Publications by authors named "André Quincozes-Santos"

106 Publications

Mild Hyperhomocysteinemia Causes Anxiety-like Behavior and Brain Hyperactivity in Rodents: Are ATPase and Excitotoxicity by NMDA Receptor Overstimulation Involved in this Effect?

Cell Mol Neurobiol 2021 Jul 29. Epub 2021 Jul 29.

Wyse´s Lab, Institute of Health Basic Sciences, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, CEP 90035-003, Brazil.

Mild hyperhomocysteinemia is a risk factor for psychiatric and neurodegenerative diseases, whose mechanisms between them are not well-known. In the present study, we evaluated the emotional behavior and neurochemical pathways (ATPases, glutamate homeostasis, and cell viability) in amygdala and prefrontal cortex rats subjected to mild hyperhomocysteinemia (in vivo studies). The ex vivo effect of homocysteine on ATPases and redox status, as well as on NMDAR antagonism by MK-801 in same structures slices were also performed. Wistar male rats received a subcutaneous injection of 0.03 µmol Homocysteine/g of body weight or saline, twice a day from 30 to 60th-67th days of life. Hyperhomocysteinemia increased anxiety-like behavior and tended to alter locomotion/exploration of rats, whereas sucrose preference and forced swimming tests were not altered. Glutamate uptake was not changed, but the activities of glutamine synthetase and ATPases were increased. Cell viability was not altered. Ex vivo studies (slices) showed that homocysteine altered ATPases and redox status and that MK801, an NMDAR antagonist, protected amygdala (partially) and prefrontal cortex (totally) effects. Taken together, data showed that mild hyperhomocysteinemia impairs the emotional behavior, which may be associated with changes in ATPase and glutamate homeostasis, including glutamine synthetase and NMDAR overstimulation that could lead to excitotoxicity. These findings may be associated with the homocysteine risk factor on psychiatric disorders development and neurodegeneration.
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http://dx.doi.org/10.1007/s10571-021-01132-0DOI Listing
July 2021

Potential Glioprotective Strategies Against Diabetes-Induced Brain Toxicity.

Neurotox Res 2021 Oct 14;39(5):1651-1664. Epub 2021 Jul 14.

Programa de Pós-Graduação Em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, RS, Brazil.

Astrocytes are crucial for the maintenance of brain homeostasis by actively participating in the metabolism of glucose, which is the main energy substrate for the central nervous system (CNS), in addition to other supportive functions. More specifically, astrocytes support neurons through the metabolic coupling of synaptic activity and glucose utilization. As such, diabetes mellitus (DM) and consequent glucose metabolism disorders induce astrocyte damage, affecting CNS functionality. Glioprotective molecules can promote protection by improving glial functions and avoiding toxicity in different pathological conditions, including DM. Therefore, this review discusses specific pathomechanisms associated with DM/glucose metabolism disorder-induced gliotoxicity, namely astrocyte metabolism, redox homeostasis/mitochondrial activity, inflammation, and glial signaling pathways. Studies investigating natural products as potential glioprotective strategies against these deleterious effects of DM/glucose metabolism disorders are also reviewed herein. These products include carotenoids, catechins, isoflavones, lipoic acid, polysaccharides, resveratrol, and sulforaphane.
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http://dx.doi.org/10.1007/s12640-021-00393-3DOI Listing
October 2021

Zika Virus Infection Associated with Autism Spectrum Disorder: A Case Report.

Neuroimmunomodulation 2021 Jun 3:1-4. Epub 2021 Jun 3.

Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.

Introduction: The aim of this case was to investigate the association of the Zika virus infection in utero with the autism spectrum disorder (ASD) as clinical outcome that presented no congenital anomalies.

Methods: ASD was diagnosed in the second year of life by different child neurologists and confirmed by DSM-5 and ASQ. After that, an extensive clinical, epidemiological, and genetic evaluations were performed, with main known ASD causes ruled out.

Results: An extensive laboratorial search was done, with normal findings. SNP array identified no pathogenic variants. Normal neuroimaging and EEG findings were also obtained. ZIKV (Zika virus) IgG was positive, while IgM was negative. Other congenital infections were negative. The exome sequencing did not reveal any pathogenic variant in genes related to ASD.

Conclusion: Accordingly, this report firstly associates ZIKV exposure to ASD.
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http://dx.doi.org/10.1159/000516560DOI Listing
June 2021

Environmental exposure to mineral coal and by-products: Influence on human health and genomic instability.

Environ Pollut 2021 Oct 12;287:117346. Epub 2021 May 12.

Laboratory of Genetic Toxicology, Postgraduate Program in Molecular and Cell Biology Applied to Health, Lutheran University of Brazil (ULBRA), Avenida Farroupilha, 8001 Bairro São José, CEP 92425-900, Canoas, RS, Brazil.

Environmental exposure to pollution generated by mining and burning coal is inevitable for people living nearby. Therefore, the aim of this study was to evaluate the influence of coal dust on health conditions and genomic instability of individuals who live near coal mines and thermoelectric power plants, and to relate the results to inorganic elements and inflammatory responses. Thus, we evaluated 284 individuals from four cities in the south of Brazil around a region with coal mines and a thermoelectric power plant (one city was considered a negative control). The results of the Comet assay and Micronucleus (MN) test did not show a genotoxic or mutagenic effect related to environmental exposure to coal, but the inflammatory cytokine tumor necrosis factor-α (TNF-α) was increased in all cities around the power plant when compared to the control conditions. Higher levels of MN were associated with body mass index and cardiovascular risk, and higher levels of Damage Index (DI), TNF-α and interleukin1β (IL-1β) with number of cigarettes/day. Principal component analysis (PCA) was used to integrate DNA damage and inflammatory results with inorganic elements. This study also demonstrated the relationship between zinc and MN, copper, and interleukin10 (IL-10), and among silicon and sulfur with DI and nucleoplasmic bridge. A relationship was also observed between the reduction of inorganic elements and both aging and quality of health. The use of different methodologies and the relationship between the results obtained in these studies, including different lifestyles, can increase the understanding of the interaction between this mineral and the health status of residents of regions affected by coal pollution.
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http://dx.doi.org/10.1016/j.envpol.2021.117346DOI Listing
October 2021

COVID-19 and hyperammonemia: Potential interplay between liver and brain dysfunctions.

Brain Behav Immun Health 2021 Jul 13;14:100257. Epub 2021 Apr 13.

Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.

Although COVID-19 affects the respiratory system, extrapulmonary manifestations frequently occur, including encephalopathy and liver damage. Here, we want to call attention to a possible connection between liver and brain dysfunctions, in which ammonia can play a role targeting astrocytes. Importantly, astrocyte dysfunction can produce future and/or long-term neurological consequences.
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http://dx.doi.org/10.1016/j.bbih.2021.100257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041743PMC
July 2021

Homocysteine and Gliotoxicity.

Neurotox Res 2021 Jun 30;39(3):966-974. Epub 2021 Mar 30.

Programa de Pós-Graduação em Ciências Biológicas - Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.

Homocysteine is a sulfur amino acid that does not occur in the diet, but it is an essential intermediate in normal mammalian metabolism of methionine. Hyperhomocysteinemia results from dietary intakes of Met, folate, and vitamin B12 and lifestyle or from the deficiency of specific enzymes, leading to tissue accumulation of this amino acid and/or its metabolites. Severe hyperhomocysteinemic patients can present neurological symptoms and structural brain abnormalities, of which the pathogenesis is poorly understood. Moreover, a possible link between homocysteine (mild hyperhomocysteinemia) and neurodegenerative/neuropsychiatric disorders has been suggested. In recent years, increasing evidence has emerged suggesting that astrocyte dysfunction is involved in the neurotoxicity of homocysteine and possibly associated with the physiopathology of hyperhomocysteinemia. This review addresses some of the findings obtained from in vivo and in vitro experimental models, indicating high homocysteine levels as an important neurotoxin determinant of the neuropathophysiology of brain damage. Recent data show that this amino acid impairs glutamate uptake, redox/mitochondrial homeostasis, inflammatory response, and cell signaling pathways. Therefore, the discussion of this review focuses on homocysteine-induced gliotoxicity, and its impacts in the brain functions. Through understanding the Hcy-induced gliotoxicity, novel preventive/therapeutic strategies might emerge for these diseases.
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http://dx.doi.org/10.1007/s12640-021-00359-5DOI Listing
June 2021

COVID-19 impacts the expression of molecular markers associated with neuropsychiatric disorders.

Brain Behav Immun Health 2021 Feb 28;11:100196. Epub 2020 Dec 28.

Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.

Coronavirus disease 2019 (COVID-19) was initially characterized due to its impacts on the respiratory system; however, many recent studies have indicated that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) significantly affects the brain. COVID-19 can cause neurological complications, probably caused by the induction of a cytokine storm, since there is no evidence of neurotropism by SARS-CoV-2. In line with this, the COVID-19 outbreak could accelerate the progression or affect the clinical outcomes of neuropsychiatric conditions. Thus, we analyzed differential gene expression datasets for clinical samples of COVID-19 patients and identified 171 genes that are associated with the pathophysiology of the following neuropsychiatric disorders: alcohol dependence, autism, bipolar disorder, depression, panic disorder, schizophrenia, and sleep disorder. Several of the genes identified are associated with causing some of these conditions (classified as elite genes). Among these elite genes, 9 were found for schizophrenia, 6 for autism, 3 for depression/major depressive disorder, and 2 for alcohol dependence. The patients with the neuropsychiatric conditions associated with the genes identified may require special attention as COVID-19 can deteriorate or accelerate neurochemical dysfunctions, thereby aggravating clinical outcomes.
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http://dx.doi.org/10.1016/j.bbih.2020.100196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7834441PMC
February 2021

Zika virus exposure affects neuron-glia communication in the hippocampal slices of adult rats.

Sci Rep 2020 12 10;10(1):21604. Epub 2020 Dec 10.

Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600 - Anexo, Bairro Santa Cecília, Porto Alegre, RS, 90035-003, Brazil.

Zika virus (ZIKV) infection during pregnancy was associated with microcephaly in neonates, but clinical and experimental evidence indicate that ZIKV also causes neurological complications in adults. However, the changes in neuron-glial communication, which is essential for brain homeostasis, are still unknown. Here, we report that hippocampal slices from adult rats exposed acutely to ZIKV showed significant cellular alterations regarding to redox homeostasis, inflammatory process, neurotrophic functions and molecular signalling pathways associated with neurons and glial cells. Our findings support the hypothesis that ZIKV is highly neurotropic and its infection readily induces an inflammatory response, characterized by an increased expression and/or release of pro-inflammatory cytokines. We also observed changes in neural parameters, such as adenosine receptor A2a expression, as well as in the release of brain-derived neurotrophic factor and neuron-specific enolase, indicating plasticity synaptic impairment/neuronal damage. In addition, ZIKV induced a glial commitment, with alterations in specific and functional parameters such as aquaporin 4 expression, S100B secretion and glutathione synthesis. ZIKV also induced p21 senescence-associated gene expression, indicating that ZIKV may induce early senescence. Taken together, our results indicate that ZIKV-induced neuroinflammation, involving nuclear factor erythroid 2-related factor 2 (Nrf2) and nuclear factor κB (NFκB) pathways, affects important aspects of neuron-glia communication. Therefore, although ZIKV infection is transient, long-term consequences might be associated with neurological and/or neurodegenerative diseases.
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http://dx.doi.org/10.1038/s41598-020-78735-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7729948PMC
December 2020

Short-Term Alterations in Behavior and Astroglial Function After Intracerebroventricular Infusion of Methylglyoxal in Rats.

Neurochem Res 2021 Feb 23;46(2):183-196. Epub 2020 Oct 23.

Federal University of Rio Grande do Sul (UFRGS), Biochemistry Post-Graduate Program, Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035003, Brazil.

Methylglyoxal (MG) is a by-product of glycolysis. In pathological conditions, particularly diabetes mellitus, this molecule is unbalanced, causing widespread protein glycation. In addition to protein glycation, other effects resulting from high levels of MG in the central nervous system may involve the direct modulation of GABAergic and glutamatergic neurotransmission, with evidence suggesting that the effects of MG may be related to behavioral changes and glial dysfunction. In order to evaluate the direct influence of MG on behavioral and biochemical parameters, we used a high intracerebroventricular final concentration (3 μM/μL) to assess acute effects on memory and locomotor behavior in rats, as well as the underlying alterations in glutamatergic and astroglial parameters. MG induced, 12 h after injection, a decrease in locomotor activity in the Open field and anxiolytic effects in rats submitted to elevated plus-maze. Subsequently, 36 h after surgery, MG injection also induced cognitive impairment in both short and long-term memory, as evaluated by novel object recognition task, and in short-term spatial memory, as evaluated by the Y-maze test. In addition, hippocampal glutamate uptake decreased and glutamine synthetase activity and glutathione levels diminished during seventy-two hours after infusion of MG. Interestingly, the astrocytic protein, S100B, was increased in the cerebrospinal fluid, accompanied by decreased hippocampal S100B mRNA expression, without any change in protein content. Taken together, these results may improve our understanding of how this product of glucose metabolism can induce the brain dysfunction observed in diabetic patients, as well as in other neurodegenerative conditions, and further defines the role of astrocytes in disease and therapeutics.
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http://dx.doi.org/10.1007/s11064-020-03154-4DOI Listing
February 2021

Sulforaphane Induces Glioprotection After LPS Challenge.

Cell Mol Neurobiol 2020 Oct 20. Epub 2020 Oct 20.

Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.

Sulforaphane is a natural compound that presents anti-inflammatory and antioxidant properties, including in the central nervous system (CNS). Astroglial cells are involved in several functions to maintain brain homeostasis, actively participating in the inflammatory response and antioxidant defense systems. We, herein, investigated the potential mechanisms involved in the glioprotective effects of sulforaphane in the C6 astrocyte cell line, when challenged with the inflammogen, lipopolysaccharide (LPS). Sulforaphane prevented the LPS-induced increase in the expression and/or release of pro-inflammatory mediators, possibly due to nuclear factor κB and hypoxia-inducible factor-1α activation. Sulforaphane also modulated the expressions of the Toll-like and adenosine receptors, which often mediate inflammatory processes induced by LPS. Additionally, sulforaphane increased the mRNA levels of nuclear factor erythroid-derived 2-like 2 (Nrf2) and heme oxygenase-1 (HO1), both of which mediate several cytoprotective responses. Sulforaphane also prevented the increase in NADPH oxidase activity and the elevations of superoxide and 3-nitrotyrosine that were stimulated by LPS. In addition, sulforaphane and LPS modulated superoxide dismutase activity and glutathione metabolism. Interestingly, the anti-inflammatory and antioxidant effects of sulforaphane were blocked by HO1 pharmacological inhibition, suggesting its dependence on HO1 activity. Finally, in support of a glioprotective role, sulforaphane prevented the LPS-induced decrease in glutamate uptake, glutamine synthetase activity, and glial-derived neurotrophic factor (GDNF) levels, as well as the augmentations in S100B release and Na, K ATPase activity. To our knowledge, this is the first study that has comprehensively explored the glioprotective effects of sulforaphane on astroglial cells, reinforcing the beneficial effects of sulforaphane on astroglial functionality.
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http://dx.doi.org/10.1007/s10571-020-00981-5DOI Listing
October 2020

Ammonia-Induced Glial-Inflammaging.

Mol Neurobiol 2020 Aug 15;57(8):3552-3567. Epub 2020 Jun 15.

Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600 - Anexo, Bairro Santa Cecília, Porto Alegre, RS, 90035-003, Brazil.

Astrocytes are functionally diverse glial cells that maintain blood-brain barrier (BBB) integrity, provide metabolic and trophic support, and react to pathogens or harmful stimuli through inflammatory response. Impairment of astrocyte functions has been implicated in hepatic encephalopathy (HE), a neurological complication associated with hyperammonemia. Although hyperammonemia is more common in adults, ammonia gliotoxicity has been mainly studied in cultured astrocytes derived from neonate animals. However, these cells can sense and respond to stimuli in different ways from astrocytes obtained from adult animals. Thus, the aim of this study was to investigate the direct effects of ammonia on astrocyte cultures obtained from adult rats compared with those obtained from neonate rats. Our main findings pointed that ammonia increased the gene expression of proteins associated with BBB permeability, in addition to cause an inflammatory response and decrease the release of trophic factors, which were dependent on p38 mitogen-activated protein kinase (p38 MAPK)/nuclear factor κB (NFκB) pathways and aquaporin 4, in both neonatal and mature astrocytes. Considering the age, mature astrocytes presented an overall increase of the expression of inflammatory signaling components and a decrease of the expression of cytoprotective pathways, compared with neonatal astrocytes. Importantly, ammonia exposure in mature astrocytes potentiated the expression of the senescence marker p21, inflammatory response, activation of p38 MAPK/NFκB pathways, and the decrease of cytoprotective pathways. In this regard, ammonia can trigger and/or accelerate the inflammaging of mature astrocytes, a phenomenon characterized by an age-related chronic and low-grade inflammation, which may be implicated in HE neurological symptoms.
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http://dx.doi.org/10.1007/s12035-020-01985-4DOI Listing
August 2020

Correction to: Systemic Inflammation as a Driver of Brain Injury: the Astrocyte as an Emerging Player.

Mol Neurobiol 2020 Jul;57(7):3243

Departamento de Bioquímica, Programa de Pós-Graduação em, Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro, Barcelos, 2600-Anexo, Bairro Santa Cecília, Porto Alegre, RS, 90035-003, Brazil.

The givenname "Paola" of the author Paola Haack Amaral Roppa (Roppa, P.H.A.) should be corrected to read Ricardo Haack Amaral Roppa (Roppa, R.H.A.) as presented above.
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http://dx.doi.org/10.1007/s12035-020-01932-3DOI Listing
July 2020

Association between Zika virus and future neurological diseases.

J Neurol Sci 2020 02 5;409:116617. Epub 2019 Dec 5.

Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul, Brazil; Centro de Pesquisa Experimental, Hospital de Clínicas de Porto Alegre, Brazil.

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http://dx.doi.org/10.1016/j.jns.2019.116617DOI Listing
February 2020

Changes in Inflammatory Response, Redox Status and Na, K-ATPase Activity in Primary Astrocyte Cultures from Female Wistar Rats Subject to Ovariectomy.

Neurotox Res 2020 Feb 26;37(2):445-454. Epub 2019 Nov 26.

Programa de Pós-Graduação em Ciências Biológicas-Bioquímica, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde (ICBS), Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.

Astrocytes are dynamic glial cells that maintain brain homeostasis, particularly metabolic functions, inflammatory response, and antioxidant defense. Since menopause may be associated with brain dysfunction, in the present study, we evaluated anti- and proinflammatory cytokine release in cortical and hippocampal astrocyte cultures obtained from adult female Wistar rats subjected to ovariectomy, a known experimental model of menopause. We also tested some parameters of metabolic functionality (Na, K-ATPase activity) and cellular redox status, such as antioxidant enzyme defenses (superoxide dismutase and catalase) and the intracellular production of reactive oxygen species in this experimental model. Female adult Wistar rats (180 days-age) were assigned to one of the following groups: sham (submitted to surgery without removal of the ovaries) and ovariectomy (submitted to surgery to removal of the ovaries). Thirty days after ovariectomy or sham surgery, we prepared astrocyte cultures from control and ovariectomy surgery animals. Ovariectomized rats presented an increase in pro-inflammatory cytokines (tumor necrosis factor α, interleukins 1β, 6, and 18) and a decrease in interleukin 10 release, an anti-inflammatory cytokine, in cortical and hippocampal astrocytes, when compared to those obtained from sham group (control). In addition, Na,K-ATPase activity decreased in hippocampal astrocytes, but not in cortical astrocyte cultures. In contrast, antioxidant enzymes did not alter in cortical astrocyte cultures, but increased in hippocampal astrocytes. In summary, our findings suggest that ovariectomy is able to induce an inflammatory response in vivo, which could be detected in in vitro astrocytes after approximately 4 weeks.
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http://dx.doi.org/10.1007/s12640-019-00128-5DOI Listing
February 2020

ZIKAVID-Zika virus infection database: a new platform to analyze the molecular impact of Zika virus infection.

J Neurovirol 2020 02 11;26(1):77-83. Epub 2019 Sep 11.

Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul, Av. Ipiranga, 2752 suit 709, Porto Alegre, RS, Brazil.

The recent outbreak of Zika virus (ZIKV) in Brazil and other countries globally demonstrated the relevance of ZIKV studies. During and after this outbreak, there was an intense increase in scientific production on ZIKV infections, especially toward alterations promoted by the infection and related to clinical outcomes. Considering this massive amount of new data, mainly thousands of genes and proteins whose expression is impacted by ZIKV infection, the ZIKA Virus Infection Database (ZIKAVID) was created. ZIKAVID is an online database that comprises all genes or proteins, and associated information, for which expression was experimentally measured and found to be altered after ZIKV infection. The database, available at https://zikavid.org, contains 16,984 entries of gene expression measurements from a total of 7348 genes. It allows users to easily perform searches for different experimental hosts (cell lines, tissues, and animal models), ZIKV strains (African, Asian, and Brazilian), and target molecules (messenger RNA [mRNA] and protein), among others, used in differential expression studies regarding ZIKV infection. In this way, the ZIKAVID will serve as an additional and important resource to improve the characterization of the molecular impact and pathogenesis associated with ZIKV infection.
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http://dx.doi.org/10.1007/s13365-019-00799-yDOI Listing
February 2020

Cross-talk between guanidinoacetate neurotoxicity, memory and possible neuroprotective role of creatine.

Biochim Biophys Acta Mol Basis Dis 2019 11 6;1865(11):165529. Epub 2019 Aug 6.

Laboratory of Neuroprotection and Neurometabolic Diseases, Biochemistry Department, ICBS, Universidade Federal do Rio Grande do Sul, Street Ramiro Barcelos, 2600-Annex, CEP 90035-003 Porto Alegre, RS, Brazil; Program of Post-graduation in Biological Sciences-Biochemistry, Biochemistry Department, ICBS, Universidade Federal do Rio Grande do Sul, Street Ramiro Barcelos, 2600-Annex, CEP 90035-003 Porto Alegre, RS, Brazil. Electronic address:

Guanidinoacetate Methyltransferase deficiency is an inborn error of metabolism that results in decreased creatine and increased guanidinoacetate (GAA) levels. Patients present neurological symptoms whose mechanisms are unclear. We investigated the effects of an intrastriatal administration of 10 μM of GAA (0.02 nmol/striatum) on energy metabolism, redox state, inflammation, glutamate homeostasis, and activities/immunocontents of acetylcholinesterase and Na,K-ATPase, as well as on memory acquisition. The neuroprotective role of creatine was also investigated. Male Wistar rats were pretreated with creatine (50 mg/kg) or saline for 7 days underwenting stereotactic surgery. Forty-eight hours after surgery, the animals (then sixty-days-old) were divided into groups: Control, GAA, GAA + Creatine, and Creatine. Experiments were performed 30 min after intrastriatal infusion. GAA decreased SDH, complexes II and IV activities, and ATP levels, but had no effect on mitochondrial mass/membrane potential. Creatine totally prevented SDH and complex II, and partially prevented COX and ATP alterations. GAA increased dichlorofluorescein levels and decreased superoxide dismutase and catalase activities. Creatine only prevented catalase and dichlorofluorescein alterations. GAA increased cytokines, nitrites levels and acetylcholinesterase activity, but not its immunocontent. Creatine prevented such effects, except nitrite levels. GAA decreased glutamate uptake, but had no effect on the immunocontent of its transporters. GAA decreased Na,K-ATPase activity and increased the immunocontent of its α3 subunit. The performance on the novel object recognition task was also impaired. Creatine partially prevented the changes in glutamate uptake and Na,K-ATPase activity, and completely prevented the memory impairment. This study helps to elucidate the protective effects of creatine against the damage caused by GAA.
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http://dx.doi.org/10.1016/j.bbadis.2019.08.005DOI Listing
November 2019

High-glucose medium induces cellular differentiation and changes in metabolic functionality of oligodendroglia.

Mol Biol Rep 2019 Oct 3;46(5):4817-4826. Epub 2019 Jul 3.

Departamento de Bioquímica, Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600-Anexo, Bairro Santa Cecília, Porto Alegre, RS, 90035-003, Brazil.

Oligodendrocyte precursor cells (OPC) are a uniformly distributed population of glial cells that are well known for proliferating and differentiating into mature oligodendrocytes to form the myelin sheet in the central nervous system (CNS). Since monocarboxylate transporter 1 (MCT1) has shown to be expressed by oligodendroglia, the involvement of these cells with the metabolic support to axons has emerged as an important role in the maintenance of neuronal functionality. Hyperglycemia is a metabolic dysfunction highly associated with oxidative stress, a classical feature linked to many disorders such as diabetes mellitus. Despite of being widely investigated in several different cell cultures, including astrocytes and neurons, such condition has been poorly investigated in OPC culture. Thus, the aim of this study was to explore the possible effects of high-glucose exposure in acute and chronic conditions on oligodendroglial development and functionality in vitro. In this sense, we have demonstrated that under high-glucose exposure OPC improved its differentiation rate without affecting its membrane integrity and its morphology. Besides, chronic high-glucose condition also increased glucose uptake and lactate release. On the other hand, our findings also showed that, unlike what happens in other glial cells and neurons, high-glucose exposure did not seem to induce oxidative stress in OPC culture. Therefore, as far as we have investigated in this present study, we suggest that OPC may be able to support neurons and other glial cells during hyperglycemia events.
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http://dx.doi.org/10.1007/s11033-019-04930-4DOI Listing
October 2019

Glycolysis-Derived Compounds From Astrocytes That Modulate Synaptic Communication.

Front Neurosci 2018 23;12:1035. Epub 2019 Jan 23.

Department of Biochemistry, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.

Based on the concept of the tripartite synapse, we have reviewed the role of glucose-derived compounds in glycolytic pathways in astroglial cells. Glucose provides energy and substrate replenishment for brain activity, such as glutamate and lipid synthesis. In addition, glucose metabolism in the astroglial cytoplasm results in products such as lactate, methylglyoxal, and glutathione, which modulate receptors and channels in neurons. Glucose has four potential destinations in neural cells, and it is possible to propose a crossroads in "X" that can be used to describe these four destinations. Glucose-6P can be used either for glycogen synthesis or the pentose phosphate pathway on the left and right arms of the X, respectively. Fructose-6P continues through the glycolysis pathway until pyruvate is formed but can also act as the initial compound in the hexosamine pathway, representing the left and right legs of the X, respectively. We describe each glucose destination and its regulation, indicating the products of these pathways and how they can affect synaptic communication. Extracellular L-lactate, either generated from glucose or from glycogen, binds to HCAR1, a specific receptor that is abundantly localized in perivascular and post-synaptic membranes and regulates synaptic plasticity. Methylglyoxal, a product of a deviation of glycolysis, and its derivative D-lactate are also released by astrocytes and bind to GABA receptors and HCAR1, respectively. Glutathione, in addition to its antioxidant role, also binds to ionotropic glutamate receptors in the synaptic cleft. Finally, we examined the hexosamine pathway and evaluated the effect of GlcNAc-modification on key proteins that regulate the other glucose destinations.
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http://dx.doi.org/10.3389/fnins.2018.01035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6351787PMC
January 2019

Combined Exposure to Alcohol and Tobacco Smoke Changes Oxidative, Inflammatory, and Neurotrophic Parameters in Different Areas of the Brains of Rats.

ACS Chem Neurosci 2019 03 30;10(3):1336-1346. Epub 2019 Jan 30.

Programa de Pós-Graduação em Ciência Biológicas: Farmacologia e Terapêutica (PPGFT) , Universidade Federal do Rio Grande do Sul (UFRGS) , Porto Alegre 90040-060 , Brazil.

Devastating effects of exposure to alcohol and tobacco smoke on health are extensively reported in the literature. However, few studies have attempted to elucidate the consequences of their combined use on the central nervous system. Here we studied the effect of this combined use on some oxidative, inflammatory, and neurotrophic parameters in the hippocampus, striatum, and frontal cortex of rats. Adult Wistar rats were allocated into control (CT), alcohol (AL), tobacco smoke (TB), or combined (ALTB) groups. Rats were exposed to environmental air (CT and AL groups) or to the smoke from six cigarettes (TB and ALTB groups) immediately after tap water (CT and TB) or 2 g of alcohol/kg (AL and ALTB) oral gavage administration, twice a day, for 4 weeks. On day 28, rats were euthanized and areas of the brain were dissected to evaluate some cellular redox parameters, pro-inflammatory cytokine levels, and brain-derived neurotrophic factor (BDNF) levels. A one-way analysis of variance showed that the ALTB combined treatment significantly increased oxidative stress levels in the hippocampus. ALTB also increased interleukin-1β levels in the striatum and frontal cortex and tumoral necrosis factor-α levels in the frontal cortex compared with those of AL, TB, and CT rats. Combined treatment also decreased the BDNF levels in the frontal cortex of rats. Oxidative damage was found, more importantly, in the hippocampus, and inflammatory parameters were extended to all areas of the brain that were studied. Our results showed an interaction between alcohol and tobacco smoke according to the area of the brain, suggesting an additional risk of neural damage in alcoholics who smoke.
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http://dx.doi.org/10.1021/acschemneuro.8b00412DOI Listing
March 2019

Adenosine receptors as a new target for resveratrol-mediated glioprotection.

Biochim Biophys Acta Mol Basis Dis 2019 03 3;1865(3):634-647. Epub 2019 Jan 3.

Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil; Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil. Electronic address:

Resveratrol, a natural polyphenolic compound, has been studied as a neuroprotective molecule. Our group has demonstrated that such effect is closely associated with modulation of glial functionality, but the underlying mechanisms are not fully understood. Because astrocytes actively participate in the brain inflammatory response, and activation of adenosine receptors can attenuate inflammatory processes, the aim of this study was to investigate the role of adenosine receptors as a mechanism for resveratrol glioprotection, particularly regarding to neuroinflammation. Therefore, primary astrocyte cultures were co-incubated with resveratrol and selective antagonists of A, A, and A adenosine receptors, as well as with caffeine (a non-selective adenosine receptor antagonist), and then challenged with bacterial inflammogen lipopolysaccharide (LPS). Caffeine and selective adenosine receptor antagonists abolished the anti-inflammatory effect of resveratrol. In accordance with these effects, resveratrol prevented LPS-induced decrease in mRNA levels of adenosine receptors. Resveratrol could also prevent the activation of pro-inflammatory signaling pathways, such as nuclear factor κB (NFκB) and p38 mitogen-activated protein kinase (p38 MAPK) in a mechanism dependent on adenosine receptors. Conversely, trophic factors and protective signaling pathways, including sirtuin 1 (SIRT1), nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and phosphoinositide 3-kinase (PI3K)/Akt were positively modulated by resveratrol in both LPS-stimulated and unstimulated astrocytes, but adenosine receptor antagonism did not abrogate all effects of resveratrol. To our knowledge, our data provide the first evidence that adenosine receptors are involved in the anti-inflammatory activity of resveratrol in astrocytes, thus exerting an important role for resveratrol-mediated glioprotection.
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http://dx.doi.org/10.1016/j.bbadis.2019.01.004DOI Listing
March 2019

Effects of short-term resistance training on endothelial function and inflammation markers in elderly patients with type 2 diabetes: A randomized controlled trial.

Exp Gerontol 2019 04 3;118:19-25. Epub 2019 Jan 3.

Exercise Research Laboratory, School of Physical Education, Phisiotherapy and Dance, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS 90690-200, Brazil.

Purpose: To evaluate the effects of 12-weeks of strength training on endothelial function and inflammatory markers in elderly individuals with T2DM.

Methods: Forty-four elderly patients with T2DM were screened for participation. After completion of the baseline assessment, participants were randomly assigned to either the resistance training group (RT) or an active control group (AC). Inflammatory (TNF-α, IL-6, IL-1β, IL-10 and CRP) and blood lipid profiles, glycated hemoglobin, basal artery diameter and flow mediated dilation were evaluated before and after the intervention. Comparisons between groups were obtained from the generalized estimation equation and all tests were two-tailed and the alpha level for significance set at 0.05.

Results: TNF-α and IL-1β were decreased in both groups, while no interactions were found for flow mediated dilation and basal artery diameter. No significant differences were found for blood lipid profile and glycated hemoglobin for both groups after the intervention period.

Conclusions: No significant changes were found between the RT and AC groups, regarding inflammatory profile and endothelial function, which does not prove the superiority of this intervention model in the studied period.
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http://dx.doi.org/10.1016/j.exger.2019.01.003DOI Listing
April 2019

Zika Virus Infection of Human Mesenchymal Stem Cells Promotes Differential Expression of Proteins Linked to Several Neurological Diseases.

Mol Neurobiol 2019 Jul 30;56(7):4708-4717. Epub 2018 Oct 30.

Centro de Pesquisa Experimental, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil.

The recent microcephaly outbreak in Brazil has been associated with Zika virus (ZIKV) infection. The current understanding of damage caused by ZIKV infection is still unclear, since it has been implicated in other neurodegenerative and developmental complications. Here, the differential proteome analysis of human mesenchymal stem cells (hMSC) infected with a Brazilian strain of ZIKV was identified by shotgun proteomics (MudPIT). Our results indicate that ZIKV induces a potential reprogramming of the metabolic machinery in nucleotide metabolism, changes in the energy production via glycolysis and other metabolic pathways, and potentially inhibits autophagy, neurogenesis, and immune response by downregulation of signaling pathways. In addition, proteins previously described in several brain pathologies, such as Alzheimer's disease, autism spectrum disorder, amyotrophic lateral sclerosis, and Parkinson's disease, were found with altered expression due to ZIKV infection in hMSC. This potential link between ZIKV and several neuropathologies beyond microcephaly is being described here for the first time and can be used to guide specific follow-up studies concerning these specific diseases and ZIKV infection.
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http://dx.doi.org/10.1007/s12035-018-1417-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6491274PMC
July 2019

Leptin stimulates the release of pro-inflammatory cytokines in hypothalamic astrocyte cultures from adult and aged rats.

Metab Brain Dis 2018 12 18;33(6):2059-2063. Epub 2018 Sep 18.

Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.

Leptin is an adipose tissue-derived hormone that acts on the hypothalamus in order to maintain energy homeostasis. However, leptin can also induce an inflammatory response. Increasing evidence has highlighted a critical role of astrocytes in the effects of leptin on the hypothalamus. In addition, astrocytes participate in neuroinflammation by producing and releasing a wide range of inflammatory mediators. In this study, we aimed to investigate the age-dependent effect of leptin on pro- and anti-inflammatory cytokines released by the hypothalamic astrocyte cultures obtained from newborn, adult, and aged Wistar rats. In hypothalamic astrocytes from newborn rats, leptin did not change the release of pro-inflammatory cytokines, tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β). On the other contrary, leptin increased the release of both TNF-α and IL-1β in astrocyte cultures from adult and aged animals. Regarding the anti-inflammatory cytokine interleukin 10 (IL-10), we did not observe any change in response to leptin. In conclusion, our data suggests a pro-inflammatory action of leptin on the hypothalamus during aging. This in turn may be related to the triggering of metabolic disorders, as both of these conditions are associated with neuroinflammation.
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http://dx.doi.org/10.1007/s11011-018-0311-6DOI Listing
December 2018

Heat-induced extracellular HSP72 release is blunted in elderly diabetic people compared with healthy middle-aged and older adults, but it is partially restored by resistance training.

Exp Gerontol 2018 10 25;111:180-187. Epub 2018 Jul 25.

Laboratory of Inflammation, Metabolism and Exercise Research (LAPIMEX) and Laboratory of Cellular Physiology, Department of Physiology, Institute of Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil. Electronic address:

Recent evidence suggests that the anti-inflammatory heat shock response (HSR) is reduced in aging and diabetes. In this study we compared HSR between healthy middle-aged adults, healthy elderly and type 2 diabetic (T2DM) elderly, and tested whether resistance training (RT) could improve the HSR in T2DM group. Thirty sedentary participants volunteered for this study. HSR (assessed as the capacity to export HSP72 during heat stress) was measured in the blood and compared between the groups. HSR was similar between healthy middle-aged and healthy elderly volunteers, but diminished in elderly T2DM (p < 0.001). Hence, T2DM subjects (n = 12) were submitted to a 12-week RT program, because exercise is a physiological HSR inducer. HSR, cytokines, metabolic parameters and visceral adipose tissue (VAT) were measured before and after the RT. Remarkably, VAT was negatively correlated with HSR (r = - 0.49, p < 0.01) while RT improved the HSR and reduced inflammation [TNF-α: from 51.5 ± 9 to 40.7 ± 4 pg/mL and TNF-α/IL-10 ratio: from 1.55 ± 0.3 to 1.16 ± 0.2 (p < 0.001)], without affecting other parameters. All together, these findings confirm the hypothesis that the anti-inflammatory HSR is depressed in elderly diabetic people, but can be partially restored by RT.
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http://dx.doi.org/10.1016/j.exger.2018.07.014DOI Listing
October 2018

Differential effects of typical and atypical antipsychotics on astroglial cells in vitro.

Int J Dev Neurosci 2018 Oct 11;69:1-9. Epub 2018 Jun 11.

Departamento de Bioquímica, Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.

Astrocytes are glial cells that are essential for the maintenance of central nervous system functions, modulating neurotransmitters, providing metabolic, trophic and antioxidant support, and producing a wide range of cytokines to modulate the inflammatory response. These cells can be targets for antipsychotics, medications used in the treatment of neuropsychiatric disorders. In this regard, several studies have shown that antipsychotics are able to modulate peripheral cytokine release, but their effects on astroglial inflammatory response need to be further investigated. In this study, we evaluated the effects of risperidone and haloperidol, common atypical and typical antipsychotics, respectively, on cytokine release and redox status in C6 astroglial cells, an astrocyte-like cell line. Risperidone showed an anti-inflammatory activity, decreasing the release of tumor necrosis factor α (TNF-α), interleukins 1β (IL-1 β) and 6 (IL-6), and increasing interleukin 10 (IL-10). This atypical antipsychotic was also able to decrease the transcriptional activity of nuclear factor κB (NFκB) and improve glutathione content. However, haloperidol induced a pro-inflammatory response, increasing the extracellular levels of TNF-α and IL-1β, in addition to decreasing IL-10. This typical antipsychotic could induce an inflammatory response by activating p38 mitogen-activated protein kinase (p38 MAPK)/NFκB pathways. In summary, our results suggest that risperidone and haloperidol present different effects on astroglial cells, in this way being able to differentially affect the neuroinflammation associated with neuropsychiatric disorders.
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http://dx.doi.org/10.1016/j.ijdevneu.2018.06.001DOI Listing
October 2018

Transcranial direct current stimulation improves long-term memory deficits in an animal model of attention-deficit/hyperactivity disorder and modulates oxidative and inflammatory parameters.

Brain Stimul 2018 Jul - Aug;11(4):743-751. Epub 2018 Apr 5.

Post-Graduate Program in Medicine: Medical Sciences, School of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; Animal Experimentation Unit and Graduate Research Group, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil; Laboratory of Pain Pharmacology and Neuromodulation: Pre Clinical Studies - Pharmacology Department, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. Electronic address:

Background: Transcranial direct current stimulation (tDCS) is a technique that modulates neuronal activity and has been proposed as a potential therapeutic tool for attention-deficit/hyperactivity disorder (ADHD) symptoms. Although pilot studies have shown evidence of efficacy, its mechanism of action remains unclear.

Objective/hypothesis: We evaluated the effects of tDCS on behavioral (working and long-term memory) and neurochemical (oxidative and inflammatory parameters) outcomes related to ADHD pathophysiology. We used the most widely accepted animal model of ADHD: spontaneously hypertensive rats (SHR). The selected behavioral outcomes have been shown to be altered in both ADHD patients and animal models, and were chosen for their relation to the proposed mechanistic action of tDCS.

Methods: Adult male SHR and their control, the Wistar Kyoto rats (WKY), were subjected to 20 min of bicephalic tDCS or sham stimulation for 8 consecutive days. Working memory, long-term memory, and neurochemical outcomes were evaluated.

Results: TDCS improved long-term memory deficits presented by the SHR. No change in working memory performance was observed. In the hippocampus, tDCS increased both the production of reactive oxygen species in SHR and the levels of the antioxidant molecule glutathione in both strains. TDCS also modulated inflammatory response in the brains of WKY by downregulating pro-inflammatory cytokines.

Conclusion: TDCS had significant effects that were specific for strain, type of behavioral and neurochemical outcomes. The long-term memory improvement in the SHR may point to a possible therapeutic role of tDCS in ADHD that does not seem to be mediated by inflammatory markers. Additionally, the anti-inflammatory effects observed in the brain of WKY after tDCS needs to be further explored.
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http://dx.doi.org/10.1016/j.brs.2018.04.001DOI Listing
February 2019

Age-Dependent Neurochemical Remodeling of Hypothalamic Astrocytes.

Mol Neurobiol 2018 Jul 4;55(7):5565-5579. Epub 2017 Oct 4.

Departamento de Bioquímica, Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600-Anexo, Bairro Santa Cecília, Porto Alegre, RS, 90035-003, Brazil.

The hypothalamus is a crucial integrative center in the central nervous system, responsible for the regulation of homeostatic activities, including systemic energy balance. Increasing evidence has highlighted a critical role of astrocytes in orchestrating hypothalamic functions; they participate in the modulation of synaptic transmission, metabolic and trophic support to neurons, immune defense, and nutrient sensing. In this context, disturbance of systemic energy homeostasis, which is a common feature of obesity and the aging process, involves inflammatory responses. This may be related to dysfunction of hypothalamic astrocytes. In this regard, the aim of this study was to evaluate the neurochemical properties of hypothalamic astrocyte cultures from newborn, adult, and aged Wistar rats. Age-dependent changes in the regulation of glutamatergic homeostasis, glutathione biosynthesis, amino acid profile, glucose metabolism, trophic support, and inflammatory response were observed. Additionally, signaling pathways including nuclear factor erythroid-derived 2-like 2/heme oxygenase-1 p38 mitogen-activated protein kinase, nuclear factor kappa B, phosphatidylinositide 3-kinase/Akt, and leptin receptor expression may represent putative mechanisms associated with the cellular alterations. In summary, our findings indicate that as age increases, hypothalamic astrocytes remodel and exhibit changes in their neurochemical properties. This process may play a role in the onset and/or progression of metabolic disorders.
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http://dx.doi.org/10.1007/s12035-017-0786-xDOI Listing
July 2018

Neuron-glia Interaction as a Possible Pathophysiological Mechanism of Bipolar Disorder.

Curr Neuropharmacol 2018 ;16(5):519-532

Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada.

Accumulating evidence has shown the importance of glial cells in the neurobiology of bipolar disorder. Activated microglia and inflammatory cytokines have been pointed out as potential biomarkers of bipolar disorder. Indeed, recent studies have shown that bipolar disorder involves microglial activation in the hippocampus and alterations in peripheral cytokines, suggesting a potential link between neuroinflammation and peripheral toxicity. These abnormalities may also be the biological underpinnings of outcomes related to neuroprogression, such as cognitive impairment and brain changes. Additionally, astrocytes may have a role in the progression of bipolar disorder, as these cells amplify inflammatory response and maintain glutamate homeostasis, preventing excitotoxicity. The present review aims to discuss neuron-glia interactions and their role in the pathophysiology and treatment of bipolar disorder.
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http://dx.doi.org/10.2174/1570159X15666170828170921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5997869PMC
September 2018

Methylglyoxal Induces Changes in the Glyoxalase System and Impairs Glutamate Uptake Activity in Primary Astrocytes.

Oxid Med Cell Longev 2017 8;2017:9574201. Epub 2017 Jun 8.

Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, 90035-003 Porto Alegre, RS, Brazil.

The impairment of astrocyte functions is associated with diabetes mellitus and other neurodegenerative diseases. Astrocytes have been proposed to be essential cells for neuroprotection against elevated levels of methylglyoxal (MG), a highly reactive aldehyde derived from the glycolytic pathway. MG exposure impairs primary astrocyte viability, as evaluated by different assays, and these cells respond to MG elevation by increasing glyoxalase 1 activity and glutathione levels, which improve cell viability and survival. However, C6 glioma cells have shown strong signs of resistance against MG, without significant changes in the glyoxalase system. Results for aminoguanidine coincubation support the idea that MG toxicity is mediated by glycation. We found a significant decrease in glutamate uptake by astrocytes, without changes in the expression of the major transporters. Carbenoxolone, a nonspecific inhibitor of gap junctions, prevented the cytotoxicity induced by MG in astrocyte cultures. Thus, our data reinforce the idea that astrocyte viability depends on gap junctions and that the impairment induced by MG involves glutamate excitotoxicity. The astrocyte susceptibility to MG emphasizes the importance of this compound in neurodegenerative diseases, where the neuronal damage induced by MG may be aggravated by the commitment of the cells charged with MG clearance.
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http://dx.doi.org/10.1155/2017/9574201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5480050PMC
January 2018

Increased Oxidative Parameters and Decreased Cytokine Levels in an Animal Model of Attention-Deficit/Hyperactivity Disorder.

Neurochem Res 2017 Nov 29;42(11):3084-3092. Epub 2017 Jun 29.

Post-Graduate Program in Medicine: Medical Sciences, School of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.

Attention-deficit/hyperactivity disorder (ADHD) is a highly heterogeneous disorder characterized by impairing levels of hyperactivity, impulsivity and inattention. Oxidative and inflammatory parameters have been recognized among its multiple predisposing pathways, and clinical studies indicate that ADHD patients have increased oxidative stress. In this study, we aimed to evaluate oxidative (DCFH oxidation, glutathione levels, glutathione peroxidase, catalase and superoxide dismutase activities) and inflammatory (TNF-α, IL-1β and IL-10) parameters in the most widely accepted animal model of ADHD, the spontaneously hypertensive rats (SHR). Prefrontal cortex, cortex (remaining regions), striatum and hippocampus of adult male SHR and Wistar Kyoto rats were studied. SHR presented increased reactive oxygen species (ROS) production in the cortex, striatum and hippocampus. In SHR, glutathione peroxidase activity was decreased in the prefrontal cortex and hippocampus. TNF-α levels were reduced in the prefrontal cortex, cortex (remaining regions), hippocampus and striatum of SHR. Besides, IL-1β and IL-10 levels were decreased in the cortex of the ADHD model. Results indicate that SHR presented an oxidative profile that is characterized by an increase in ROS production without an effective antioxidant counterbalance. In addition, this strain showed a decrease in cytokine levels, mainly TNF-α, indicating a basal deficit. These results may present a new approach to the cognitive disturbances seen in the SHR.
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http://dx.doi.org/10.1007/s11064-017-2341-6DOI Listing
November 2017
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