Publications by authors named "Helton José Reis"

32 Publications

Cannabidiol prevents lipopolysaccharide-induced sickness behavior and alters cytokine and neurotrophic factor levels in the brain.

Pharmacol Rep 2021 Jul 3. Epub 2021 Jul 3.

Neuroscience Program, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.

Background: Major depressive disorder (MDD) affects millions of people worldwide. While the exact pathogenesis is yet to be elucidated, the role of neuro-immune signaling has recently emerged. Despite major advances in pharmacotherapy, antidepressant use is marred by limited efficacy and potential side effects. Cannabidiol (CBD), a phytocannabinoid, exerts antidepressant-like effects in experimental animals. This study investigated the impact of CBD on sickness behavior (SB), a measure of depressive-like response, and neuro-immune changes induced by lipopolysaccharides (LPS) in mice.

Methods: Socially isolated rodents were administered with LPS to trigger SB. and treated with CBD or its vehicle. Animals were submitted to forced swimming test, to evaluate depressive-like behavior, and to open field test, to evaluate locomotory activity. Immediately after behavioral analyses, animals were euthanized and had their hypothalamus, prefrontal cortex and hippocampus dissected, to proceed neurotrophins and cytokines analyses. ELISA was used to detect IL-1β, BDNF and NGF; and cytometric beads array to measure IL-2, IL-4, IL-6, IFN-γ, TNF-α and IL-10 levels.

Results: CBD effectively prevented SB-induced changes in the forced swim test without altering spontaneous locomotion. This phytocannabinoid also partially reversed LPS-evoked IL-6 increase in both the hypothalamus and hippocampus. In addition, CBD prevented endotoxin-induced increase in BDNF and NGF levels in the hippocampus of SB animals.

Conclusions: Apparently, CBD prevents both behavioral and neuro-immunological changes associated with LPS-induced SB, which reinforces its potential use as an antidepressant which modulates neuroinflammation. This opens up potentially new therapeutic avenues in MDD.
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http://dx.doi.org/10.1007/s43440-021-00301-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8254454PMC
July 2021

Serotonin and dopamine receptors profile on peripheral immune cells from patients with temporal lobe epilepsy.

J Neuroimmunol 2021 05 5;354:577534. Epub 2021 Mar 5.

Laboratório de Neurofarmacologia, Departamento de Farmacologia, ICB, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Brazil; Programa de Neurociências, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Brazil. Electronic address:

The role of inflammation and immune cells has been demonstrated in neurological diseases, including epilepsy. Leukocytes, as well as inflammatory mediators, contribute to abnormal processes that lead to a reduction in seizure threshold and synaptic reorganization. In this sense, identifying different phenotypes of circulating immune cells is essential to understanding the role of these cells in epilepsy. Immune cells can express a variety of surface markers, including neurotransmitter receptors, such as serotonin and dopamine. Alteration in these receptors expression patterns may affect the level of inflammatory mediators and the pathophysiology of epilepsy. Therefore, in the current study, we evaluated the expression of dopamine and serotonin receptors on white blood cells from patients with temporal lobe epilepsy with hippocampal sclerosis (TLE-HS). Blood samples from 17 patients with TLE-HS and 21 controls were collected. PBMC were isolated and stained ex vivo for flow cytometry. We evaluated the expression of serotonin (5-HT, 5-HT, 5-HT, 5-HT, 5-HT, 5-HT, 5-HT), and dopamine receptors (D, D, D, D, and D) on the cell surface of lymphocytes and innate immune cells (monocytes and granulocytes). Our results demonstrated that innate cells and lymphocytes from patients with TLE-HS showed high mean fluorescent intensity (MFI) for 5-HT, 5-HT, 5-HT and 5-HT compared to controls. No difference was observed for 5-HT. For dopamine receptors, the expression of D, D, D and D receptors was higher on innate cells from patients with TLE-HS when compared to controls for the MFI. Regarding lymphocytes population, D expression was increased in patients with TLE-HS. In conclusion, there are alterations in the expression of serotonin and dopamine receptors on immune blood cells of patients with TLE-HS. Although the biological significance of these findings still needs to be further investigated, these changes may contribute to the understanding of TLE-HS pathophysiology.
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http://dx.doi.org/10.1016/j.jneuroim.2021.577534DOI Listing
May 2021

Evaluation of Brain Cytokines and the Level of Brain-Derived Neurotrophic Factor in an Inflammatory Model of Depression.

Neuroimmunomodulation 2020 11;27(2):87-96. Epub 2020 Nov 11.

Department of Pharmacology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil,

Introduction: Major depressive disorder is considered a global public health problem. Inflammatory processes are likely involved in its pathophysiology, but the underlying mechanisms have remained uncertain.Here, we used the model of systemic lipopolysaccharide (LPS) injection to test the hypothesis that depressive-like behaviors occur along with changes in the levels of cytokines and brain-derived neurotrophic factor (BDNF) in the hippocampus (HC), prefrontal cortex (PFC), and hypothalamus (HT), and can be prevented by dexamethasone administration.

Methods: Adult C57Bl/6 male mice were first isolated for 10 days, and thereafter received an injection of dexamethasone (6 mg/kg, intraperitoneal [i.p.]), saline followed by LPS (0.83 mg/kg, i.p.), or saline. After 6 h, animals were subjected to the forced-swim test (FST) and open-field tests. Immediately after the behavioral tests, they were euthanized and their brains were collected for the biochemical analyses.

Results: LPS increased the immobility time and reduced the distance travelled in the FST and open-field test, respectively. Dexamethasone increased the immobility time in saline-treated mice but reduced this behavior in the LPS group. LPS increased the levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6 and interferon (IFN)-γ in most of the regions evaluated. Dexamethasone prevented LPS-induced IL-6 in the HC, PFC, and HT. Interestingly, dexamethasone increased IL-4 and IL-10 levels in both the LPS- and saline-treated groups. Although dexamethasone reduced BDNF in saline-treated mice, it prevented LPS-induced reduction in this neurotrophic factor.

Conclusion: In summary, dexamethasone decreased proinflammatory and increased anti-inflammatory levels of cytokines and prevented a reduction in BDNF levels induced by the inflammatory stimulus. Thus, the attenuation of depressive-like behavior induced by dexamethasone may be related to the effects on these parameters.
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http://dx.doi.org/10.1159/000511181DOI Listing
November 2020

Comparison of Inflammatory Mediators in Patients With Atrial Fibrillation Using Warfarin or Rivaroxaban.

Front Cardiovasc Med 2020 24;7:114. Epub 2020 Jul 24.

Neurofar Laboratory, Departamento de Farmacologia, ICB, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.

Atrial fibrillation (AF) is the most common arrhythmia associated with high risk of venous thromboembolism. Inflammatory mechanisms may be involved in the pathophysiology of AF and in the AF-related thrombogenesis, and patients with AF might benefit from the use of anticoagulants with anti-inflammatory properties. However, the evidence is still scarce, and it points out the need of trials seeking to investigate the levels of inflammatory mediators in patients with AF under different anticoagulant therapies. Therefore, this study was designed to define whether patients with AF treated either with an activated coagulation factor X (FXa) inhibitor (rivaroxaban) or with a vitamin K inhibitor (warfarin) present changes in peripheral levels of inflammatory mediators, mainly cytokines and chemokines. A total of 127 subjects were included in this study, divided into three groups: patients with non-valvular atrial fibrillation (NVAF) using warfarin ( = 42), patients with NVAF using rivaroxaban ( = 29), and controls ( = 56). Plasma levels of inflammatory mediators were quantified by immunoassays. Patients with AF (both warfarin and rivaroxaban groups) presented increased levels of inflammatory cytokines in comparison with controls. The use of rivaroxaban was associated with decreased levels of inflammatory cytokines in comparison with warfarin. On the other hand, patients with AF using rivaroxaban presented increased levels of the chemokines (MCP-1 in comparison with warfarin users; MIG and IP-10 in comparison with controls). AF is associated with an inflammatory profile that was less pronounced in patients on rivaroxaban in comparison with warfarin users. Further studies are necessary to assess the clinical implications of our results and whether patients with AF would benefit from rivaroxaban anti-inflammatory effects.
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http://dx.doi.org/10.3389/fcvm.2020.00114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393940PMC
July 2020

Thrombin Generation and other hemostatic parameters in patients with atrial fibrillation in use of warfarin or rivaroxaban.

J Thromb Thrombolysis 2021 Jan;51(1):47-57

Department of Clinical and Toxicological Analysis, Faculty of Pharmacy - Federal, University of Minas Gerais, Av. Antônio Carlos, 6627 - Pampulha, Belo Horizonte, 31270-910, Brazil.

Patients with atrial fibrillation (AF) present hyperactivation of both platelets and coagulation leading to a hypercoagulable state which contributes to an increased risk of thromboembolism. Therefore, one of the main strategies for treatment of AF is prevention of these events through the use of oral anticoagulants (OAC). The aim of this study was to evaluate hemostasis as a whole in patients with non-valvular AF undergoing warfarin or rivaroxaban by thrombin generation test (TGT), in addition to monocyte-platelet aggregates (MPA), glycoprotein IIb/IIIa (GPIIb/IIIa), and platelet (PMP) and endothelium (EMP) microparticles, compared to age and sex matched controls. PT/INR for OAC use was also determined. In patients taking OAC, compared to control group, a decrease in TGT (p = 0.000 for all parameters) were observed. Patients taking warfarin showed to be more hypocoagulable, presenting lower levels of ETP (p = 0.000) and peak (p = 0.002) than patients using rivaroxaban. Patients on warfarin use with INR > 3 had also lower levels of ETP (p = 0.01) and peak (p = 0.006). A decrease in ETP (p = 0.03) and peak (p = 0.02) values was also observed in patients using rivaroxaban with PT > 21.4 s. Patients using warfarin (p = 0.000) and rivaroxaban (p = 0.000) presented lower levels of MPA in relation to control group. It was also observed in patients using warfarin, lower GPIIb/IIIa levels in relation to control group (p = 0.011). Patients taking rivaroxaban (p = 0.003) and warfarin (p = 0.001) had higher PMP levels compared to control group. There was no difference in levels of EMP between the groups (p = 0.0536). The present study reinforces the usefulness of OAC in AF, which decisively contribute to a better management of the disease preventing possible complications.
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http://dx.doi.org/10.1007/s11239-020-02126-3DOI Listing
January 2021

Inflammatory and Infectious Processes Serve as Links between Atrial Fibrillation and Alzheimer's Disease.

Int J Mol Sci 2020 May 2;21(9). Epub 2020 May 2.

Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Brazil.

Atrial fibrillation (AF) is one of the most prevalent forms of arrhythmia that carries an increased risk of stroke which, in turn, is strongly associated with cognitive decline. The majority of dementia cases are caused by Alzheimer's disease (AD) with obscure pathogenesis. While the exact mechanisms are unknown, the role of inflammatory processes and infectious agents have recently been implicated in both AD and AF, suggesting a common link between these maladies. Here, we present the main shared pathways underlying arrhythmia and memory loss. The overlapping predictive biomarkers and emerging joint pharmacological approaches are also discussed.
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http://dx.doi.org/10.3390/ijms21093226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7247326PMC
May 2020

Circulating levels of neurotrophic factors are unchanged in patients with Parkinson's disease.

Arq Neuropsiquiatr 2018 May;76(5):310-315

The University of Texas Health Science Center at Houston, McGovern Medical School, Department of Psychiatry and Behavioral Sciences, Neuropsychiatry Program, Houston, TX, USA.

There is great evidence linking neurotrophic factor (NF) dysfunction with Parkinson's disease (PD) pathophysiology. This study was conducted to evaluate plasma levels of NFs and their possible associations with clinical symptoms in PD. For this purpose, 40 PD patients and 25 controls were subjected to a clinical evaluation and peripheral blood draw. Plasma levels of brain-derived neurotrophic factor (BDNF), pro-BDNF, neurotrophin 3, neurotrophin 4, nerve growth, glial cell line-derived neurotrophic factor and ciliary neurotrophic factor were measured by enzyme-linked immunosorbent assay. There was no significant difference between PD patients and controls regarding the plasma levels of the evaluated NFs. In addition, NF levels were not associated with disease duration, degree of motor or functional impairment, cognitive performance or severity of depressive symptoms. In conclusion, although NFs may play relevant roles in the pathophysiology of PD, the circulating levels of these molecules are not necessarily changed in patients with PD.
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http://dx.doi.org/10.1590/0004-282X20180035DOI Listing
May 2018

Inflammation as a Possible Link Between Dyslipidemia and Alzheimer's Disease.

Neuroscience 2018 04 14;376:127-141. Epub 2018 Feb 14.

Department of Pharmacology, Universidade Federal de Minas Gerais, Belo Horizonte, 31270-901, Brazil. Electronic address:

Alzheimer's disease (AD) is the leading cause of dementia worldwide. This pathological condition is characterized not only by Aβ and tau accumulation in the central nervous system (CNS), but also by inflammation, processes that can lead to neurodegeneration. Besides that, other factors may contribute to the development of AD, such as dyslipidemias. Changes in lipid levels can either influence the activity of enzymes related to the protein deposition that occurs in this pathological condition, or enhance the peripheral and CNS immune responses. Furthermore, cholesterol-associated genes are frequently associated with AD. Here, we extensively reviewed the literature and, based on the existing evidences, we suggest inflammation as an important link between dyslipidemias and AD.
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http://dx.doi.org/10.1016/j.neuroscience.2018.02.012DOI Listing
April 2018

Thrombin generation assays for global evaluation of the hemostatic system: perspectives and limitations.

Rev Bras Hematol Hemoter 2017 Jul - Sep;39(3):259-265. Epub 2017 May 9.

Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brazil. Electronic address:

The existing techniques to evaluate hemostasis in clinical laboratories are not sensitive enough to detect hypercoagulable and mild hypocoagulable states. Under different experimental conditions, the thrombin generation test may meet these requirements. This technique evaluates the overall balance between procoagulant and anticoagulant forces and has provided new insights in our understanding of the coagulation cascade, as well as of the diagnosis of hypocoagulability and hypercoagulability conditions. Thrombin generated in the thrombin generation test can be quantified as platelet-rich or platelet-poor plasma using the calibrated automated thrombogram method, which monitors the cleavage of a fluorogenic substrate that is simultaneously compared to the known thrombin activity in a non-clotting plasma sample. The calibrated automated thrombogram method is an open system, in which different antibodies, proteins, enzymes and peptides can be introduced to answer specific questions regarding hemostatic processes. The thrombin generation test has great clinical potential, such as in monitoring patients taking anticoagulants and antiplatelet drugs, screening for genetic or acquired thrombotic disorders, and evaluating bleeding risk control in patients with hemophilia using bypass agents or replacement therapy. Different to conventional coagulation tests, the thrombin generation test can be used for an overall evaluation of hemostasis, the results of which can then be used to evaluate specific characteristics of hemostasis, such as prothrombin time, activated partial thromboplastin time, and levels of fibrinogen and other coagulation factors. The introduction of this method will contribute to a better understanding and evaluation of overall hemostatic processes; however, this method still requires standardization and clinical validation.
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http://dx.doi.org/10.1016/j.bjhh.2017.03.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5568585PMC
May 2017

Reduced Activated T Lymphocytes (CD4+CD25+) and Plasma Levels of Cytokines in Parkinson's Disease.

Mol Neurobiol 2018 02 7;55(2):1488-1497. Epub 2017 Feb 7.

Laboratório Interdisciplinar de Investigação Médica (LIIM), Faculdade de Medicina, Universidade Federal de Minas Gerais, Av. Prof. Alfredo Balena, 190, Sala 281, Belo Horizonte, MG, 30130-100, Brazil.

Parkinson's disease (PD) is the second most common neurodegenerative disease. The cause of neurodegeneration in PD is not completely understood, and evidence has shown that inflammatory/immune changes may be involved in PD pathophysiology. Herein, we aimed to determine the profile of the peripheral immune system in patients with PD in comparison with controls. Forty patients with PD and 25 age- and gender-matched controls were enrolled in this study. From these, 23 PD patients and 21 controls were included in the immunophenotyping analyses. Peripheral blood was drawn on the same day of the clinical assessment and submitted to plasma separation for enzyme-linked immunosorbent assay or cytometric bead array. Immunophenotyping analyses of the peripheral blood were performed by flow cytometry. We found that patients with PD presented peripheral immune changes evidenced by decreased percentage of T lymphocytes (CD3+ cells), especially activated T lymphocytes (CD4+CD25+ cells), when compared with controls. In line with these results, we also found decreased plasma levels of the cytokines IL-4, IL-6, IL-10, TNF, IFN-γ, and IL-17A in the PD group. In vitro experiments demonstrated that the production of cytokines by peripheral blood mononuclear cells harvested from healthy young donors was reduced after exposure to the anti-parkinsonian drugs levodopa and pramipexole. Our data corroborate the hypothesis that immunological mechanisms are involved in PD. It is not clear whether the differences that we have found are due to adaptive mechanisms or to changes associated with PD, including pharmacological treatment, or even directly related to the disease pathophysiology. Future studies are needed in this regard.
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http://dx.doi.org/10.1007/s12035-017-0404-yDOI Listing
February 2018

Peripheral levels of angiotensins are associated with depressive symptoms in Parkinson's disease.

J Neurol Sci 2016 Sep 14;368:235-9. Epub 2016 Jul 14.

Laboratório Interdisciplinar de Investigação Médica (LIIM), Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil; Neuropsychiatry Program, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, United States.

Background: The pathogenesis of PD remains elusive. The renin-angiotensin-system (RAS) has recently been implicated in the degeneration of dopaminergic neurons. This study aimed to compare plasma levels of components of the RAS of individuals with PD with controls. We also investigated the association between these circulating markers and motor, depressive and cognitive parameters.

Methods: Thirty PD patients and twenty controls were subjected to clinical evaluation, including cognitive and depressive symptoms assessment. Plasma levels of Angiotensin (Ang) I, Ang II, Ang- (1-7), angiotensin-converting enzyme (ACE) and ACE2 were measured by Enzyme-Linked Immunosorbent Assay (ELISA).

Results: PD patients presented lower plasma levels of Ang I, Ang II and Ang- (1-7) than control individuals. Among PD patients, lower circulating levels of angiotensins were associated with increased severity of depressive symptoms.

Conclusions: This is the first study showing that peripheral levels of RAS components are changed in PD and associated with depressive symptoms.
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http://dx.doi.org/10.1016/j.jns.2016.07.031DOI Listing
September 2016

Neuroprotective effects of the anticancer drug NVP-BEZ235 (dactolisib) on amyloid-β 1-42 induced neurotoxicity and memory impairment.

Sci Rep 2016 05 4;6:25226. Epub 2016 May 4.

Department of Pharmacology, Universidade Federal de Minas Gerais, Belo Horizonte, 31270-901, Brazil.

Alzheimer's Disease (AD) is a progressive neurodegenerative disease and the main cause of dementia. Substantial evidences indicate that there is over-activation of the PI3K/Akt/mTOR axis in AD. Therefore, the aim of the present study was to investigate the effects of NVP-BEZ235 (BEZ; dactolisib), a dual PI3K/mTOR inhibitor that is under phase I/II clinical trials for the treatment of some types of cancer, in hippocampal neuronal cultures stimulated with amyloid-β (Aβ) 1-42 and in mice injected with Aβ 1-42 in the hippocampus. In cell cultures, BEZ reduced neuronal death induced by Aβ. BEZ, but not rapamycin, a mTOR inhibitor, or LY294002, a PI3K inhibitor that also inhibits mTOR, reduced the memory impairment induced by Aβ. The effect induced by Aβ was also prevented in PI3Kγ(-/-) mice. Neuronal death and microgliosis induced by Aβ were reduced by BEZ. In addition, the compound increased IL-10 and TNF-α levels in the hippocampus. Finally, BEZ did not change the phosphorylation of Akt and p70s6K, suggesting that the involvement of PI3K and mTOR in the effects induced by BEZ remains controversial. Therefore, BEZ represents a potential strategy to prevent the pathological outcomes induced by Aβ and should be investigated in other models of neurodegenerative conditions.
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http://dx.doi.org/10.1038/srep25226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4855228PMC
May 2016

Neuroinflammation and Neurodegeneration: Pinpointing Pathological and Pharmacological Targets.

Biomed Res Int 2015 30;2015:487241. Epub 2015 Jul 30.

Department of Pharmacology, Federal University of State Minas Gerais, Avenida Antonio Carlos 6627, 31270-901 Belo Horizonte, MG, Brazil.

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http://dx.doi.org/10.1155/2015/487241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4534599PMC
May 2016

Wistar Audiogenic Rats (WAR) exhibit altered levels of cytokines and brain-derived neurotrophic factor following audiogenic seizures.

Neurosci Lett 2015 Jun 30;597:154-8. Epub 2015 Apr 30.

Department of Pharmacology, Brazil. Electronic address:

Increasing body of evidence suggests that inflammatory and neurotrophic factors might be important for epileptogenesis. Most animal studies demonstrated altered levels of these mediators in drug-induced models of seizures and epilepsy. In the present study, we investigated the production of cytokines and a neurotrophin in the brain of Wistar Audiogenic Rats (WAR), a genetic model of epilepsy, stimulated with high-intensity sound. Four hours after stimulation, animals were decapitated and the hippocampus, inferior colliculus, striatum and cortex were removed for evaluation of the levels of interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α and brain derived neurotrophic factor (BDNF). All the cytokines and BDNF levels were increased in the cortex. Increased levels of TNF-α and IL-6 were also observed in the striatum. Finally, TNF-α also increased in the inferior colliculus after the seizures induced by high-intensity sound. Although different studies have demonstrated that the levels of cytokines and BDNF increase in animal models of epilepsy induced by chemical stimuli, we provided here evidence that these mediators are also increased in WAR, a genetic model of epilepsy. Thus, the observed increase in these mediators might be involved in the pathophysiology of epilepsy.
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http://dx.doi.org/10.1016/j.neulet.2015.04.046DOI Listing
June 2015

Cognitive Status Correlates with CXCL10/IP-10 Levels in Parkinson's Disease.

Parkinsons Dis 2014 15;2014:903796. Epub 2014 Oct 15.

Laboratório de Neurofarmacologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Avenida Presidente Antônio Carlos 6627, 31270-901 Belo Horizonte, MG, Brazil.

Cognitive impairment and depressive symptoms are of great interest in Parkinson's disease (PD), since they are very common and lead to increased disability with poor quality of life. Inflammatory mechanisms have been implicated in PD and its nonmotor symptoms. In the current pilot study, we aimed to evaluate plasma levels of chemokines in PD patients and to analyze the putative association of chemokines with depressive symptoms and cognitive performance. We hypothesized that higher chemokines levels are associated with worse cognitive performance and increased depressive symptoms in PD. For this purpose, 40 PD patients and 25 age- and gender-matched controls were subjected to a clinical evaluation including cognitive and mood tests. Peripheral blood was drawn and plasma levels of CCL2/MCP-1, CCL11/eotaxin, CCL24/eotaxin-2, and CXCL10/IP-10 were measured by enzyme-linked immunosorbent assay. PD patients and control individuals presented comparable plasma concentrations of all the evaluated chemokines. In PD patients, CXCL10/IP-10 plasma levels correlated positively with Hoehn and Yahr staging scale. In addition, the higher CXCL10/IP-10 levels, the worse performance on cognitive tests. Although there was no significant difference between PD patients and control individuals regarding chemokines levels, our preliminary results showed that CXCL10/IP-10 may be associated with cognitive status in PD.
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http://dx.doi.org/10.1155/2014/903796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4216701PMC
November 2014

The astrocyte marker Aldh1L1 does not reliably label enteric glial cells.

Neurosci Lett 2014 Apr 1;566:102-5. Epub 2014 Mar 1.

Laboratory for Enteric NeuroScience (LENS), Translational Research Center for GastroIntestinal Disorders (TARGID), Department of Clinical and Experimental Medicine, University of Leuven, Leuven, Belgium. Electronic address:

Enteric glial cells are increasingly acknowledged as important partners of enteric neurons in the control of gastrointestinal function. They share morphological features and expression of antigenic markers with astrocytes of the central nervous system. Recently, aldehyde dehydrogenase 1 family member L1 (Aldh1L1) has been proposed as a novel and specific marker for astrocytes. Taking the known similarities between astrocytes and enteric glia into account, we sought to investigate whether enteric glial cells also express Aldh1L1. To this end, we performed immunostaining on preparations of myenteric plexus obtained from adult Aldh1L1-eGFP bacterial artificial chromosome (BAC) transgenic mice and found that the Aldh1L1 promoter is indeed active in enteric glia, albeit mainly in cells residing outside the myenteric ganglia. Apart from enteric glia, we also observed eGFP expression in interstitial cells of Cajal. Furthermore, myenteric ganglia of the large intestine contained eGFP positive neurons. Taken together, our data indicate that Aldh1L1 is not a suitable marker for enteric glial cells.
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http://dx.doi.org/10.1016/j.neulet.2014.02.042DOI Listing
April 2014

Depression and cognitive impairment in Parkinson's disease: a role for inflammation and immunomodulation?

Neuroimmunomodulation 2014 14;21(2-3):88-94. Epub 2014 Feb 14.

Laboratório Interdisciplinar de Investigação Médica, Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil.

The etiology of Parkinson's disease (PD) is complex and not fully understood, most probably because of the multiplicity of factors involved. Inflammatory and abnormal immune responses have been hypothesized to play a crucial role in PD. Not only in the brain, but also peripherally, inflammation is believed to contribute to the onset and progression of the neurodegenerative process seen in PD. Furthermore, increased inflammatory responses have been described both in the brain and peripheral blood of PD subjects. Although PD is considered a motor disorder, nonmotor symptoms are extremely frequent and disabling. Cognitive impairment and mood alterations are such symptoms that deserve increased attention since on the one hand they can appear even before typical motor disturbances are recognized, and on the other hand they are associated with high morbidity and mortality. A growing body of evidence suggests the existence of a link between inflammatory-immune responses and the occurrence of depression and cognitive impairment in PD patients. However, not all data are equally conclusive and are sometimes even conflicting. The aim of this brief review is to give an overview of the possible role that inflammation and immunomodulation may play in PD together with their putative impact on mood and cognitive alterations. What clearly emerges from this work is the fact that studies performed until now lack standardized and comparable methods to analyze both clinical and biological parameters. It is thus difficult to conclusively link mood and cognitive changes to underlying pathological mechanisms. Additional studies in this direction are warranted to convincingly establish or refute any causative relation.
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http://dx.doi.org/10.1159/000356531DOI Listing
October 2014

Circulating levels of adipokines in Parkinson's disease.

J Neurol Sci 2014 Apr 23;339(1-2):64-8. Epub 2014 Jan 23.

Laboratório Interdisciplinar de Investigação Médica, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil. Electronic address:

Introduction: Adipokines are adipocyte-derived secretory factors, which have functions in satiety, energetic homeostasis, insulin sensitivity, vascular disease and also immune response. Parkinson's disease (PD) has been associated with unintended weight loss and reduced prevalence of cardiovascular risk factors. In addition, inflammation has been proposed as one of the factors contributing to PD pathophysiology. Therefore, we sought to investigate if adipokine levels - adiponectin, leptin and resistin - are altered in PD patients. Also, we aimed to evaluate association between adipokine levels and clinical variables in PD.

Methods: Forty PD patients and twenty-five age-, gender- and body mass index-matched controls were enrolled in this study. Peripheral blood was drawn and plasma levels of adiponectin, leptin and resistin were measured by Enzyme-Linked Immunosorbent Assay.

Results: There was no significant difference between PD patients and controls regarding plasma levels of the evaluated adipokines. In PD patients, higher leptin levels were associated with increased age and body mass index. No other correlation was found between adipokine levels and clinical or demographic data.

Conclusions: Although adipokines play important roles in inflammation, it seems that they are not implicated in the inflammatory response associated with PD.
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http://dx.doi.org/10.1016/j.jns.2014.01.021DOI Listing
April 2014

Plasma levels of soluble tumor necrosis factor receptors are associated with cognitive performance in Parkinson's disease.

Mov Disord 2014 Apr 3;29(4):527-31. Epub 2013 Dec 3.

Laboratório Interdisciplinar de Investigação Médica, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil; Laboratório de Neurofarmacologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.

Inflammatory mechanisms have been implicated in a series of neuropsychiatric conditions, including behavioral disturbances, cognitive dysfunction, and affective disorders. Accumulating evidence also strongly suggests their involvement in the pathophysiology of Parkinson's disease (PD). This study aimed to evaluate plasma levels of inflammatory biomarkers, and their association with cognitive performance and other non-motor symptoms of PD. PD patients and control individuals were subjected to various psychometric tests, including the Mini-Mental State Examination (MMSE), Frontal Assessment Battery (FAB), and Beck's Depression Inventory (BDI). Biomarker plasma levels were measured by enzyme-linked immunosorbent assay (ELISA). PD patients exhibited worse performance on MMSE and the programming task of FAB, and presented higher soluble tumor necrosis factor receptor (sTNFR) plasma levels than control individuals. Among PD patients, increased sTNFR1 and sTNFR2 concentrations were associated with poorer cognitive test scores. After multiple linear regression, sTNFR1 and education remained a significant predictor for FAB scores. Our data suggest that PD is associated with a proinflammatory profile, and sTNFRs are putative biomarkers of cognitive performance, with elevated sTNFR1 levels predicting poorer executive functioning in PD patients.
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http://dx.doi.org/10.1002/mds.25752DOI Listing
April 2014

Increased BDNF levels in long-term bipolar disorder patients.

Braz J Psychiatry 2013 Mar;35(1):67-9

Graduate Program in Neurosciences, Universidade Federal de Minas Gerais, Brazil.

Introduction: Bipolar disorder (BD) is a prevalent, chronic and progressive illness. There is a growing body of evidence indicating that brain-derived neurotrophic factor (BDNF) plays an important role in the pathophysiology of BD.

Objective: The aim of this study was to evaluate BDNF plasma levels in BD patients with long term illness in comparison with controls.

Methods: 87 BD type I patients and 58 controls matched by age, gender and education level were enrolled in this study. All subjects were assessed by the Mini-International Neuropsychiatric Interview and the patients by the Young Mania Rating Scale and the Hamilton Depression Rating Scale. The plasma levels of BDNF were measured by ELISA.

Results: On average, patients had suffered from BD for 23.4 years. In comparison with controls, BD patients with mania presented a 1.90-fold increase in BDNF plasma levels (p = .001), while BD patients in remission presented a 1.64-fold increase in BDNF plasma levels (p = .03). BDNF plasma levels were not influenced by age, length of illness or current medications.

Conclusions: The present study suggests that long-term BD patients exhibit increased circulating levels of BDNF.
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http://dx.doi.org/10.1016/j.rbp.2012.05.011DOI Listing
March 2013

Disease-specific expression of the serotonin-receptor 5-HT(2C) in natural killer cells in Alzheimer's dementia.

J Neuroimmunol 2012 Oct 3;251(1-2):73-9. Epub 2012 Jul 3.

Laboratório de Neurociência, Instituto Nacional de Ciência e Tecnologia (INCT) de Medicina Molecular, Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), Avenida Alfredo Balena 190, 30130-100 Belo Horizonte, Minas Gerais, Brazil.

Alzheimer's dementia (AD) is a degenerative brain disorder characterized mainly by cholinergic failure, but other neuro-transmitters are also deficient especially at late stages of the disease. Misfolded β-amyloid peptide has been identified as a causative agent, however inflammatory changes also play a pivotal role. Even though the most prominent pathology is seen in the cognitive functions, specific abnormalities of the central nervous system (CNS) are also reflected in the periphery, particularly in the immune responses of the body. The aim of this study was to characterize the dopaminergic and serotonergic systems in AD, which are also markedly disrupted along with the hallmark acetyl-choline dysfunction. Peripheral blood mono-nuclear cells (PBMCs) from demented patients were judged against comparison groups including individuals with late-onset depression (LOD), as well as non-demented and non-depressed subjects. Cellular sub-populations were evaluated by mono-clonal antibodies against various cell surface receptors: CD4/CD8 (T-lymphocytes), CD19 (B-lymphocytes), CD14 (monocytes), and CD56 (natural-killer (NK)-cells). The expressions of dopamine D(3) and D(4), as well as serotonin 5-HT(1A), 5-HT(2A), 5-HT(2B) and 5-HT(2C) were also assessed. There were no significant differences among the study groups with respect to the frequency of the cellular sub-types, however a unique profound increase in 5-HT(2C) receptor exclusively in NK-cells was observed in AD. The disease-specific expression of 5-HT(2C), as well as the NK-cell cyto-toxicity, has been linked with cognitive derangement in dementia. These changes not only corroborate the existence of bi-directional communication between the immune system and the CNS, but also elucidate the role of inflammatory activity in AD pathology, and may serve as potential biomarkers for less invasive and early diagnostic purposes as well.
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http://dx.doi.org/10.1016/j.jneuroim.2012.06.003DOI Listing
October 2012

Chemokines in bipolar disorder: trait or state?

Eur Arch Psychiatry Clin Neurosci 2013 Mar 15;263(2):159-65. Epub 2012 May 15.

Programa de Pós-Graduação em Neurociências, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.

Recent evidence has suggested that inflammatory and immune mechanisms may play a role in the pathophysiology of bipolar disorder (BD). Only a few studies have assessed the profile of chemokines, a family of chemotactic cytokines related to the recruitment of leukocytes, in BD. The objective of our study was to evaluate the plasma levels of chemokines in BD patients in different mood states in comparison with healthy controls. Seventy BD type I patients (35 in euthymia and 35 in mania), and 50 healthy controls matched by age, gender, and education level were enrolled in this study. All subjects were assessed by the Mini-International Neuropsychiatry Interview and the patients by the Young Mania Rating Scale and the Hamilton Depression Rating Scale. The plasma levels of CCL2, CCL3, CCL11, CCL24, CXCL8, and CXCL10 were measured by enzyme-linked immunosorbent assay. BD patients presented higher plasma levels of CCL11 (1.69-fold increase; p < 0.001), CCL24 (1.40-fold increase; p = 0.02), CXCL10 (1.45-fold increase; p < 0.001) and decreased plasma levels of CXCL8 (8.68-fold decrease p < 0.001). Logistic regression stressed the main effect of increased plasma levels of CXCL10 (OR = 1.009, 95 % CI = 1.000-1.018, p = 0.042) and CCL11 (OR = 1.002, 95 % CI = 1.001-1.003, p = 0.003) and decreased plasma levels of CXCL8 (OR = 0.995, 95 % CI = 0.990-0.999, p = 0.013) to BD. This study reinforces the view that BD is associated with an immune dysfunction.
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http://dx.doi.org/10.1007/s00406-012-0327-6DOI Listing
March 2013

Differential effects of swimming training on neuronal calcium sensor-1 expression in rat hippocampus/cortex and in object recognition memory tasks.

Brain Res Bull 2012 Jul 12;88(4):385-91. Epub 2012 Apr 12.

Núcleo de Neurociências, Departamento de Fisiologia e Biofísica, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.

Physical activity has been proposed as a behavioral intervention that improves learning and memory; nevertheless, the mechanisms underlying these health benefits are still not well understood. Neuronal Calcium Sensor-1 (NCS-1) is a member of a superfamily of proteins that respond to local Ca(2+) changes shown to have an important role in learning and memory. The aim of the present study was to investigate the effects of swimming training on NCS-1 levels in the rat brain after accessing cognitive performance. Wistar rats were randomly assigned to sedentary (SG) or exercised groups (EG). The EG was subject to forced swimming activity, 30 min/day, 5 days/week, during 8 weeks. Progressive load trials were performed in the first and last week in order to access the efficiency of the training. After the 8 week training protocol, memory performance was evaluated by the novel object preference and object location tasks. NCS-1 levels were measured in the cortex and hippocampus using immunoblotting. The EG performed statistically better for the spatial short-term memory (0.73 ± 0.01) when compared to the SG (0.63 ± 0.02; P<0.05). No statistically significant exercise-effect was observed in the novel object preference task (SG 0.65 ± 0.02 and EG 0.68 ± 0.02; p>0.05). In addition, chronic exercise promoted a significant increase in hippocampal NCS-1 levels (1.8 ± 0.1) when compared to SG (1.17 ± 0.08; P<0,05), but had no effect on cortical NCS-1 levels (SG 1.6 ± 0.1 and EG 1.5 ± 0.1; p>0.05). Results suggest that physical exercise would modulate the state of the neural network regarding its potential for plastic changes: physical exercise could be modulating NCS-1 in an activity dependent manner, for specific neural substrates, thus enhancing the cellular/neuronal capability for plastic changes in these areas; which, in turn, would differentially effect ORM task performance for object recognition and displacement.
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http://dx.doi.org/10.1016/j.brainresbull.2012.04.005DOI Listing
July 2012

Increase in dopaminergic, but not serotoninergic, receptors in T-cells as a marker for schizophrenia severity.

J Psychiatr Res 2012 Jun 11;46(6):738-42. Epub 2012 Apr 11.

Laboratório de Imunologia, Universidade Federal dos Vales Jequitinhona e Mucuri, Brazil.

Schizophrenia is characterized by a slow deteriorating mental illness. Although the pathophysiology mechanisms are not fully understood, different studies have suggested a role for the immune system in the pathogenesis of schizophrenia. To date, an altered expression or signaling of neurotransmitters receptors is observed in immune cells during psychiatric disorders. In the present study, we investigated the expression of different serotonin and dopamine receptors in T-cells of schizophrenic and control patients. We used flow cytometry to determine the pattern of expression of dopamine (D2 and D4) and serotonine receptors (SR1A, SR1C, SR2A, SR2B), as well as serotonin transporter (ST), in T-cell subsets (CD4 and CD8). Expression of serotonin receptors and ST in T-cells of schizophrenic patients were not different from controls. However, the percentages of CD4+D4+ and CD8+D4+ were increased in schizophrenic patients as compared to controls. In addition, increased percentages of CD8+D2+ cells were also observed in schizophrenic patients, albeit this population revealed lower CD4+D2+ cells in comparison to controls. Interestingly, a relationship between clinical symptoms and immunological parameters was also observed. We showed that the Brief Psychiatric Rating Scale (BPRS), the Positive and Negative Syndrome Scale (PANSS) and the Abnormal Involuntary Movement Scale (AIMS) were positively related to CD8+D2+ cells, though AIMS was inversely related to CD4+D4+ cells. In conclusion, the alteration in the pattern of cell population and molecules expressed by them might serve as a promising biomarker for diagnosis of schizophrenia.
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http://dx.doi.org/10.1016/j.jpsychires.2012.03.004DOI Listing
June 2012

Behavioral investigation of mice with experimental autoimmune encephalomyelitis.

Arq Neuropsiquiatr 2011 Dec;69(6):938-42

Laboratório de Imunofarmacologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.

Multiple sclerosis is a neuroinflammatory disease that results in serious neurological disability. Besides physical impairment, behavioral symptoms are also common in patients with multiple sclerosis. Experimental autoimmune encephalomyelitis (EAE) is considered to be a model of multiple sclerosis and mimics the main features of the disease, such as demyelination and motor impairment. In this work, we aimed to study behavioral parameters in animals with EAE using the MOG(35-55) model in C57BL/6 mice. We analyzed memory and anxiety in animals using the elevated plus maze, the step down inhibitory avoidance task and the memory recognition test. No differences in any tests were found when comparing controls and animals induced with EAE. Therefore, we conclude that behavioral changes in animals with EAE induced with MOG(35-55) are probably subtle or absent.
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http://dx.doi.org/10.1590/s0004-282x2011000700018DOI Listing
December 2011

Peripheral blood mono-nuclear cells derived from Alzheimer's disease patients show elevated baseline levels of secreted cytokines but resist stimulation with β-amyloid peptide.

Mol Cell Neurosci 2012 Jan 25;49(1):77-84. Epub 2011 Sep 25.

Laboratório de Neurofarmacologia, Departamento de Farmacologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Avenida Antônio Carlos 6627, 31270-901 Campus Pampulha, Belo Horizonte, Minas Gerais, Brazil.

Objectives: Among several other factors, the neuro-toxic β-amyloid peptide (βAP)-induced inflammatory mechanisms have also been implicated in the pathogenesis of Alzheimer's dementia (AD). Cytokines have recently emerged as prime candidates underlying this immune reaction. The purpose of this study was to evaluate the inflammatory response of peripheral blood mono-nuclear cells (PBMC) in AD.

Design: Cross-sectional (observational) study.

Setting: Behavioral and cognitive neurology clinic of the Universidade Federal de Minas Gerais in Belo Horizonte, Brazil.

Participants: AD patients (n=19), healthy elderly (n=19) and young (n=14) individuals.

Measurements: Cytokine levels were assessed by enzyme-linked immuno-sorbent assay (ELISA) after exposing cells to a broad range of βAP concentrations (10(-4)-10(-10)M) as a stimulus. AD samples were weighed against leukocytes harvested from non-demented young and elderly subjects.

Results: Cytokine production of PBMCs in the youth was characterized by low baseline levels when compared to cells from the older generation. In the aging population, AD cells were distinguished from the healthy elderly sub-group by an even higher basal cytokine secretion. The low resting concentration in young individuals was markedly increased after treatment with βAP, however cells from the elderly, irrespective of their disease status, showed unchanged cytokine release following βAP administration. Non-specific activation of PBMCs with anti-CD3/CD28 antibodies resulted in elevated interleukin (IL)-1β concentrations in AD.

Conclusions: These results demonstrate a general over-production of cytokines and resistance to βAP in the old comparison group, with a more pronounced disruption/boosted pattern in AD. Our findings are in line with the hypothesis of "inflammaging", i.e. an enhanced inflammatory profile with normal aging and a further perturbed environment in AD. The observed cytokine profiles may serve as diagnostic biomarkers in dementia.
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http://dx.doi.org/10.1016/j.mcn.2011.09.005DOI Listing
January 2012

Impaired nerve growth factor homeostasis in patients with bipolar disorder.

World J Biol Psychiatry 2011 Apr 6;12(3):228-32. Epub 2010 Oct 6.

Programa de Neurociências, Universidade Federal de Minas Gerais (UFMG), Campus Pampulha, Belo Horizonte, Minas Gerais, Brazil.

Objective: Neuro-trophins are critically involved in neuro-plasticity, the impairment of which is a major role-player in bipolar disorder (BD), and their altered levels have been recently advocated in the patho-physiology of this affective malady. The aim of this study, therefore, was to evaluate the plasma levels of nerve growth factor (NGF) in BD patients in comparison with control subjects.

Methods: Forty-nine BD type-I individuals (30 in mania and 19 in euthymia) and 36 healthy controls were assessed by Mini-plus, Young mania and Hamilton depression rating scales. NGF levels were detected by ELISA.

Results: Plasma NGF concentrations were decreased in BD patients when compared to that seen with controls. BD individuals in mania had lower NGF levels than euthymic patients or controls. NGF levels were negatively correlated with the severity of mania.

Conclusions: This is the first study to evaluate NGF levels in BD patients, providing further support to the hypothesis of impaired neuro-plasticity in BD. These data also suggest that NGF measurement could be used for the biological marker for manic state.
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http://dx.doi.org/10.3109/15622975.2010.518629DOI Listing
April 2011

A thioacetamide-induced hepatic encephalopathy model in C57BL/6 mice: a behavioral and neurochemical study.

Arq Neuropsiquiatr 2010 Aug;68(4):597-602

Laboratory of Immunopharmacology, Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.

Objective: Hepatic encephalopathy (HE) is a neuropsychiatric syndrome resulting from liver failure. In the present study, we aimed to standardize an animal model of HE induced by thioacetamide (TAA) in C57BL/6 mice evaluating behavioral symptoms in association with liver damage and alterations in neurotransmitter release.

Method: HE was induced by an intraperitoneal single dose of TAA (200 mg/kg, 600 mg/kg or 1,200 mg/kg). Behavioral symptoms were evaluated using the SHIRPA battery. Liver damage was confirmed by histopathological analysis. The glutamate release was measured using fluorimetric assay.

Results: The neuropsychiatric state, motor behavior and reflex and sensory functions were significantly altered in the group receiving 600 mg/kg of TAA. Biochemical analysis revealed an increase in the glutamate release in the cerebral cortex of HE mice.

Conclusion: HE induced by 600 mg/kg TAA injection in C57BL/6 mice seems to be a suitable model to investigate the pathogenesis and clinical disorders of HE.
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http://dx.doi.org/10.1590/s0004-282x2010000400022DOI Listing
August 2010

Increased plasma levels of brain-derived neurotrophic factor in patients with long-term bipolar disorder.

Neurosci Lett 2010 May 27;475(2):95-8. Epub 2010 Mar 27.

Programa de Neurociências, Universidade Federal de Minas Gerais (UFMG), Avenida Antônio Carlos 6627, 31270-901 Campus Pampulha, Belo Horizonte, Minas Gerais, Brazil.

Recent data indicate that neurotrophins may play a role in the physiopathology of bipolar disorder (BD) and may be useful as biomarkers of the disease. The aim of this study was to evaluate the plasma concentrations of brain-derived neurotrophic factor (BDNF) in BD patients, and to correlate their levels with clinical parameters. BDNF was measured in plasma from 53 BD type I subjects (34 during mania and 19 during euthymia) and 38 healthy controls by enzyme-linked immuno-sorbent assay (ELISA). Patients were assessed by a structured clinical interview (Mini-plus), Young mania and Hamilton depression rating scales. Plasma BDNF levels were significantly increased in patients with mania (P
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http://dx.doi.org/10.1016/j.neulet.2010.03.055DOI Listing
May 2010

Increased serum levels of inflammatory markers in chronic institutionalized patients with schizophrenia.

Neuroimmunomodulation 2008 5;15(2):140-4. Epub 2008 Aug 5.

Group of Neuroimmunology, Laboratory of Immunopharmacology, Department of Biochemistry and Immunology, Federal University of Minas Gerais, Belo Horizonte, Brazil.

Unlabelled: Activation of the cytokine systems may be involved in the neuropathological changes occurring in the central nervous systems of schizophrenic patients. However, associations between the levels of cytokines and the severity of symptoms have not been completely established.

Objective: It was the aim of this study to evaluate serum levels of tumor necrosis factor (TNF)-alpha and their soluble receptors (sTNFR) in schizophrenic patients and healthy controls.

Methods: Forty male institutionalized schizophrenic patients (mean age +/- SD, 52.3 +/- 9.9 years) and 20 asymptomatic matched controls were recruited. The severity of symptoms was assessed using the Brief Psychiatric Rating Scale, the Positive and Negative Syndrome Scale and the Abnormal Involuntary Movement Scale. Serum levels of cytokines were measured by ELISAs.

Results: Serum levels of sTNFR1 and sTNFR2 were increased in schizophrenic patients when compared with controls (all p < 0.05), but there was no difference in TNF-alpha levels. There was no correlation between the length of disease/hospitalization or the severity of symptoms and the serum levels of these molecules.

Conclusion: Inflammatory markers are increased in schizophrenia but they do not correlate with symptom severity.
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http://dx.doi.org/10.1159/000148197DOI Listing
November 2008
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