand was conducted by Dean et al
.,26 who investigated differences in the levels of [3
H] CP-55940 binding (a CB1-R agonist) in area 9 of the dorsolateral prefrontal cortex (dlPFC), caudato-putamen and hippocampus of 14 patients with schizophrenia and 14 controls. The authors detected an increase of CB1-R density in the dlPFC of the patients, a result not related to cannabis
consumption. There was no difference in other brain regions. In addition, Dalton et al
.27 evaluated the density of CB1-R in another area of the dlPFC (area 46) with the same ligand and found an increase in the density of this receptor in patients with paranoid schizophrenia (n = 16) as compared to controls (n = 37). Zavitsanou et al.28 focused on the anterior cingulate cortex (ACC) using the CB1-R antagonist [3
H]-SR141716A in 10 patients with schizophrenia versus 10 controls, describing an increase in CB1-R density. Newell et al
.29 also found an increase in CB1-R expression in posterior cingulate cortex (PCC), as revealed by the CB1-R agonist [3
H]-CP-55940 in eight patients and eight controls. Finally, Deng et al
.30 evaluated differences in [3
H]-SR141716A binding in the superior temporal gyrus (STG), a brain region proposed to be particularly involved in the auditory hallucinations. However, they did not find any difference between patients (n = 8) and controls (n = 8).
studies employed different techniques to measure CB1-R density. Through imunohistochemistry, Koethe et al
.31 did not find differences in the ACC of patients with schizophrenia in relation to their controls (n = 15 per group). However, Eggan et al
.32 observed a reduction in CB1-R in the dlPFC (area 9), as revealed by protein and mRNA expression of 23 patients and equal number of controls. Likewise, Urigüen et al
.33 found reduced CB1-R protein expression (though not mRNA) in this same region in a sample of 31 young patients as compared to 33 controls. Finally, Eggan et al
.34 also evaluated CB1-R density in dlPFC, area 46, in two cohorts of patients and controls. In the first, comprising the same group from their previous study, they found reduction in CB1-R density in this brain region. In the second cohort, comprising 14 patients with schizophrenia, 14 with major depression and 14 controls, there was also a reduction in CB1-R density in schizophrenia as compared to controls, as well as to the major depression group.
Regarding in vivo
studies, there were two investigating the levels of CB1-R in brain through neuroimaging methods. Wong et al
.35 employed PET scan to evaluate receptor expression in several brain areas (frontal, temporal, parietal, occipital and cingulated cortices; fusiform gyrus, hippocampus, insula, putamen, caudate nucleus, globe pallidum, thalamus, cerebellum and pons) of 10 patients and equal number of controls. They found a significant increase in receptor expression only in the pons. There was also a tendency in this direction in most of the other regions (except for the fusiform gyrus and the cerebellum). In addition, they found that CB1-R expression correlated directly with positive symptoms and inversely with negative. Ceccarini et al
.36 also employed PET scan to evaluate the levels of the receptor in three brain areas (nucleus accumbens, insula and ACC) of 49 patients with schizophrenia treated with antipsychotics, 9 untreated patients and 12 controls. They observed an increase in CB1-R density in the nucleus accumbens, regardless treatment status and an increase in the insula and ACC in treated patients in relation to controls.
To summarize, studies measuring CB1-R expression in schizophrenia yield contradictory results. Five of them evaluated the dlPFC (three focusing on area 9 and two on 46). In area 9, one found an increase26 and two, a decrease32,33 in schizophrenia. Regarding area 46, one found an increase27 and other a decrease.34 In the ACC, two studies observed higher CB1-R levels,28,36 whereas another did not find any difference between patients and controls.31 Otherwise, there was an increase in the PCC,29 pons,35 nucleus accumbens and insula.36 No differences were observed in caudato-putamen, hippocampus26 and STG.30 Changes in endocannabinoid levels in CSF and blood
In addition to changes in the ECS in brain regions, studies described altered levels of eCBs in the CSF and blood collected from patients. The eight studies retrieved by our search are summarized in Table 3.
Four of them measured the levels of eCBs in the CSF. Leweke et al
.37 focused on the levels of AEA and PEA in 10 patients with schizophrenia and 11 controls and found increased levels of AEA in patients. In another study, Giuffrida et al
.38 measured AEA, PEA and OEA in four groups: 47 patients with untreated first episode of paranoid schizophrenia; 71 paranoid patients undergoing antipsychotic treatment (36 typical and 35 atypical); 22 patients with mood disorders and 13 patients with dementia syndrome. The levels of AEA were increased, whereas PEA was reduced in the first group of patients. Both eCBs were increased in patients under treatment with atypical antipsychotic. In patients with schizophrenia treated with typical antipsychotic, in those with mood disorders or those with dementia there were no changes in the levels of AEA as compared to controls. The levels of OEA in patients with untreated first episode of paranoid schizophrenia did not differ from controls. Noteworthy, there was a negative correlation between the levels of AEA in the CSF in patients with schizophrenia and the symptoms (as revealed by the Positive and Negative Syndrome Scale, PANSS), suggesting that AEA may represent a modulatory response against the hyperdopaminergic state characteristic of schizophrenia.
In order to evaluate the effects of cannabis
consumption on the levels of eCBs, in the CSF, Leweke et al
.39 measured the levels of AEA, PEA and OEA in 44 patients with schizophrenia and 81 controls, both being divided in subgroups accordingly to high or low cannabis
consumption. The authors detected a higher level of AEA in the CSF in patients who consumed less cannabis
as compared to those who used it frequently as well as to the controls. The levels of other eCBs were not altered. There was a negative correlation between the levels of AEA in the CSF and the PANSS score, but only in the low consumption patient subgroup. The authors suggested that heavy cannabis
use by subjects with a hyperactive ECS may down-regulate AEA signalling in the central nervous system and disrupt the eCB modulation over the dopaminergic system.39
Koethe et al
.40 tested the hypothesis that the increase in eCBs in schizophrenia could be detected in the early stages of the disorder. Thus, they measured the levels of AEA and OEA in 27 psychotic patients in the prodromic phase and 81 controls. The levels of AEA, but not OEA were increased in the patients. Again, there was an inverse correlation between the PANSS score, although only with the cognitive dimensions. Patients in prodromic stage with higher levels of AEA in the CSF tend to develop less psychosis, supporting the hypothesis that the ECS might exert a modulatory role upon the dopaminergic system that, in turn, protect against positive symptoms. Giuffrida et al
.,38 Leweke et al
.39 and Koethe et al
.40 also measured the levels of AEA, PEA and OEA in the blood (serum), but did not observe differences in relation to controls. By contrast Yao et al
.41 measured AEA and 2-AG in 17 untreated first episode patients with schizophrenia, 20 stable patients and 20 controls. They observed an increase in AEA in the first group in relation to controls, and reduced levels of 2-AG in relation to stable patients. Shwarz et al
.42 measure fatty acid amides (FAAs, a class of lipids that include the eCBs) in 70 untreated patients with paranoid schizophrenia, 74 patients with paranoid schizophrenia undergoing antipsychotic therapy (34 with atypical and 40 with typical antipsychotic), 37 patients with mood disorders and 59 controls. They observed that the levels of FAAs were increased in untreated patients with schizophrenia in relation to controls and that these levels were normalized in patients treated with typical, but not atypical antipsychotic.
Finally, two studies evaluated the blood levels of eCBs before and after treatment with antipsychotics. De Marchi et al
.43 measured AEA and mRNA for FAAH, for CB1-R and for CB2-R in the blood of 12 patients with schizophrenia presenting acute psychosis and 20 controls. Before treatment, AEA levels were higher in patients, but after olanzapine treatment and improvement in positive symptoms in 5 patients, AEA levels were similar to controls. There was also a reduction in FAAH and CB2-R mRNA, but not CB1-R mRNA. Potvin et al
.44 tested the hypothesis that quetiapine could help to reduce drug abuse in patients with schizophrenia through modulation of the ECS. They quantified the levels of AEA, 2-AG, PEA and OEA in 27 addicted patients with schizophrenia and 17 controls. Before treatment, the levels of AEA, PEA and OEA, but not 2-AG, were increased. After 12 weeks on quetiapine treatment, there was a reduction in drug abuse and improvement in positive, negative and depressive symptoms, but no reduction in AEA, PEA or OEA levels.
In summary, four studies detected an increase in the levels of AEA in the CSF.37-40 Regarding measures in the blood, three also reached this result,41,43,44 whereas other three did not find any difference.38,39,40 The levels of 2-AG in the blood were found to be reduced in one study41 and unchanged in another.44 The levels of OEA in the CSF did not differ from controls in two studies,38,39 although in the blood they were either higher44 or unchanged.39,40 One study found that the levels of PEA in the CSF were increased in patients receiving atypical antipsychotics and reduced in the untreated.38 Other studies found that the blood levels were either increased44 or unchanged.40 The treatment with atypical antipsychotics was inversely correlated with the levels of AEA in the blood in two studies,38,43 but another one did not find any change.44 As for typical AP, their use changed AEA and FAAs to levels similar to controls.38,42 CONCLUSION
The present systematic review described the literature investigating changes in the ECS in patients suffering from schizophrenia. The original papers reviewed here studied genetic polymorphisms, the expression of cannabinoid receptors in specific brain regions and levels of eCBs in CSF or blood.
So far, it is difficult to draw any consistent theory on the role of the ECS in this major psychiatric disorder. Taking into account the acute effects of Cannabis sativa
and cannabinoids, which induce psychotomimetic effects,45 and the epidemiologic evidence suggesting that chronic consumption of Cannabis
may be a predisposing factor to schizophrenia,10,11,12 there is a rationale to link changes in the ECS to symptoms in this disorder. Indeed, an endocannabinoid hypothesis of schizophrenia has been proposed.46 Nonetheless, from the studies retrieved in our review, no clear picture has emerged.
This topic is relevant not only for theoretical reasons. The current pharmacological therapy of schizophrenia is limited to the antagonism of dopamine receptors, which presents limited efficacy and significant side effects.3 Thus, alternative pharmacological strategies must be pursued and one approach involves the characterization of other neurotransmitters systems affected in this disorder. Such a strategy has been put into practice, for instance, with the glutamate system. Based on the theory that schizophrenia might be related to a low functioning of glutamate, there have been attempts to develop drugs that enhance this neurotransmitter.6,7 As for the ECS, it has been investigated whether CB1-R antagonism induces antipsychotic effects, as a corollary to the psychotomimetic effects of cannabinoids, which activate this receptor. However, results to date have been mixed.47 Studies in experimental animals have also been inconsistent.48
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1. Neurosciences Post-Graduation Program, Pharmacology Department, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Brazil
2. Pharmacology Department, Biological Sciences Institute, Universidade Federal de Minas Gerais, Brazil
3. Internal Medicine Department, Faculdade de Medicina, Universidade Federal de Minas Gerais, Brazil
4. Morphology Department, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Brazil
5. Instituto Raul Soares, Hospital Foundation of the State of Minas Gerais (Fundaçao Hospitalar do Estado de Minas Gerais, FHEMIG), Brazil
Joao V. Salgado
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31270-901, Belo Horizonte, MG, Brazil
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