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Schmitz I, Bobermin LD, da Silva A, Weber FB, Thomaz NK, Schmitz F, Brondani M, Fachinetto R, Leipnitz G, Wyse ATS, Gonçalves CA, Quincozes-Santos A. A single dose of haloperidol decanoate induces short-term hippocampal neuroinflammation: focus on the glial response. Pharmacol Rep 2025; 77:800-808. [PMID: 39982625 DOI: 10.1007/s43440-025-00706-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Revised: 02/07/2025] [Accepted: 02/10/2025] [Indexed: 02/22/2025]
Abstract
BACKGROUND Haloperidol is a widely used antipsychotic for the treatment of neuropsychiatric disorders, the pathophysiology of which may involve hippocampal alterations. Hippocampus is affected by long-term use of the drug, but the effects of acute doses on the hippocampus remain unclear. The present study investigated whether a single dose of haloperidol decanoate could induce short-term hippocampal neuroinflammation and changes in cholinergic, glutamatergic and redox homeostasis in adult rats, focusing on the glial response. METHODS Male Wistar rats (60 days old) received a single intramuscular injection of haloperidol decanoate (38 mg/kg) or vehicle. After 7 days, hippocampal tissue was used to assess gene expression of inflammatory mediators, glutamate transporters, and transcriptional factors that regulate neuroinflammation. The enzymatic activities of acetylcholinesterase (AChE), glutamine synthetase (GS), and glutathione peroxidase (GPx), and glutamate uptake and reduced glutathione (GSH) levels were also determined. RESULTS Haloperidol decanoate increased the gene expression of pro-inflammatory cytokines, cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS). Moreover, downregulation of the transcriptional factor erythroid 2-related factor 2 (Nrf2) and the peroxisome proliferator-activated receptor-gamma coactivator (PGC-1α) was observed. In contrast, nuclear factor κB (NFκB) transcriptional levels remained unchanged. Haloperidol also increased glutamate uptake, the glutamate transporter GLAST gene expression, and the AChE and GPx activities. CONCLUSIONS Our findings show that a single dose of haloperidol decanoate induces short-term hippocampal neuroinflammation and changes in glial parameters, highlighting the need for future adjuvant glioprotective strategies that can attenuate these effects.
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Affiliation(s)
- Izaviany Schmitz
- 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
| | - Larissa Daniele Bobermin
- 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
- Programa de Pós-Graduação em Neurociências, 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
| | - Amanda da Silva
- 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
| | - Fernanda Becker Weber
- 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
| | - Natalie K Thomaz
- 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
| | - Felipe Schmitz
- 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
| | - Morgana Brondani
- 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
| | - Roselei Fachinetto
- Programa de Pós-Graduação em Farmacologia, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil
| | - Guilhian Leipnitz
- 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
- Programa de Pós-Graduação em Neurociências, 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
- Programa de Pós-Graduação em Ciências Biológicas: Fisiologia, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Angela T S Wyse
- 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
| | - Carlos-Alberto Gonçalves
- 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
- Programa de Pós-Graduação em Neurociências, 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
| | - André Quincozes-Santos
- 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.
- Programa de Pós-Graduação em Neurociências, 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.
- Laboratório de Neurotoxicidade e Glioproteção (LABGLIO), Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600- Anexo Bairro Santa Cecília, Porto Alegre, RS, 90035-003, Brazil.
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Quincozes-Santos A, Bobermin LD, Tramontina AC, Wartchow KM, Da Silva VF, Gayger-Dias V, Thomaz NK, de Moraes ADM, Schauren D, Nardin P, Gottfried C, Souza DO, Gonçalves CA. Glioprotective Effects of Resveratrol Against Glutamate-Induced Cellular Dysfunction: The Role of Heme Oxygenase 1 Pathway. Neurotox Res 2025; 43:7. [PMID: 39869271 DOI: 10.1007/s12640-025-00730-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 10/21/2024] [Accepted: 01/19/2025] [Indexed: 01/28/2025]
Abstract
Resveratrol, a natural polyphenol, has shown promising neuroprotective effects in several in vivo and in vitro experimental models. However, the mechanisms by which resveratrol mediates these effects are not fully understood. Glutamate is the major excitatory neurotransmitter in the brain; however, excessive extracellular glutamate levels can affect neural activity in several neurological diseases. Astrocytes are the glial cells that maintain brain homeostasis and can attenuate excitotoxicity by actively participating in glutamate neurotransmission. This study aimed to investigate the glioprotective effects of resveratrol against glutamate-induced cellular dysfunction in hippocampal slices and primary astrocyte cultures, with a focus on the role of heme-oxygenase 1 (HO-1). Glutamate impaired glutamate uptake activity through a glutamate receptor-dependent mechanism, in addition to altering other important astroglial parameters, including glutamine synthetase activity, glutathione levels and cystine uptake, which were normalized by resveratrol. Resveratrol also prevented glutamate-induced disruption in antioxidant defenses, as well as in trophic and inflammatory functions, including the nuclear factor κB (NFκB) transcriptional activity. Most of the effects of resveratrol, mainly in astrocytes, were dependent on the HO-1 signaling pathway, as they were abrogated when HO-1 was pharmacologically inhibited. Resveratrol also increased HO-1 mRNA expression and its transcriptional regulator, nuclear factor erythroid-derived 2-like 2 (Nrf2). Finally, resveratrol prevented glutamate-induced p21 senescence marker, indicating an anti-aging effect. Therefore, we demonstrated that the activation of the Nrf2/HO-1 system in astrocytes by resveratrol represents an astrocyte-targeted neuroprotective mechanism in neurodegeneration, with glutamate excitotoxicity, oxidative stress, and neuroinflammation as common neurochemical alterations.
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Affiliation(s)
- André Quincozes-Santos
- 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
- Programa de Pós-Graduação em Neurociências, 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, Rua Ramiro Barcelos, 2600- Anexo Bairro Santa Cecília, Porto Alegre, RS, 90035-003, Brazil
| | - Larissa Daniele Bobermin
- 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.
- Programa de Pós-Graduação em Neurociências, 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, Rua Ramiro Barcelos, 2600- Anexo Bairro Santa Cecília, Porto Alegre, RS, 90035-003, Brazil.
| | - Ana Carolina Tramontina
- Programa de Pós-Graduação em Ambiente e Sustentabilidade, Universidade Estadual do Rio Grande do Sul, São Francisco de Paula, RS, Brazil
| | - Krista Minéia Wartchow
- Brain Health Imaging Institute, Department of Radiology, Weill Cornell Medicine, New York City, NY, USA
| | - Vanessa-Fernanda Da Silva
- 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
| | - Vitor Gayger-Dias
- 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
| | - Natalie K Thomaz
- 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
| | - Aline Daniel Moreira de Moraes
- 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
| | - Daniele Schauren
- 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
| | - Patrícia Nardin
- Escola de Saúde, Universidade do Vale do Rio dos Sinos (Unisinos), São Leopoldo, RS, Brazil
| | - Carmem Gottfried
- 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
- Programa de Pós-Graduação em Neurociências, 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, Rua Ramiro Barcelos, 2600- Anexo Bairro Santa Cecília, Porto Alegre, RS, 90035-003, Brazil
- National Institute of Science and Technology in Neuroimmunomodulation (INCT-NIM), Oswaldo Cruz Institute, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
| | - Diogo Onofre Souza
- 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, Rua Ramiro Barcelos, 2600- Anexo Bairro Santa Cecília, Porto Alegre, RS, 90035-003, Brazil
| | - Carlos-Alberto Gonçalves
- 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
- Programa de Pós-Graduação em Neurociências, 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, Rua Ramiro Barcelos, 2600- Anexo Bairro Santa Cecília, Porto Alegre, RS, 90035-003, Brazil
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da Silva A, Bobermin LD, Santos CL, de Souza Almeida RR, Lissner LJ, Dos Santos TM, Seady M, Leite MC, Wyse ATS, Gonçalves CA, Quincozes-Santos A. Glia-related Acute Effects of Risperidone and Haloperidol in Hippocampal Slices and Astrocyte Cultures from Adult Wistar Rats: A Focus on Inflammatory and Trophic Factor Release. Neurochem Res 2024; 50:22. [PMID: 39560678 DOI: 10.1007/s11064-024-04273-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Revised: 09/08/2024] [Accepted: 09/16/2024] [Indexed: 11/20/2024]
Abstract
Antipsychotics are drugs commonly prescribed to treat a variety of psychiatric conditions. They are classified as typical and atypical, depending on their affinity for dopaminergic and serotonergic receptors. Although neurons have been assumed to be the major mediators of the antipsychotic pharmacological effects, glia, particularly astrocytes, have emerged as important cellular targets for these drugs. In the present study, we investigated the effects of acute treatments with the antipsychotics risperidone and haloperidol of hippocampal slices and astrocyte cultures, focusing on neuron-glia communication and how antipsychotics act in astrocytes. For this, we obtained hippocampal slices and primary astrocyte cultures from 30-day-old Wistar rats and incubated them with risperidone or haloperidol (1 and 10 μM) for 30 min and 24 h, respectively. We evaluated metabolic and enzymatic activities, the glutathione level, the release of inflammatory and trophic factors, as well as the gene expression of signaling proteins. Haloperidol increased glucose metabolism; however, neither of the tested antipsychotics altered the glutathione content or glutamine synthetase and Na+K+-ATPase activities. Haloperidol induced a pro-inflammatory response and risperidone promoted an anti-inflammatory response, while both antipsychotics seemed to decrease trophic support. Haloperidol and risperidone increased Nrf2 and HO-1 gene expression, but only haloperidol upregulated NFκB and AMPK gene expression. Finally, astrocyte cultures confirmed the predominant effect of the tested antipsychotics on glia and their opposite effects on astrocytes. Therefore, antipsychotics cause functional alterations in the hippocampus. This information is important to drive future research for strategies to attenuate antipsychotics-induced neural dysfunction, focusing on glia.
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Affiliation(s)
- Amanda da Silva
- 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
| | - Larissa Daniele Bobermin
- 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
- Programa de Pós-Graduação Em Neurociências, Instituto de Ciências Básicas da Saúde, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, RS, Brazil
| | - Camila Leite Santos
- 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
| | - Rômulo Rodrigo de Souza Almeida
- Programa de Pós-Graduação Em Neurociências, Instituto de Ciências Básicas da Saúde, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, RS, Brazil
| | | | - Tiago Marcon Dos Santos
- 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
| | - Marina Seady
- 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
| | - Marina Concli Leite
- 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, Rua Ramiro Barcelos, 2600-Anexo, Bairro Santa Cecília, Porto Alegre, RS, 90035-003, Brazil
| | - Angela T S Wyse
- 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, Rua Ramiro Barcelos, 2600-Anexo, Bairro Santa Cecília, Porto Alegre, RS, 90035-003, Brazil
| | - Carlos-Alberto Gonçalves
- 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
- Programa de Pós-Graduação Em Neurociências, 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, Rua Ramiro Barcelos, 2600-Anexo, Bairro Santa Cecília, Porto Alegre, RS, 90035-003, Brazil
| | - André Quincozes-Santos
- 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.
- Programa de Pós-Graduação Em Neurociências, 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, Rua Ramiro Barcelos, 2600-Anexo, Bairro Santa Cecília, Porto Alegre, RS, 90035-003, Brazil.
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Vizuete AFK, Gonçalves CA. Is Methylglyoxal a Potential Biomarker for the Warburg Effect Induced by the Lipopolysaccharide Neuroinflammation Model? Neurochem Res 2024; 49:1823-1837. [PMID: 38727985 DOI: 10.1007/s11064-024-04142-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 02/26/2024] [Accepted: 05/02/2024] [Indexed: 06/02/2024]
Abstract
Methylglyoxal (MG) is considered a classical biomarker of diabetes mellitus and its comorbidities. However, a role for this compound in exacerbated immune responses, such as septicemia, is being increasingly observed and requires clarification, particularly in the context of neuroinflammatory responses. Herein, we used two different approaches (in vivo and acute hippocampal slice models) to investigate MG as a biomarker of neuroinflammation and the neuroimmunometabolic shift to glycolysis in lipopolysaccharide (LPS) inflammation models. Our data reinforce the hypothesis that LPS-induced neuroinflammation stimulates the cerebral innate immune response by increasing IL-1β, a classical pro-inflammatory cytokine, and the astrocyte reactive response, via elevating S100B secretion and GFAP levels. Acute neuroinflammation promotes an early neuroimmunometabolic shift to glycolysis by elevating glucose uptake, lactate release, PFK1, and PK activities. We observed high serum and cerebral MG levels, in association with a reduction in glyoxalase 1 detoxification activity, and a close correlation between serum and hippocampus MG levels with the systemic and neuroinflammatory responses to LPS. Findings strongly suggest a role for MG in immune responses.
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Affiliation(s)
- Adriana Fernanda Kuckartz Vizuete
- Laboratory of Calcium-Binding Proteins in the CNS, Department of Biochemistry, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul (UFRGS) Ramio Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil.
- Pos Graduate Program in Biochemistry, Institute of Basic Health Sciences, UFRGS, Porto Alegre, RS, Brazil.
| | - Carlos-Alberto Gonçalves
- Laboratory of Calcium-Binding Proteins in the CNS, Department of Biochemistry, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul (UFRGS) Ramio Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil
- Pos Graduate Program in Biochemistry, Institute of Basic Health Sciences, UFRGS, Porto Alegre, RS, Brazil
- Department of Biochemistry, Institute of Basic Health Sciences, UFRGS, Porto Alegre, RS, Brazil
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Vizuete AFK, Fróes F, Seady M, Hansen F, Ligabue-Braun R, Gonçalves CA, Souza DO. A Mechanism of Action of Metformin in the Brain: Prevention of Methylglyoxal-Induced Glutamatergic Impairment in Acute Hippocampal Slices. Mol Neurobiol 2024; 61:3223-3239. [PMID: 37980327 DOI: 10.1007/s12035-023-03774-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Accepted: 11/05/2023] [Indexed: 11/20/2023]
Abstract
Metformin, a biguanide compound (N-1,1-dimethylbiguanide), is widely prescribed for diabetes mellitus type 2 (T2D) treatment. It also presents a plethora of properties, such as anti-oxidant, anti-inflammatory, anti-apoptosis, anti-tumorigenic, and anti-AGE formation activity. However, the precise mechanism of action of metformin in the central nervous system (CNS) needs to be clarified. Herein, we investigated the neuroprotective role of metformin in acute hippocampal slices exposed to methylglyoxal (MG), a highly reactive dicarbonyl compound and a key molecule in T2D developmental pathophysiology. Metformin protected acute hippocampal slices from MG-induced glutamatergic neurotoxicity and neuroinflammation by reducing IL-1β synthesis and secretion and RAGE protein expression. The drug also improved astrocyte function, particularly with regard to the glutamatergic system, increasing glutamate uptake. Moreover, we observed a direct effect of metformin on glutamate transporters, where the compound prevented glycation, by facilitating enzymatic phosphorylation close to Lys residues, suggesting a new neuroprotective role of metformin via PKC ζ in preventing dysfunction in glutamatergic system induced by MG.
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Affiliation(s)
- Adriana Fernanda K Vizuete
- Laboratory of Calcium-Binding Proteins in the CNS, Department of Biochemistry, Institute of Basic Health Sciences, Universidade Federal Do Rio Grande Do Sul (UFRGS), Porto Alegre, RS, Brazil.
- Post Graduate Program in Biochemistry, Institute of Basic Health Sciences, UFRGS, Porto Alegre, RS, Brazil.
- Department of Biochemistry, Institute of Basic Health Sciences, UFRGS, Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil.
| | - Fernanda Fróes
- Laboratory of Calcium-Binding Proteins in the CNS, Department of Biochemistry, Institute of Basic Health Sciences, Universidade Federal Do Rio Grande Do Sul (UFRGS), Porto Alegre, RS, Brazil
- Post Graduate Program in Biochemistry, Institute of Basic Health Sciences, UFRGS, Porto Alegre, RS, Brazil
| | - Marina Seady
- Laboratory of Calcium-Binding Proteins in the CNS, Department of Biochemistry, Institute of Basic Health Sciences, Universidade Federal Do Rio Grande Do Sul (UFRGS), Porto Alegre, RS, Brazil
- Post Graduate Program in Biochemistry, Institute of Basic Health Sciences, UFRGS, Porto Alegre, RS, Brazil
| | - Fernanda Hansen
- Department of Nutrition, Health Sciences Center, Federal University of Santa Catarina, University Campus, Trindade, Florianópolis, Santa Catarina, 88040-900, Brazil
| | - Rodrigo Ligabue-Braun
- Department of Pharmacosciences, Federal University of Health Sciences of Porto Alegre (UFCSPA), Avenida Sarmento Leite 245, Porto Alegre, 90050-130, Brazil
| | - Carlos-Alberto Gonçalves
- Laboratory of Calcium-Binding Proteins in the CNS, Department of Biochemistry, Institute of Basic Health Sciences, Universidade Federal Do Rio Grande Do Sul (UFRGS), Porto Alegre, RS, Brazil
- Post Graduate Program in Biochemistry, Institute of Basic Health Sciences, UFRGS, Porto Alegre, RS, Brazil
- Department of Biochemistry, Institute of Basic Health Sciences, UFRGS, Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil
| | - Diogo O Souza
- Post Graduate Program in Biochemistry, Institute of Basic Health Sciences, UFRGS, Porto Alegre, RS, Brazil
- Department of Biochemistry, Institute of Basic Health Sciences, UFRGS, Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil
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Selistre NG, Rodrigues L, Federhen BC, Gayger-Dias V, Taday J, Wartchow KM, Gonçalves CA. S100B Secretion in Astrocytes, Unlike C6 Glioma Cells, Is Downregulated by Lactate. Metabolites 2023; 14:7. [PMID: 38276297 PMCID: PMC10819463 DOI: 10.3390/metabo14010007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 12/14/2023] [Accepted: 12/18/2023] [Indexed: 01/27/2024] Open
Abstract
S100B is a calcium-binding protein produced and secreted by astrocytes in response to various extracellular stimuli. C6 glioma cells are a lineage commonly employed for astroglial studies due to the expression of astrocyte specific markers and behavior. However, in high-glucose medium, C6 S100B secretion increases, in contrast to the trend in primary astrocyte cultures. Additionally, S100B secretion decreases due to fluorocitrate (FC), a Krebs cycle inhibitor, highlighting a connection between S100B and metabolism. Herein, we investigate the impact of FC on S100B secretion in primary astrocyte cultures, acute hippocampal slices and C6 glioma cells, as well as lactate mediation. Our results demonstrated that C6 responded similarly to astrocytes in various parameters, despite the decrease in S100B secretion, which was inversely observed in astrocytes and slices. Furthermore, FC inversely altered extracellular lactate in both models, suggesting a role for lactate in S100B secretion. This was reinforced by a decrease in S100B secretion in hippocampal slices treated with lactate and its agonist, but not in C6 cells, despite HCAR1 expression. Our findings indicate that extracellular lactate mediates the decrease in S100B secretion in astrocytes exposed to FC. They also emphasize the differences in C6 glioma cells regarding energetic metabolism. The proposed mechanism via HCAR1 provides further compelling evidence of the relationship between S100B and glucose metabolism.
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Affiliation(s)
- Nicholas Guerini Selistre
- Biochemistry Post-Graduate Program, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre 90010-150, Brazil; (N.G.S.); (L.R.); (B.C.F.); (V.G.-D.); (J.T.); (C.-A.G.)
| | - Leticia Rodrigues
- Biochemistry Post-Graduate Program, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre 90010-150, Brazil; (N.G.S.); (L.R.); (B.C.F.); (V.G.-D.); (J.T.); (C.-A.G.)
| | - Barbara Carolina Federhen
- Biochemistry Post-Graduate Program, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre 90010-150, Brazil; (N.G.S.); (L.R.); (B.C.F.); (V.G.-D.); (J.T.); (C.-A.G.)
| | - Vitor Gayger-Dias
- Biochemistry Post-Graduate Program, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre 90010-150, Brazil; (N.G.S.); (L.R.); (B.C.F.); (V.G.-D.); (J.T.); (C.-A.G.)
| | - Jéssica Taday
- Biochemistry Post-Graduate Program, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre 90010-150, Brazil; (N.G.S.); (L.R.); (B.C.F.); (V.G.-D.); (J.T.); (C.-A.G.)
| | - Krista Mineia Wartchow
- Brain Health Imaging Institute, Department of Radiology, Weill Cornell Medicine, New York, NY 10044, USA
| | - Carlos-Alberto Gonçalves
- Biochemistry Post-Graduate Program, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre 90010-150, Brazil; (N.G.S.); (L.R.); (B.C.F.); (V.G.-D.); (J.T.); (C.-A.G.)
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7
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Leite MC, Galland F, Guerra MC, Rodrigues L, Taday J, Monteforte PT, Hirata H, Gottfried C, Donato R, Smaili S, Gonçalves CA. Astroglial S100B Secretion Is Mediated by Ca 2+ Mobilization from Endoplasmic Reticulum: A Study Using Forskolin and DMSO as Secretagogues. Int J Mol Sci 2023; 24:16576. [PMID: 38068900 PMCID: PMC10706453 DOI: 10.3390/ijms242316576] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Revised: 11/01/2023] [Accepted: 11/09/2023] [Indexed: 12/18/2023] Open
Abstract
S100B, a homodimeric Ca2+-binding protein, is produced and secreted by astrocytes, and its extracellular levels have been used as a glial marker in brain damage and neurodegenerative and psychiatric diseases; however, its mechanism of secretion is elusive. We used primary astrocyte cultures and calcium measurements from real-time fluorescence microscopy to investigate the role of intracellular calcium in S100B secretion. In addition, the dimethyl sulfoxide (DMSO) effect on S100B was investigated in vitro and in vivo using Wistar rats. We found that DMSO, a widely used vehicle in biological assays, is a powerful S100B secretagogue, which caused a biphasic response of Ca2+ mobilization. Our data show that astroglial S100B secretion is triggered by the increase in intracellular Ca2+ and indicate that this increase is due to Ca2+ mobilization from the endoplasmic reticulum. Also, blocking plasma membrane Ca2+ channels involved in the Ca2+ replenishment of internal stores decreased S100B secretion. The DMSO-induced S100B secretion was confirmed in vivo and in ex vivo hippocampal slices. Our data support a nonclassic vesicular export of S100B modulated by Ca2+, and the results might contribute to understanding the mechanism underlying the astroglial release of S100B.
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Affiliation(s)
- Marina C. Leite
- Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul, Ramiro Barcelos, 2600-Anexo, Porto Alegre 90035-003, RS, Brazil; (M.C.G.); (L.R.); (J.T.); (C.G.); (C.-A.G.)
| | - Fabiana Galland
- Centro de Ciências e Qualidade dos Alimentos, Instituto de Tecnologia de Alimentos, Campinas 13070-178, SP, Brazil;
| | - Maria Cristina Guerra
- Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul, Ramiro Barcelos, 2600-Anexo, Porto Alegre 90035-003, RS, Brazil; (M.C.G.); (L.R.); (J.T.); (C.G.); (C.-A.G.)
| | - Letícia Rodrigues
- Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul, Ramiro Barcelos, 2600-Anexo, Porto Alegre 90035-003, RS, Brazil; (M.C.G.); (L.R.); (J.T.); (C.G.); (C.-A.G.)
| | - Jéssica Taday
- Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul, Ramiro Barcelos, 2600-Anexo, Porto Alegre 90035-003, RS, Brazil; (M.C.G.); (L.R.); (J.T.); (C.G.); (C.-A.G.)
| | - Priscila T. Monteforte
- Departamento de Ciências Naturais, Universidade Federal de São João Del-Rei, São João Del Rei 36301-160, MG, Brazil;
| | - Hanko Hirata
- Departamento de Farmacologia, Universidade Federal de São Paulo, São Paulo 04044-020, SP, Brazil; (H.H.); (S.S.)
| | - Carmem Gottfried
- Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul, Ramiro Barcelos, 2600-Anexo, Porto Alegre 90035-003, RS, Brazil; (M.C.G.); (L.R.); (J.T.); (C.G.); (C.-A.G.)
| | - Rosario Donato
- Interuniversity Institute of Myology, 06132 Perugia, Italy;
| | - Soraya Smaili
- Departamento de Farmacologia, Universidade Federal de São Paulo, São Paulo 04044-020, SP, Brazil; (H.H.); (S.S.)
| | - Carlos-Alberto Gonçalves
- Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul, Ramiro Barcelos, 2600-Anexo, Porto Alegre 90035-003, RS, Brazil; (M.C.G.); (L.R.); (J.T.); (C.G.); (C.-A.G.)
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8
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Rojas DB, Vizuete AFK, de Andrade VS, de Andrade RB, Gemelli T, Kim TDH, Gonçalves CA, Leipnitz G, Wannmacher CMD. Lipopolysaccharide impairs neurodevelopment and induces changes in astroglial reactivity, antioxidant defenses and bioenergetics in the cerebral cortex of neonatal rats. Int J Dev Neurosci 2023; 83:600-614. [PMID: 37477051 DOI: 10.1002/jdn.10288] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 07/01/2023] [Accepted: 07/03/2023] [Indexed: 07/22/2023] Open
Abstract
Neonates have an immature immune system, which increases their vulnerability to infectious agents and inflammatory insults. The administration of the immunostimulatory agent lipopolysaccharide (LPS) has been shown to induce the expression of pro-inflammatory cytokines and cause behavior alterations in rodents at different ages. However, the effects of LPS administration during the neonatal period and its consequences during immune system maturation remain to be elucidated. We showed here that a single intraperitoneal administration of LPS in rats on postnatal day (PND) 7 caused early and variable alterations in TNF-α, S100B and GFAP levels in the cerebral cortex, CSF and serum of the animals, indicating long-term induction of neuroinflammation and astroglial reactivity. However, on PND 21, only GFAP levels were increased by LPS. Additionally, LPS induced oxidative stress and altered energy metabolism enzymes in the cerebral cortex on PND 21, and caused neurodevelopment impairment over time. These data suggest that neuroinflammation induction during the neonatal period induces glial reactivity, oxidative stress and bioenergetic disruption that may lead to neurodevelopment impairment and cognitive deficit in adult life.
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Affiliation(s)
- Denise Bertin Rojas
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil
| | - Adriana Fernanda K Vizuete
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil
- Laboratory of Calcium-Binding Proteins in the CNS, Department of Biochemistry, Institute of Basic Health Sciences, UFRGS, Porto Alegre, Rio Grande do Sul, Brazil
| | - Vivian Strassburger de Andrade
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil
| | | | - Tanise Gemelli
- Universidade do Vale do Rio dos Sinos, São Leopoldo, Rio Grande do Sul, Brazil
| | - Tomas Duk Hwa Kim
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil
| | - Carlos Alberto Gonçalves
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil
- Laboratory of Calcium-Binding Proteins in the CNS, Department of Biochemistry, Institute of Basic Health Sciences, UFRGS, Porto Alegre, Rio Grande do Sul, Brazil
- Departmento de Bioquímica, Instituto de Ciências Básicas da Saúde, UFRGS, Porto Alegre, Rio Grande do Sul, Brazil
| | - Guilhian Leipnitz
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil
- Departmento de Bioquímica, Instituto de Ciências Básicas da Saúde, UFRGS, Porto Alegre, Rio Grande do Sul, Brazil
| | - Clovis Milton Duval Wannmacher
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil
- Departmento de Bioquímica, Instituto de Ciências Básicas da Saúde, UFRGS, Porto Alegre, Rio Grande do Sul, Brazil
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9
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Gayger-Dias V, Vizuete AFK, Rodrigues L, Wartchow KM, Bobermin L, Leite MC, Quincozes-Santos A, Kleindienst A, Gonçalves CA. How S100B crosses brain barriers and why it is considered a peripheral marker of brain injury. Exp Biol Med (Maywood) 2023; 248:2109-2119. [PMID: 38058025 PMCID: PMC10800124 DOI: 10.1177/15353702231214260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/08/2023] Open
Abstract
S100B is a 21-kDa protein that is produced and secreted by astrocytes and widely used as a marker of brain injury in clinical and experimental studies. The majority of these studies are based on measurements in blood serum, assuming an associated increase in cerebrospinal fluid and a rupture of the blood-brain barrier (BBB). Moreover, extracerebral sources of S100B are often underestimated. Herein, we will review these interpretations and discuss the routes by which S100B, produced by astrocytes, reaches the circulatory system. We discuss the concept of S100B as an alarmin and its dual activity as an inflammatory and neurotrophic molecule. Furthermore, we emphasize the lack of data supporting the idea that S100B acts as a marker of BBB rupture, and the need to include the glymphatic system in the interpretations of serum changes of S100B. The review is also dedicated to valorizing extracerebral sources of S100B, particularly adipocytes. Furthermore, S100B per se may have direct and indirect modulating roles in brain barriers: on the tight junctions that regulate paracellular transport; on the expression of its receptor, RAGE, which is involved in transcellular protein transport; and on aquaporin-4, a key protein in the glymphatic system that is responsible for the clearance of extracellular proteins from the central nervous system. We hope that the data on S100B, discussed here, will be useful and that it will translate into further health benefits in medical practice.
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Affiliation(s)
- Vitor Gayger-Dias
- Graduate Program in Biochemistry, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre 90.035-003, Brazil
| | - Adriana FK Vizuete
- Graduate Program in Biochemistry, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre 90.035-003, Brazil
| | - Letícia Rodrigues
- Graduate Program in Neurosciences, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre 90.035-003, Brazil
| | - Krista Minéia Wartchow
- Brain Health Imaging Institute, Department of Radiology, Weill Cornell Medicine, New York, NY 10044, USA
| | - Larissa Bobermin
- Graduate Program in Neurosciences, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre 90.035-003, Brazil
| | - Marina Concli Leite
- Graduate Program in Biochemistry, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre 90.035-003, Brazil
| | - André Quincozes-Santos
- Graduate Program in Biochemistry, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre 90.035-003, Brazil
| | - Andrea Kleindienst
- Department of Neurosurgery, Friedrich-Alexander University, 91054 Erlangen, Germany
| | - Carlos-Alberto Gonçalves
- Graduate Program in Biochemistry, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre 90.035-003, Brazil
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10
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Montenegro YHA, Bobermin LD, Sesterheim P, Salvato RS, Anschau F, de Oliveira MJS, Wyse ATS, Netto CA, Gonçalves CAS, Quincozes-Santos A, Leipnitz G. Serum of COVID-19 patients changes neuroinflammation and mitochondrial homeostasis markers in hippocampus of aged rats. J Neurovirol 2023; 29:577-587. [PMID: 37501054 DOI: 10.1007/s13365-023-01156-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 05/18/2023] [Accepted: 06/26/2023] [Indexed: 07/29/2023]
Abstract
Patients affected by COVID-19 present mostly with respiratory symptoms but acute neurological symptoms are also commonly observed. Furthermore, a considerable number of individuals develop persistent and often remitting symptoms months after infection, characterizing the condition called long-COVID. Since the pathophysiology of acute and persistent neurological manifestations is not fully established, we evaluated the expression of different genes in hippocampal slices of aged rats exposed to the serum of a post-COVID (sPC) individual and to the serum of patients infected by SARS-CoV-2 [Zeta (sZeta) and Gamma (sGamma) variants]. The expression of proteins related to inflammatory process, redox homeostasis, mitochondrial quality control and glial reactivity was determined. Our data show that the exposure to sPC, sZeta and sGamma differentially altered the mRNA levels of most inflammatory proteins and reduced those of antioxidant response markers in rat hippocampus. Furthermore, a decrease in the expression of mitochondrial biogenesis genes was induced by all serum samples, whereas a reduction in mitochondrial dynamics was only caused by sPC. Regarding the glial reactivity, S100B expression was modified by sPC and sZeta. These findings demonstrate that changes in the inflammatory response and a reduction of mitochondrial biogenesis and dynamics may contribute to the neurological damage observed in COVID-19 patients.
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Affiliation(s)
- Yorran Hardman A Montenegro
- Programa de Pós-Graduação em Neurociências, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, RS, Porto Alegre, Brazil.
| | - Larissa Daniele Bobermin
- Programa de Pós-Graduação em Neurociências, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, RS, Porto Alegre, Brazil
| | - Patrícia Sesterheim
- Programa de Pós-Graduação em Neurociências, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, RS, Porto Alegre, Brazil
- Programa de Pós-Graduação em Ciências da Saúde: Cardiologia, Instituto de Cardiologia/ Fundação Universitária de Cardiologia, RS, Porto Alegre, Brazil
- Centro de Desenvolvimento Científico e Tecnológico, Centro Estadual de Vigilância em Saúde da Secretaria de Saúde do Estado do Rio Grande do Sul, RS, Porto Alegre, Brazil
| | - Richard Steiner Salvato
- Centro de Desenvolvimento Científico e Tecnológico, Centro Estadual de Vigilância em Saúde da Secretaria de Saúde do Estado do Rio Grande do Sul, RS, Porto Alegre, Brazil
| | - Fernando Anschau
- Programa de Pós-Graduação em Neurociências, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, RS, Porto Alegre, Brazil
- Setor de Pesquisa da Gerência de Ensino, Pesquisa e Inovação do Grupo Hospitalar Conceição (GHC), RS, Porto Alegre, Brazil
- Programa de Pós-Graduação em Avaliação de Tecnologias para o SUS do GHC, Porto Alegre, RS, Brazil
- Escola de Medicina, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Maria José Santos de Oliveira
- Programa de Pós-Graduação em Neurociências, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, RS, Porto Alegre, Brazil
| | - Angela T S Wyse
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, RS, Porto Alegre, Brazil
| | - Carlos Alexandre Netto
- Programa de Pós-Graduação em Neurociências, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, RS, Porto Alegre, Brazil
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, RS, Porto Alegre, Brazil
| | - Carlos-Alberto Saraiva Gonçalves
- Programa de Pós-Graduação em Neurociências, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, RS, Porto Alegre, Brazil
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, RS, Porto Alegre, Brazil
| | - André Quincozes-Santos
- Programa de Pós-Graduação em Neurociências, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, RS, Porto Alegre, Brazil
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, RS, Porto Alegre, Brazil
| | - Guilhian Leipnitz
- Programa de Pós-Graduação em Neurociências, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, RS, Porto Alegre, Brazil.
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, RS, Porto Alegre, Brazil.
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11
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Vizuete AFK, Leal MB, Moreira AP, Seady M, Taday J, Gonçalves CA. Arundic acid (ONO-2506) downregulates neuroinflammation and astrocyte dysfunction after status epilepticus in young rats induced by Li-pilocarpine. Prog Neuropsychopharmacol Biol Psychiatry 2023; 123:110704. [PMID: 36565981 DOI: 10.1016/j.pnpbp.2022.110704] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Revised: 08/08/2022] [Accepted: 12/19/2022] [Indexed: 12/24/2022]
Abstract
Astrocytes, the most abundant glial cells, have several metabolic functions, including ionic, neurotransmitter and energetic homeostasis for neuronal activity. Reactive astrocytes and their dysfunction have been associated with several brain disorders, including the epileptogenic process. Glial Fibrillary Acidic Protein (GFAP) and S100 calcium-binding protein B (S100B) are astrocyte biomarkers associated with brain injury. We hypothesize that arundic acid (ONO-2506), which is known as an inhibitor of S100B synthesis and secretion, protects the hippocampal tissue from neuroinflammation and astrocyte dysfunction after status epileptics (SE) induction by Li-pilocarpine in young rats. Herein, we investigated the effects of arundic acid treatment, at time points of 6 or 24 h after the induction of SE by Li-pilocarpine, in young rats. In SE animals, arundic acid was able to prevent the damage induced by Li-pilocarpine in the hippocampus, decreasing neuroinflammatory signaling (reducing IL-1β, COX2, TLR4 and RAGE contents), astrogliosis (decreasing GFAP and S100B) and astrocytic dysfunction (recovering levels of GSH, glutamine synthetase and connexin-43). Furthermore, arundic acid improved glucose metabolism and reduced the glutamate excitotoxicity found in epilepsy. Our data reinforce the role of astrocytes in epileptogenesis development and the neuroprotective role of arundic acid, which modulates astrocyte function and neuroinflammation in SE animals.
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Affiliation(s)
- Adriana Fernanda K Vizuete
- Laboratory of Calcium-Binding Proteins in CNS, Department of Biochemistry, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil; Pos Graduate Program in Biochemistry, Institute of Basic Health Sciences, UFRGS, Porto Alegre, RS, Brazil.
| | - Miriara B Leal
- Laboratory of Calcium-Binding Proteins in CNS, Department of Biochemistry, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil; Pos Graduate Program in Biochemistry, Institute of Basic Health Sciences, UFRGS, Porto Alegre, RS, Brazil
| | - Ana Paula Moreira
- Laboratory of Calcium-Binding Proteins in CNS, Department of Biochemistry, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil; Pos Graduate Program in Biochemistry, Institute of Basic Health Sciences, UFRGS, Porto Alegre, RS, Brazil
| | - Marina Seady
- Laboratory of Calcium-Binding Proteins in CNS, Department of Biochemistry, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil; Pos Graduate Program in Biochemistry, Institute of Basic Health Sciences, UFRGS, Porto Alegre, RS, Brazil
| | - Jéssica Taday
- Laboratory of Calcium-Binding Proteins in CNS, Department of Biochemistry, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil; Pos Graduate Program in Biochemistry, Institute of Basic Health Sciences, UFRGS, Porto Alegre, RS, Brazil
| | - Carlos-Alberto Gonçalves
- Laboratory of Calcium-Binding Proteins in CNS, Department of Biochemistry, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil; Pos Graduate Program in Biochemistry, Institute of Basic Health Sciences, UFRGS, Porto Alegre, RS, Brazil
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12
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Nosova O, Guselnikova V, Korzhevskii D. The application of alcian blue to identify astrocyte-associated amyloid plaques by using fluorescence and confocal microscopy. J Neurosci Methods 2023; 387:109797. [PMID: 36682730 DOI: 10.1016/j.jneumeth.2023.109797] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Revised: 01/15/2023] [Accepted: 01/18/2023] [Indexed: 01/21/2023]
Abstract
BACKGROUND Astrocytes play an essential role in the normal functioning of the nervous system and are active contributors to the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD). Therefore, to comprehend the astrocytes and amyloid plaques relationship there is a need for imaging techniques providing simultaneous visualization of astrocytes using fluorescence and amyloid plaques revealed by transmitted light microscopy. NEW METHOD The possibility of simultaneous detection of astrocytes by immunocytochemistry (fluorescent) and amyloid plaques by cytochemical Alcian Blue (transparent) using confocal microscopy in 8-month-old 5хFAD mice samples shown. RESULTS The described method supposes performing astrocytes fluorescent labelling by GFAP or S100beta and amyloid plaques staining by Alcian Blue. COMPARISON WITH EXISTING METHODS Proposed approach circumvents some limitations of fluorescence microscopy, such as weak fluorescence, low contrast, fluorophore broad excitation/emission profile and chemical instability. CONCLUSIONS The proposed technique provides high-quality resulting images of GFAP/s100beta- labelled astrocytes and Alcian Blue-stained amyloid plaques. These images are appliable for prospective qualitative and quantitative three-dimensional analysis due to the z-axis scanning. Moreover, it demonstrated the formation of stable Alcian Blue staining.
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Affiliation(s)
- Olga Nosova
- Institute of Experimental Medicine, St. Petersburg 197376, Russia.
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13
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Polykretis I, Michmizos KP. The role of astrocytes in place cell formation: A computational modeling study. J Comput Neurosci 2022; 50:505-518. [PMID: 35840871 PMCID: PMC9671849 DOI: 10.1007/s10827-022-00828-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 05/20/2022] [Accepted: 07/12/2022] [Indexed: 11/30/2022]
Abstract
Place cells develop spatially-tuned receptive fields during the early stages of novel environment exploration. The generative mechanism underlying these spatially-selective responses remains largely elusive, but has been associated with theta rhythmicity. An important factor implicating the transformation of silent cells to place cells is a spatially-uniform depolarization that is mediated by a persistent sodium current. This neuronal current is modulated by extracellular calcium concentration, which, in turn, is actively controlled by astrocytes. However, there is no established relationship between the neuronal depolarization and astrocytic activity. To consider this link, we designed a bioplausible computational model of a neuronal-astrocytic network, where astrocytes induced the transient emergence of place fields in silent cells, and accelerated the plasticity-induced consolidation of place cells. Interestingly, theta oscillations emerged naturally at the network level, resulting from the astrocytic modulation of subcellular neuronal properties. Our results suggest that astrocytes participate in spatial mapping and exploration, and further highlight the computational roles of these cells in the brain.
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Affiliation(s)
- Ioannis Polykretis
- Computational Brain Lab, Department of Computer Science, Rutgers University, New Brunswick, New Jersey, USA
| | - Konstantinos P Michmizos
- Computational Brain Lab, Department of Computer Science, Rutgers University, New Brunswick, New Jersey, USA.
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14
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Mafuika SN, Naicker T, Harrichandparsad R, Lazarus L. The potential of serum S100 calcium-binding protein B and glial fibrillary acidic protein as biomarkers for traumatic brain injury. TRANSLATIONAL RESEARCH IN ANATOMY 2022. [DOI: 10.1016/j.tria.2022.100228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
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15
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Vizuete AFK, Fróes F, Seady M, Zanotto C, Bobermin LD, Roginski AC, Wajner M, Quincozes-Santos A, Gonçalves CA. Early effects of LPS-induced neuroinflammation on the rat hippocampal glycolytic pathway. J Neuroinflammation 2022; 19:255. [PMID: 36221097 PMCID: PMC9552490 DOI: 10.1186/s12974-022-02612-w] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 09/27/2022] [Indexed: 11/10/2022] Open
Abstract
Neuroinflammation is a common feature during the development of neurological disorders and neurodegenerative diseases, where glial cells, such as microglia and astrocytes, play key roles in the activation and maintenance of inflammatory responses in the central nervous system. Neuroinflammation is now known to involve a neurometabolic shift, in addition to an increase in energy consumption. We used two approaches (in vivo and ex vivo) to evaluate the effects of lipopolysaccharide (LPS)-induced neuroinflammation on neurometabolic reprogramming, and on the modulation of the glycolytic pathway during the neuroinflammatory response. For this, we investigated inflammatory cytokines and receptors in the rat hippocampus, as well as markers of glial reactivity. Mitochondrial respirometry and the glycolytic pathway were evaluated by multiple parameters, including enzymatic activity, gene expression and regulation by protein kinases. Metabolic (e.g., metformin, 3PO, oxamic acid, fluorocitrate) and inflammatory (e.g., minocycline, MCC950, arundic acid) inhibitors were used in ex vivo hippocampal slices. The induction of early inflammatory changes by LPS (both in vivo and ex vivo) enhanced glycolytic parameters, such as glucose uptake, PFK1 activity and lactate release. This increased glucose consumption was independent of the energy expenditure for glutamate uptake, which was in fact diverted for the maintenance of the immune response. Accordingly, inhibitors of the glycolytic pathway and Krebs cycle reverted neuroinflammation (reducing IL-1β and S100B) and the changes in glycolytic parameters induced by LPS in acute hippocampal slices. Moreover, the inhibition of S100B, a protein predominantly synthesized and secreted by astrocytes, inhibition of microglia activation and abrogation of NLRP3 inflammasome assembly confirmed the role of neuroinflammation in the upregulation of glycolysis in the hippocampus. Our data indicate a neurometabolic glycolytic shift, induced by inflammatory activation, as well as a central and integrative role of astrocytes, and suggest that interference in the control of neurometabolism may be a promising strategy for downregulating neuroinflammation and consequently for diminishing negative neurological outcomes.
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Affiliation(s)
- Adriana Fernanda K Vizuete
- Laboratory of Calcium-Binding Proteins in the CNS, Department of Biochemistry, Institute of Basic Health Sciences, Universidade Federal Do Rio Grande Do Sul (UFRGS), Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, Zip Code: 90035-003, Brazil. .,Pos Graduate Program in Biochemistry, Institute of Basic Health Sciences, UFRGS, Porto Alegre, RS, Brazil.
| | - Fernanda Fróes
- Laboratory of Calcium-Binding Proteins in the CNS, Department of Biochemistry, Institute of Basic Health Sciences, Universidade Federal Do Rio Grande Do Sul (UFRGS), Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, Zip Code: 90035-003, Brazil.,Pos Graduate Program in Biochemistry, Institute of Basic Health Sciences, UFRGS, Porto Alegre, RS, Brazil
| | - Marina Seady
- Laboratory of Calcium-Binding Proteins in the CNS, Department of Biochemistry, Institute of Basic Health Sciences, Universidade Federal Do Rio Grande Do Sul (UFRGS), Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, Zip Code: 90035-003, Brazil.,Pos Graduate Program in Biochemistry, Institute of Basic Health Sciences, UFRGS, Porto Alegre, RS, Brazil
| | - Caroline Zanotto
- Laboratory of Calcium-Binding Proteins in the CNS, Department of Biochemistry, Institute of Basic Health Sciences, Universidade Federal Do Rio Grande Do Sul (UFRGS), Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, Zip Code: 90035-003, Brazil.,Pos Graduate Program in Biochemistry, Institute of Basic Health Sciences, UFRGS, Porto Alegre, RS, Brazil
| | - Larissa Daniele Bobermin
- Pos Graduate Program in Biochemistry, Institute of Basic Health Sciences, UFRGS, Porto Alegre, RS, Brazil
| | - Ana Cristina Roginski
- Pos Graduate Program in Biochemistry, Institute of Basic Health Sciences, UFRGS, Porto Alegre, RS, Brazil
| | - Moacir Wajner
- Pos Graduate Program in Biochemistry, Institute of Basic Health Sciences, UFRGS, Porto Alegre, RS, Brazil.,Department of Biochemistry, Institute of Basic Health Sciences, UFRGS, Porto Alegre, RS, Brazil.,Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil
| | - André Quincozes-Santos
- Pos Graduate Program in Biochemistry, Institute of Basic Health Sciences, UFRGS, Porto Alegre, RS, Brazil.,Department of Biochemistry, Institute of Basic Health Sciences, UFRGS, Porto Alegre, RS, Brazil
| | - Carlos Alberto Gonçalves
- Laboratory of Calcium-Binding Proteins in the CNS, Department of Biochemistry, Institute of Basic Health Sciences, Universidade Federal Do Rio Grande Do Sul (UFRGS), Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, Zip Code: 90035-003, Brazil.,Pos Graduate Program in Biochemistry, Institute of Basic Health Sciences, UFRGS, Porto Alegre, RS, Brazil.,Department of Biochemistry, Institute of Basic Health Sciences, UFRGS, Porto Alegre, RS, Brazil
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16
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The S100 Protein Family as Players and Therapeutic Targets in Pulmonary Diseases. Pulm Med 2021; 2021:5488591. [PMID: 34239729 PMCID: PMC8214497 DOI: 10.1155/2021/5488591] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Accepted: 05/27/2021] [Indexed: 02/07/2023] Open
Abstract
The S100 protein family consists of over 20 members in humans that are involved in many intracellular and extracellular processes, including proliferation, differentiation, apoptosis, Ca2+ homeostasis, energy metabolism, inflammation, tissue repair, and migration/invasion. Although there are structural similarities between each member, they are not functionally interchangeable. The S100 proteins function both as intracellular Ca2+ sensors and as extracellular factors. Dysregulated responses of multiple members of the S100 family are observed in several diseases, including the lungs (asthma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, cystic fibrosis, pulmonary hypertension, and lung cancer). To this degree, extensive research was undertaken to identify their roles in pulmonary disease pathogenesis and the identification of inhibitors for several S100 family members that have progressed to clinical trials in patients for nonpulmonary conditions. This review outlines the potential role of each S100 protein in pulmonary diseases, details the possible mechanisms observed in diseases, and outlines potential therapeutic strategies for treatment.
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Vizuete AFK, de Lima Cordeiro J, Neves JD, Seady M, Grun LK, Barbé-Tuana FM, Leite MC, Netto CA, Gonçalves CA. Arundic acid (ONO-2526) inhibits stimulated-S100B secretion in inflammatory conditions. Neurosci Lett 2021; 751:135776. [PMID: 33727126 DOI: 10.1016/j.neulet.2021.135776] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 02/21/2021] [Accepted: 02/23/2021] [Indexed: 11/18/2022]
Abstract
Astrocytes respond to injury by modifying the expression profile of several proteins, including the S100 calcium-binding protein B (S100B), assumed to be a marker as well as a mediator of brain injury. AA is an inhibitor of S100B synthesis and plays a protective role in different models of brain injury, as decreases in S100B expression cause decreases in extracellular S100B. However, S100B mRNA expression, S100B protein content and S100B secretion do not always occur in association; as such, we herein investigated the effect of AA on S100B secretion, using different approaches with three stimulating conditions for S100B secretion, namely, low potassium medium, TNF-α (in hippocampal slices) and LPS exposure (in astrocyte cultures). Our data indicate that AA directly affects S100B secretion, indicating that the extracellular levels of this astroglial protein may be mediating the action of this compound. More importantly, AA had no effect on basal S100B secretion, but inhibited stimulated S100B secretion (stimulated either by the proinflammatory molecules, LPS or TNF-α, or by low potassium medium). Data from hippocampal slices that were directly exposed to AA, or from animals that received the acid by intracerebroventricular infusion, contribute to understanding its neuroprotective effect.
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Affiliation(s)
| | - Juliana de Lima Cordeiro
- Graduate Program in Neuroscience, Institute of Basic Health Sciences, UFRGS, Porto Alegre, Brazil
| | - Juliana Dalibor Neves
- Graduate Program in Neuroscience, Institute of Basic Health Sciences, UFRGS, Porto Alegre, Brazil
| | - Marina Seady
- Graduate Program in Biochemistry, Institute of Basic Health Sciences, UFRGS, Porto Alegre, Brazil
| | - Lucas Kich Grun
- Graduate Program in Neuroscience, Institute of Basic Health Sciences, UFRGS, Porto Alegre, Brazil
| | | | - Marina Concli Leite
- Graduate Program in Biochemistry, Institute of Basic Health Sciences, UFRGS, Porto Alegre, Brazil
| | - Carlos Alexandre Netto
- Graduate Program in Biochemistry, Institute of Basic Health Sciences, UFRGS, Porto Alegre, Brazil; Graduate Program in Neuroscience, Institute of Basic Health Sciences, UFRGS, Porto Alegre, Brazil
| | - Carlos-Alberto Gonçalves
- Graduate Program in Biochemistry, Institute of Basic Health Sciences, UFRGS, Porto Alegre, Brazil; Graduate Program in Neuroscience, Institute of Basic Health Sciences, UFRGS, Porto Alegre, Brazil
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18
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Zika virus exposure affects neuron-glia communication in the hippocampal slices of adult rats. Sci Rep 2020; 10:21604. [PMID: 33303883 PMCID: PMC7729948 DOI: 10.1038/s41598-020-78735-y] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Accepted: 11/13/2020] [Indexed: 02/06/2023] Open
Abstract
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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Sreejit G, Flynn MC, Patil M, Krishnamurthy P, Murphy AJ, Nagareddy PR. S100 family proteins in inflammation and beyond. Adv Clin Chem 2020; 98:173-231. [PMID: 32564786 DOI: 10.1016/bs.acc.2020.02.006] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The S100 family proteins possess a variety of intracellular and extracellular functions. They interact with multiple receptors and signal transducers to regulate pathways that govern inflammation, cell differentiation, proliferation, energy metabolism, apoptosis, calcium homeostasis, cell cytoskeleton and microbial resistance. S100 proteins are also emerging as novel diagnostic markers for identifying and monitoring various diseases. Strategies aimed at targeting S100-mediated signaling pathways hold a great potential in developing novel therapeutics for multiple diseases. In this chapter, we aim to summarize the current knowledge about the role of S100 family proteins in health and disease with a major focus on their role in inflammatory conditions.
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Affiliation(s)
| | - Michelle C Flynn
- Division of Immunometabolism, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
| | - Mallikarjun Patil
- Department of Biomedical Engineering, Schools of Medicine and Engineering, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Prasanna Krishnamurthy
- Department of Biomedical Engineering, Schools of Medicine and Engineering, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Andrew J Murphy
- Division of Immunometabolism, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia; Department of Immunology, Monash University, Melbourne, VIC, Australia
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20
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Rodrigues L, Wartchow KM, Suardi LZ, Federhen BC, Selistre NG, Gonçalves CA. Streptozotocin causes acute responses on hippocampal S100B and BDNF proteins linked to glucose metabolism alterations. Neurochem Int 2019; 128:85-93. [PMID: 31009650 DOI: 10.1016/j.neuint.2019.04.013] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Revised: 04/12/2019] [Accepted: 04/19/2019] [Indexed: 02/07/2023]
Abstract
Streptozotocin (STZ) is a glucosamine-nitrosourea commonly used to induce long-lasting models of diabetes mellitus and Alzheimer's disease. Direct toxicity of STZ on the pancreas and kidneys has been well characterized, but the acute effect of this compound on brain tissue has received less attention. Herein, we investigated the acute and direct toxicity of STZ on fresh hippocampal slices, measuring changes in BDNF and S100B secretion (two widely-used peripheral markers of brain injury), as well as glucose metabolism. Moreover, we investigated in vivo changes of these proteins in the hippocampus, 48 h after intracerebroventricular STZ administration. Transverse hippocampal slices (0.3 mm thick) were obtained using a McIlwain tissue chopper and target proteins were measured in the incubation medium by ELISA. STZ decreased S100B secretion, but increased BDNF secretion as well as causing impairment in glucose uptake in hippocampal slices, measured using [3H] deoxy-glucose. Glucose levels and glucose metabolism differentially modulated S100B secretion in astrocytes and BDNF secretion in neurons, when evaluated under specific conditions (high-potassium medium, presence of tetrodotoxin or fluorocitrate). Moreover, at 48 h after intracerebroventricular STZ, hippocampal BDNF content, but not S100B, was reduced. Our results indicate that BDNF and S100B are useful and sensitive markers of glucose metabolism disturbance and reinforce these proteins as general acute markers of brain disorders.
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Affiliation(s)
- Leticia Rodrigues
- Department of Biochemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
| | - Krista Minéia Wartchow
- Department of Biochemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Lucas Zingano Suardi
- Department of Biochemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
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21
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Vizuete AFK, Hansen F, Da Ré C, Leal MB, Galland F, Concli Leite M, Gonçalves CA. GABAA Modulation of S100B Secretion in Acute Hippocampal Slices and Astrocyte Cultures. Neurochem Res 2018; 44:301-311. [DOI: 10.1007/s11064-018-2675-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Revised: 10/05/2018] [Accepted: 10/30/2018] [Indexed: 10/28/2022]
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Zanotto C, Hansen F, Galland F, Batassini C, Federhen BC, da Silva VF, Leite MC, Nardin P, Gonçalves CA. Glutamatergic Alterations in STZ-Induced Diabetic Rats Are Reversed by Exendin-4. Mol Neurobiol 2018; 56:3538-3551. [PMID: 30145785 DOI: 10.1007/s12035-018-1320-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2017] [Accepted: 08/14/2018] [Indexed: 01/25/2023]
Abstract
Diabetes mellitus is a metabolic disorder that results in glucotoxicity and the formation of advanced glycated end products (AGEs), which mediate several systemic adverse effects, particularly in the brain tissue. Alterations in glutamatergic neurotransmission and cognitive impairment have been reported in DM. Exendin-4 (EX-4), an analogue of glucagon-like peptide-1 (GLP-1), appears to have beneficial effects on cognition in rats with chronic hyperglycemia. Herein, we investigated the ability of EX-4 to reverse changes in AGE content and glutamatergic transmission in an animal model of DM looking principally at glutamate uptake and GluN1 subunit content of the N-methyl-D-aspartate (NMDA) receptor. Additionally, we evaluated the effects of EX-4 on in vitro models and the signaling pathway involved in these effects. We found a decrease in glutamate uptake and GluN1 content in the hippocampus of diabetic rats; EX-4 was able to revert these parameters, but had no effect on the other parameters evaluated (glycemia, C-peptide, AGE levels, RAGE, and glyoxalase 1). EX-4 abrogated the decrease in glutamate uptake and GluN1 content caused by methylglyoxal (MG) in hippocampal slices, in addition to leading to an increase in glutamate uptake in astrocyte culture cells and hippocampal slices under basal conditions. The effect of EX-4 on glutamate uptake was mediated by the phosphatidylinositide 3-kinases (PI3K) signaling pathway, which could explain the protective effect of EX-4 in the brain tissue, since PI3K is involved in cell metabolism, inhibition of apoptosis, and reduces inflammatory responses. These results suggest that EX-4 could be used as an adjuvant treatment for brain impairment associated with excitotoxicity.
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Affiliation(s)
- Caroline Zanotto
- Department of Biochemistry, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.
| | - Fernanda Hansen
- Department of Nutrition, Federal University of Santa Catarina, Florianópolis, Brazil
| | - Fabiana Galland
- Department of Biochemistry, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
| | - Cristiane Batassini
- Department of Biological Sciences, Integrated Regional University of Alto Uruguai and Missões, Frederico Westphalen, Brazil
| | | | | | - Marina Concli Leite
- Department of Biochemistry, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
| | - Patrícia Nardin
- Department of Biochemistry, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
| | - Carlos-Alberto Gonçalves
- Department of Biochemistry, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
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Vizuete AFK, Hansen F, Negri E, Leite MC, de Oliveira DL, Gonçalves CA. Effects of dexamethasone on the Li-pilocarpine model of epilepsy: protection against hippocampal inflammation and astrogliosis. J Neuroinflammation 2018; 15:68. [PMID: 29506554 PMCID: PMC5839012 DOI: 10.1186/s12974-018-1109-5] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2017] [Accepted: 02/28/2018] [Indexed: 11/25/2022] Open
Abstract
Background Temporal lobe epilepsy (TLE) is the most common form of partial epilepsy and is accompanied, in one third of cases, by resistance to antiepileptic drugs (AED). Most AED target neuronal activity modulated by ionic channels, and the steroid sensitivity of these channels has supported the use of corticosteroids as adjunctives to AED. Assuming the importance of astrocytes in neuronal activity, we investigated inflammatory and astroglial markers in the hippocampus, a key structure affected in TLE and in the Li-pilocarpine model of epilepsy. Methods Initially, hippocampal slices were obtained from sham rats and rats subjected to the Li-pilocarpine model of epilepsy, at 1, 14, and 56 days after status epilepticus (SE), which correspond to the acute, silent, and chronic phases. Dexamethasone was added to the incubation medium to evaluate the secretion of S100B, an astrocyte-derived protein widely used as a marker of brain injury. In the second set of experiments, we evaluated the in vivo effect of dexamethasone, administrated at 2 days after SE, on hippocampal inflammatory (COX-1/2, PGE2, and cytokines) and astroglial parameters: GFAP, S100B, glutamine synthetase (GS) and water (AQP-4), and K+ (Kir 4.1) channels. Results Basal S100B secretion and S100B secretion in high-K+ medium did not differ at 1, 14, and 56 days for the hippocampal slices from epileptic rats, in contrast to sham animal slices, where high-K+ medium decreased S100B secretion. Dexamethasone addition to the incubation medium per se induced a decrease in S100B secretion in sham and epileptic rats (1 and 56 days after SE induction). Following in vivo dexamethasone administration, inflammatory improvements were observed, astrogliosis was prevented (based on GFAP and S100B content), and astroglial dysfunction was partially abrogated (based on Kir 4.1 protein and GSH content). The GS decrease was not prevented by dexamethasone, and AQP-4 was not altered in this epileptic model. Conclusions Changes in astroglial parameters emphasize the importance of these cells for understanding alterations and mechanisms of epileptic disorders in this model. In vivo dexamethasone administration prevented most of the parameters analyzed, reinforcing the importance of anti-inflammatory steroid therapy in the Li-pilocarpine model and possibly in other epileptic conditions in which neuroinflammation is present. Electronic supplementary material The online version of this article (10.1186/s12974-018-1109-5) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Adriana Fernanda K Vizuete
- Department of Biochemistry, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil.
| | - Fernanda Hansen
- Department of Biochemistry, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil
| | - Elisa Negri
- Department of Biochemistry, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil
| | - Marina Concli Leite
- Department of Biochemistry, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil
| | - Diogo Losch de Oliveira
- Department of Biochemistry, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil
| | - Carlos-Alberto Gonçalves
- Department of Biochemistry, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil
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Galland F, Negri E, Da Ré C, Fróes F, Strapazzon L, Guerra MC, Tortorelli LS, Gonçalves CA, Leite MC. Hyperammonemia compromises glutamate metabolism and reduces BDNF in the rat hippocampus. Neurotoxicology 2017; 62:46-55. [PMID: 28506823 DOI: 10.1016/j.neuro.2017.05.006] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2017] [Revised: 03/31/2017] [Accepted: 05/11/2017] [Indexed: 12/31/2022]
Abstract
Ammonia is putatively the major toxin associated with hepatic encephalopathy (HE), a neuropsychiatric manifestation that results in cognitive impairment, poor concentration and psychomotor alterations. The hippocampus, a brain region involved in cognitive impairment and depressive behavior, has been studied less than neocortical regions. Herein, we investigated hippocampal astrocyte parameters in a hyperammonemic model without hepatic lesion and in acute hippocampal slices exposed to ammonia. We also measured hippocampal BDNF, a neurotrophin commonly related to synaptic plasticity and cognitive deficit, and peripheral S100B protein, used as a marker for brain damage. Hyperammonemia directly impaired astrocyte function, inducing a decrease in glutamate uptake and in the activity of glutamine synthetase, in turn altering the glutamine-glutamate cycle, glutamatergic neurotransmission and ammonia detoxification itself. Hippocampal BDNF was reduced in hyperammonemic rats via a mechanism that may involve astrocyte production, since the same effect was observed in astrocyte cultures exposed to ammonia. Ammonia induced a significant increase in S100B secretion in cultured astrocytes; however, no significant changes were observed in the serum or in cerebrospinal fluid. Data demonstrating hippocampal vulnerability to ammonia toxicity, particularly due to reduced glutamate uptake activity and BDNF content, contribute to our understanding of the neuropsychiatric alterations in HE.
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Affiliation(s)
- Fabiana Galland
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
| | - Elisa Negri
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
| | - Carollina Da Ré
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
| | - Fernanda Fróes
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
| | - Liliane Strapazzon
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
| | - Maria Cristina Guerra
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
| | - Lucas Silva Tortorelli
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
| | - Carlos-Alberto Gonçalves
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
| | - Marina Concli Leite
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
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da Cunha Franceschi R, Nardin P, Machado CV, Tortorelli LS, Martinez-Pereira MA, Zanotto C, Gonçalves CA, Zancan DM. Enteric glial reactivity to systemic LPS administration: Changes in GFAP and S100B protein. Neurosci Res 2017; 119:15-23. [PMID: 28063977 DOI: 10.1016/j.neures.2016.12.005] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Revised: 11/29/2016] [Accepted: 12/27/2016] [Indexed: 02/07/2023]
Abstract
Lipopolysaccharide (LPS) is used to induce inflammation and promotes nervous system activation. Different regions of the brain present heterogeneous glial responses; thus, in order to verify whether systemic LPS-induced inflammation affects the enteric glia differently across the intestinal segments, we evaluated the expressions of two glial activity markers, GFAP and S100B protein, in different intestine segments, at 1h, 24h and 7days after acute systemic LPS administration (0.25 or 2.5mgkg-1) in rats. Histological inflammatory analysis indicated that the cecum was most affected when compared to the duodenum and proximal colon at the highest doses of LPS. LPS induced an increased S100B content after 24h in all three regions, which decreased at 7days after the highest dose in all regions. Moreover, at 24h, this dose of LPS increased ex-vivo S100B secretion only in the cecum. The highest dose of LPS also increased GFAP in all regions at 24h, but earlier in the cecum, where LPS-induced enteric S100B and GFAP alterations were dependent on dose, time and intestine region. No associated changes in serum S100B were observed. Our results indicate heterogeneous enteric glial responses to inflammatory insult, as observed in distinct brain areas.
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Affiliation(s)
- Raphaela da Cunha Franceschi
- Laboratory of Comparative Neurobiology, Department of Physiology, Institute of Basic Health Sciences (ICBS), Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Brazil; Graduate Program in Neuroscience, ICBS, UFRGS, Brazil
| | - Patrícia Nardin
- Laboratory of Calcium-Binding Proteins, Department of Biochemistry, ICBS, UFRGS, Brazil
| | - Clivia Valle Machado
- Laboratory of Comparative Neurobiology, Department of Physiology, Institute of Basic Health Sciences (ICBS), Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Brazil; Graduate Program in Neuroscience, ICBS, UFRGS, Brazil
| | | | | | - Caroline Zanotto
- Laboratory of Calcium-Binding Proteins, Department of Biochemistry, ICBS, UFRGS, Brazil
| | - Carlos-Alberto Gonçalves
- Graduate Program in Neuroscience, ICBS, UFRGS, Brazil; Laboratory of Calcium-Binding Proteins, Department of Biochemistry, ICBS, UFRGS, Brazil.
| | - Denise Maria Zancan
- Laboratory of Comparative Neurobiology, Department of Physiology, Institute of Basic Health Sciences (ICBS), Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Brazil; Graduate Program in Neuroscience, ICBS, UFRGS, Brazil
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de Senna PN, Bagatini PB, Galland F, Bobermin L, do Nascimento PS, Nardin P, Tramontina AC, Gonçalves CA, Achaval M, Xavier LL. Physical exercise reverses spatial memory deficit and induces hippocampal astrocyte plasticity in diabetic rats. Brain Res 2017; 1655:242-251. [PMID: 27984020 DOI: 10.1016/j.brainres.2016.10.024] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2016] [Revised: 10/11/2016] [Accepted: 10/26/2016] [Indexed: 12/26/2022]
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Intracerebroventricular administration of okadaic acid induces hippocampal glucose uptake dysfunction and tau phosphorylation. Brain Res Bull 2016; 124:136-43. [DOI: 10.1016/j.brainresbull.2016.04.014] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2016] [Revised: 04/19/2016] [Accepted: 04/20/2016] [Indexed: 01/31/2023]
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Hansen F, Pandolfo P, Galland F, Torres FV, Dutra MF, Batassini C, Guerra MC, Leite MC, Gonçalves CA. Methylglyoxal can mediate behavioral and neurochemical alterations in rat brain. Physiol Behav 2016; 164:93-101. [PMID: 27235733 DOI: 10.1016/j.physbeh.2016.05.046] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2016] [Revised: 05/20/2016] [Accepted: 05/24/2016] [Indexed: 12/17/2022]
Abstract
Diabetes is associated with loss of cognitive function and increased risk for Alzheimer's disease (AD). Advanced glycation end products (AGEs) are elevated in diabetes and AD and have been suggested to act as mediators of the cognitive decline observed in these pathologies. Methylglyoxal (MG) is an extremely reactive carbonyl compound that propagates glycation reactions and is, therefore, able to generate AGEs. Herein, we evaluated persistent behavioral and biochemical parameters to explore the hypothesis that elevated exogenous MG concentrations, induced by intracerebroventricular (ICV) infusion, lead to cognitive decline in Wistar rats. A high and sustained administration of MG (3μmol/μL; subdivided into 6days) was found to decrease the recognition index of rats, as evaluated by the object-recognition test. However, MG was unable to impair learning-memory processes, as shown by the habituation in the open field (OF) and Y-maze tasks. Moreover, a single high dose of MG induced persistent alterations in anxiety-related behavior, diminishing the anxiety-like parameters evaluated in the OF test. Importantly, MG did not alter locomotion behavior in the different tasks performed. Our biochemical findings support the hypothesis that MG induces persistent alterations in the hippocampus, but not in the cortex, related to glyoxalase 1 activity, AGEs content and glutamate uptake. Glial fibrillary acidic protein and S100B content, as well as S100B secretion (astroglial-related parameters of brain injury), were not altered by ICV MG administration. Taken together, our data suggest that MG interferes directly in brain function and that the time and the levels of exogenous MG determine the different features that can be seen in diabetic patients.
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Affiliation(s)
- Fernanda Hansen
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, 90035-003 Porto Alegre, RS, Brazil.
| | - Pablo Pandolfo
- Departamento de Neurobiologia, Instituto de Biologia, Universidade Federal Fluminense, 24020-141 Niterói, RJ, Brazil
| | - Fabiana Galland
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, 90035-003 Porto Alegre, RS, Brazil
| | - Felipe Vasconcelos Torres
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, 90035-003 Porto Alegre, RS, Brazil
| | - Márcio Ferreira Dutra
- Departamento de Biologia Celular, Embriologia e Genética, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Campus Trindade, 88040-970 Florianópolis, SC, Brazil
| | - Cristiane Batassini
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, 90035-003 Porto Alegre, RS, Brazil
| | - Maria Cristina Guerra
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, 90035-003 Porto Alegre, RS, Brazil
| | - Marina Concli Leite
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, 90035-003 Porto Alegre, RS, Brazil
| | - Carlos-Alberto Gonçalves
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, 90035-003 Porto Alegre, RS, Brazil
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Nardin P, Zanotto C, Hansen F, Batassini C, Gasparin MS, Sesterheim P, Gonçalves CA. Peripheral Levels of AGEs and Astrocyte Alterations in the Hippocampus of STZ-Diabetic Rats. Neurochem Res 2016; 41:2006-16. [PMID: 27084774 DOI: 10.1007/s11064-016-1912-2] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2016] [Revised: 04/05/2016] [Accepted: 04/06/2016] [Indexed: 12/25/2022]
Abstract
Diabetic patients and streptozotocin (STZ)-induced diabetes mellitus (DM) models exhibit signals of brain dysfunction, evidenced by neuronal damage and memory impairment. Astrocytes surrounding capillaries and synapses modulate many brain activities that are connected to neuronal function, such as nutrient flux and glutamatergic neurotransmission. As such, cognitive changes observed in diabetic patients and experimental models could be related to astroglial alterations. Herein, we investigate specific astrocyte changes in the rat hippocampus in a model of DM induced by STZ, particularly looking at glial fibrillary acidic protein (GFAP), S100B protein and glutamate uptake, as well as the content of advanced glycated end products (AGEs) in serum and cerebrospinal fluid (CSF), as a consequence of elevated hyperglycemia and the content of receptor for AGEs in the hippocampus. We found clear peripheral alterations, including hyperglycemia, low levels of proinsulin C-peptide, elevated levels of AGEs in serum and CSF, as well as an increase in RAGE in hippocampal tissue. We found specific astroglial abnormalities in this brain region, such as reduced S100B content, reduced glutamate uptake and increased S100B secretion, which were not accompanied by changes in GFAP. We also observed an increase in the glucose transporter, GLUT-1. All these changes may result from RAGE-induced inflammation; these astroglial alterations together with the reduced content of GluN1, a subunit of the NMDA receptor, in the hippocampus may be associated with the impairment of glutamatergic communication in diabetic rats. These findings contribute to understanding the cognitive deficits in diabetic patients and experimental models.
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Affiliation(s)
- Patrícia Nardin
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil.
| | - Caroline Zanotto
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil
| | - Fernanda Hansen
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil
| | - Cristiane Batassini
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil
| | - Manuela Sangalli Gasparin
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil
| | - Patrícia Sesterheim
- Centro de Desenvolvimento Científico e Tecnológico, Fundação Estadual de Produção e Pesquisa em Saúde, Porto Alegre, Brazil
| | - Carlos-Alberto Gonçalves
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil
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Insulin Stimulates S100B Secretion and These Proteins Antagonistically Modulate Brain Glucose Metabolism. Neurochem Res 2016; 41:1420-9. [PMID: 26875731 DOI: 10.1007/s11064-016-1851-y] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2015] [Revised: 01/21/2016] [Accepted: 01/26/2016] [Indexed: 12/24/2022]
Abstract
Brain metabolism is highly dependent on glucose, which is derived from the blood circulation and metabolized by the astrocytes and other neural cells via several pathways. Glucose uptake in the brain does not involve insulin-dependent glucose transporters; however, this hormone affects the glucose influx to the brain. Changes in cerebrospinal fluid levels of S100B (an astrocyte-derived protein) have been associated with alterations in glucose metabolism; however, there is no evidence whether insulin modulates glucose metabolism and S100B secretion. Herein, we investigated the effect of S100B on glucose metabolism, measuring D-(3)H-glucose incorporation in two preparations, C6 glioma cells and acute hippocampal slices, and we also investigated the effect of insulin on S100B secretion. Our results showed that: (a) S100B at physiological levels decreases glucose uptake, through the multiligand receptor RAGE and mitogen-activated protein kinase/ERK signaling, and (b) insulin stimulated S100B secretion via PI3K signaling. Our findings indicate the existence of insulin-S100B modulation of glucose utilization in the brain tissue, and may improve our understanding of glucose metabolism in several conditions such as ketosis, streptozotocin-induced dementia and pharmacological exposure to antipsychotics, situations that lead to changes in insulin signaling and extracellular levels of S100B.
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de Souza DF, Wartchow KM, Lunardi PS, Brolese G, Tortorelli LS, Batassini C, Biasibetti R, Gonçalves CA. Changes in Astroglial Markers in a Maternal Immune Activation Model of Schizophrenia in Wistar Rats are Dependent on Sex. Front Cell Neurosci 2015; 9:489. [PMID: 26733814 PMCID: PMC4689875 DOI: 10.3389/fncel.2015.00489] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2015] [Accepted: 12/03/2015] [Indexed: 01/26/2023] Open
Abstract
Data from epidemiological studies suggest that prenatal exposure to bacterial and viral infection is an important environmental risk factor for schizophrenia. The maternal immune activation (MIA) animal model is used to study how an insult directed at the maternal host can have adverse effects on the fetus, leading to behavioral and neurochemical changes later in life. We evaluated whether the administration of LPS to rat dams during late pregnancy affects astroglial markers (S100B and GFAP) of the offspring in later life. The frontal cortex and hippocampus were compared in male and female offspring on postnatal days (PND) 30 and 60. The S100B protein exhibited an age-dependent pattern of expression, being increased in the frontal cortex and hippocampus of the MIA group at PND 60, while at PND 30, male rats presented increased S100B levels only in the frontal cortex. Considering that S100B secretion is reduced by elevation of glutamate levels, we may hypothesize that this early increment in frontal cortex tissue of males is associated with elevated extracellular levels of glutamate and glutamatergic hypofunction, an alteration commonly associated with SCZ pathology. Moreover, we also found augmented GFAP in the frontal cortex of the LPS group at PND 30, but not in the hippocampus. Taken together data indicate that astroglial changes induced by MIA are dependent on sex and brain region and that these changes could reflect astroglial dysfunction. Such alterations may contribute to our understanding of the abnormal neuronal connectivity and developmental aspects of SCZ and other psychiatric disorders.
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Affiliation(s)
- Daniela F de Souza
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul Porto Alegre, Brazil
| | - Krista M Wartchow
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul Porto Alegre, Brazil
| | - Paula S Lunardi
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul Porto Alegre, Brazil
| | - Giovana Brolese
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul Porto Alegre, Brazil
| | - Lucas S Tortorelli
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul Porto Alegre, Brazil
| | - Cristiane Batassini
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul Porto Alegre, Brazil
| | - Regina Biasibetti
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul Porto Alegre, Brazil
| | - Carlos-Alberto Gonçalves
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul Porto Alegre, Brazil
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Hansen F, Battú CE, Dutra MF, Galland F, Lirio F, Broetto N, Nardin P, Gonçalves CA. Methylglyoxal and carboxyethyllysine reduce glutamate uptake and S100B secretion in the hippocampus independently of RAGE activation. Amino Acids 2015; 48:375-85. [PMID: 26347375 DOI: 10.1007/s00726-015-2091-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2015] [Accepted: 08/28/2015] [Indexed: 01/29/2023]
Abstract
Diabetes is a metabolic disease characterized by high fasting-glucose levels. Diabetic complications have been associated with hyperglycemia and high levels of reactive compounds, such as methylglyoxal (MG) and advanced glycation endproducts (AGEs) formation derived from glucose. Diabetic patients have a higher risk of developing neurodegenerative diseases, such as Alzheimer's disease or Parkinson's disease. Herein, we examined the effect of high glucose, MG and carboxyethyllysine (CEL), a MG-derived AGE of lysine, on oxidative, metabolic and astrocyte-specific parameters in acute hippocampal slices, and investigated some of the mechanisms that could mediate these effects. Glucose, MG and CEL did not alter reactive oxygen species (ROS) formation, glucose uptake or glutamine synthetase activity. However, glutamate uptake and S100B secretion were decreased after MG and CEL exposure. RAGE activation and glycation reactions, examined by aminoguanidine and L-lysine co-incubation, did not mediate these changes. Acute MG and CEL exposure, but not glucose, were able to induce similar effects on hippocampal slices, suggesting that conditions of high glucose concentrations are primarily toxic by elevating the rates of these glycation compounds, such as MG, and by generation of protein cross-links. Alterations in the secretion of S100B and the glutamatergic activity mediated by MG and AGEs can contribute to the brain dysfunction observed in diabetic patients.
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Affiliation(s)
- Fernanda Hansen
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil
| | - Cíntia Eickhoff Battú
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil
| | - Márcio Ferreira Dutra
- Departamento de Biologia Celular, Embriologia e Genética, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Campus Trindade, Florianópolis, SC, 88040-970, Brazil
| | - Fabiana Galland
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil
| | - Franciane Lirio
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil
| | - Núbia Broetto
- Programa de Pós-Graduação em Neurociências, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, 90046-900, Brazil
| | - Patrícia Nardin
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil
| | - Carlos-Alberto Gonçalves
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil.
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Brolese G, Lunardi P, de Souza DF, Lopes FM, Leite MC, Gonçalves CA. Pre- and postnatal exposure to moderate levels of ethanol can have long-lasting effects on hippocampal glutamate uptake in adolescent offspring. PLoS One 2015; 10:e0127845. [PMID: 25978644 PMCID: PMC4433332 DOI: 10.1371/journal.pone.0127845] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2015] [Accepted: 04/21/2015] [Indexed: 12/25/2022] Open
Abstract
The developing brain is vulnerable to the effects of ethanol. Glutamate is the main mediator of excitatory signals in the brain and is probably involved in most aspects of normal brain function during development. The aim of this study was to investigate vulnerability to and the impact of ethanol toxicity on glutamate uptake signaling in adolescent rats after moderate pre and postnatal ethanol exposure. Pregnant female rats were divided into three groups and treated only with water (control), non-alcoholic beer (vehicle) or 10% (v/v) beer solution (moderate prenatal alcohol exposure—MPAE). Thirty days after birth, adolescent male offspring were submitted to hippocampal acute slice procedure. We assayed glutamate uptake and measured glutathione content and also quantified glial glutamate transporters (EAAT 1 and EAAT 2). The glutamate system vulnerability was tested with different acute ethanol doses in naïve rats and compared with the MPAE group. We also performed a (lipopolysaccharide-challenge (LPS-challenge) with all groups to test the glutamate uptake response after an insult. The MPAE group presented a decrease in glutamate uptake corroborating a decrease in glutathione (GSH) content. The reduction in GSH content suggests oxidative damage after acute ethanol exposure. The glial glutamate transporters were also altered after prenatal ethanol treatment, suggesting a disturbance in glutamate signaling. This study indicates that impairment of glutamate uptake can be dose-dependent and the glutamate system has a higher vulnerability to ethanol toxicity after moderate ethanol exposure In utero. The effects of pre- and postnatal ethanol exposure can have long-lasting impacts on the glutamate system in adolescence and potentially into adulthood.
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Affiliation(s)
- Giovana Brolese
- Department of Neuroscience, Basic Science Health Institute, Federal University of Rio Grande do Sul—UFRGS—Porto Alegre, Rio Grande do Sul, Brazil
- * E-mail:
| | - Paula Lunardi
- Department of Biochemistry—Basic Science Health Institute—Federal University of Rio Grande do Sul—UFRGS—Porto Alegre, Rio Grande do Sul, Brazil
| | - Daniela F. de Souza
- Department of Biochemistry—Basic Science Health Institute—Federal University of Rio Grande do Sul—UFRGS—Porto Alegre, Rio Grande do Sul, Brazil
| | - Fernanda M. Lopes
- Department of Neuroscience, Basic Science Health Institute, Federal University of Rio Grande do Sul—UFRGS—Porto Alegre, Rio Grande do Sul, Brazil
| | - Marina C. Leite
- Department of Biochemistry—Basic Science Health Institute—Federal University of Rio Grande do Sul—UFRGS—Porto Alegre, Rio Grande do Sul, Brazil
| | - Carlos-Alberto Gonçalves
- Department of Neuroscience, Basic Science Health Institute, Federal University of Rio Grande do Sul—UFRGS—Porto Alegre, Rio Grande do Sul, Brazil
- Department of Biochemistry—Basic Science Health Institute—Federal University of Rio Grande do Sul—UFRGS—Porto Alegre, Rio Grande do Sul, Brazil
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Moderate prenatal alcohol exposure alters behavior and neuroglial parameters in adolescent rats. Behav Brain Res 2014; 269:175-84. [DOI: 10.1016/j.bbr.2014.04.023] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2013] [Revised: 03/18/2014] [Accepted: 04/14/2014] [Indexed: 11/21/2022]
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Quincozes-Santos A, Bobermin LD, Tramontina AC, Wartchow KM, Tagliari B, Souza DO, Wyse AT, Gonçalves CA. Oxidative stress mediated by NMDA, AMPA/KA channels in acute hippocampal slices: Neuroprotective effect of resveratrol. Toxicol In Vitro 2014; 28:544-51. [DOI: 10.1016/j.tiv.2013.12.021] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2013] [Revised: 12/19/2013] [Accepted: 12/28/2013] [Indexed: 12/19/2022]
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Demircan C, Gül Z, Büyükuysal RL. High glutamate attenuates S100B and LDH outputs from rat cortical slices enhanced by either oxygen-glucose deprivation or menadione. Neurochem Res 2014; 39:1232-44. [PMID: 24710790 DOI: 10.1007/s11064-014-1301-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2013] [Revised: 03/28/2014] [Accepted: 04/01/2014] [Indexed: 12/18/2022]
Abstract
One hour incubation of rat cortical slices in a medium without oxygen and glucose (oxygen-glucose deprivation, OGD) increased S100B release to 6.53 ± 0.3 ng/ml/mg protein from its control value of 3.61 ± 0.2 ng/ml/mg protein. When these slices were then transferred to a medium containing oxygen and glucose (reoxygenation, REO), S100B release rose to 344 % of its control value. REO also caused 192 % increase in lactate dehydrogenase (LDH) leakage. Glutamate added at millimolar concentration into the medium decreased OGD or REO-induced S100B release and REO-induced LDH leakage. Alpha-ketoglutarate, a metabolic product of glutamate, was found to be as effective as glutamate in decreasing the S100B and LDH outputs. Similarly lactate, 2-ketobutyrate and ethyl pyruvate, a lipophilic derivative of pyruvate, also exerted a glutamate-like effect on S100B and LDH outputs. Preincubation with menadione, which produces H2O2 intracellularly, significantly increased S100B and LDH levels in normoxic medium. All drugs tested in the present study, with the exception of pyruvate, showed a complete protection against menadione preincubation. Additionally, each OGD-REO, menadione or H2O2-induced mitochondrial energy impairments determined by 2,3,5-triphenyltetrazolium chloride (TTC) staining and OGD-REO or menadione-induced increases in reactive oxygen substances (ROS) determined by 2,7-dichlorofluorescin diacetate (DCFH-DA) were also recovered by glutamate. Interestingly, H2O2-induced increase in fluorescence intensity derived from DCFH-DA in a slice-free physiological medium was attenuated significantly by glutamate and alpha-keto acids. All these drug actions support the conclusion that high glutamate, such as alpha-ketoglutarate and other keto acids, protects the slices against OGD- and REO-induced S100B and LDH outputs probably by scavenging ROS in addition to its energy substrate metabolite property.
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Affiliation(s)
- Celaleddin Demircan
- Department of Medical Pharmacology, Medical Faculty, Uludağ University, 16059, Bursa, Turkey
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Bobermin LD, Souza DO, Gonçalves CA, Quincozes-Santos A. Lipoic acid protects C6 cells against ammonia exposure through Na+-K+-Cl− co-transporter and PKC pathway. Toxicol In Vitro 2013; 27:2041-8. [DOI: 10.1016/j.tiv.2013.07.006] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2013] [Revised: 07/12/2013] [Accepted: 07/12/2013] [Indexed: 01/09/2023]
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Abstract
The S100 protein family consists of 24 members functionally distributed into three main subgroups: those that only exert intracellular regulatory effects, those with intracellular and extracellular functions and those which mainly exert extracellular regulatory effects. S100 proteins are only expressed in vertebrates and show cell-specific expression patterns. In some instances, a particular S100 protein can be induced in pathological circumstances in a cell type that does not express it in normal physiological conditions. Within cells, S100 proteins are involved in aspects of regulation of proliferation, differentiation, apoptosis, Ca2+ homeostasis, energy metabolism, inflammation and migration/invasion through interactions with a variety of target proteins including enzymes, cytoskeletal subunits, receptors, transcription factors and nucleic acids. Some S100 proteins are secreted or released and regulate cell functions in an autocrine and paracrine manner via activation of surface receptors (e.g. the receptor for advanced glycation end-products and toll-like receptor 4), G-protein-coupled receptors, scavenger receptors, or heparan sulfate proteoglycans and N-glycans. Extracellular S100A4 and S100B also interact with epidermal growth factor and basic fibroblast growth factor, respectively, thereby enhancing the activity of the corresponding receptors. Thus, extracellular S100 proteins exert regulatory activities on monocytes/macrophages/microglia, neutrophils, lymphocytes, mast cells, articular chondrocytes, endothelial and vascular smooth muscle cells, neurons, astrocytes, Schwann cells, epithelial cells, myoblasts and cardiomyocytes, thereby participating in innate and adaptive immune responses, cell migration and chemotaxis, tissue development and repair, and leukocyte and tumor cell invasion.
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Affiliation(s)
- R Donato
- Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Via del Giochetto, 06122 Perugia, Italy.
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Lunardi P, Nardin P, Guerra MC, Abib R, Leite MC, Gonçalves CA. Huperzine A, but not tacrine, stimulates S100B secretion in astrocyte cultures. Life Sci 2013; 92:701-7. [DOI: 10.1016/j.lfs.2013.01.029] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2012] [Revised: 01/11/2013] [Accepted: 01/25/2013] [Indexed: 01/09/2023]
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Sorci G, Riuzzi F, Arcuri C, Tubaro C, Bianchi R, Giambanco I, Donato R. S100B protein in tissue development, repair and regeneration. World J Biol Chem 2013; 4:1-12. [PMID: 23580916 PMCID: PMC3622753 DOI: 10.4331/wjbc.v4.i1.1] [Citation(s) in RCA: 77] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2012] [Accepted: 03/01/2013] [Indexed: 02/05/2023] Open
Abstract
The Ca2+-binding protein of the EF-hand type, S100B, exerts both intracellular and extracellular regulatory activities. As an intracellular regulator, S100B is involved in the regulation of energy metabolism, transcription, protein phosphorylation, cell proliferation, survival, differentiation and motility, and Ca2+ homeostasis, by interacting with a wide array of proteins (i.e., enzymes, enzyme substrates, cytoskeletal subunits, scaffold/adaptor proteins, transcription factors, ubiquitin E3 ligases, ion channels) in a restricted number of cell types. As an extracellular signal, S100B engages the pattern recognition receptor, receptor for advanced glycation end-products (RAGE), on immune cells as well as on neuronal, astrocytic and microglial cells, vascular smooth muscle cells, skeletal myoblasts and cardiomyocytes. However, RAGE may not be the sole receptor activated by S100B, the protein being able to enhance bFGF-FGFR1 signaling by interacting with FGFR1-bound bFGF in particular cell types. Moreover, extracellular effects of S100B vary depending on its local concentration. Increasing evidence suggests that at the concentration found in extracellular fluids in normal physiological conditions and locally upon acute tissue injury, which is up to a few nM levels, S100B exerts trophic effects in the central and peripheral nervous system and in skeletal muscle tissue thus participating in tissue homeostasis. The present commentary summarizes results implicating intracellular and extracellular S100B in tissue development, repair and regeneration.
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Zanotto C, Abib RT, Batassini C, Tortorelli LS, Biasibetti R, Rodrigues L, Nardin P, Hansen F, Gottfried C, Leite MC, Gonçalves CA. Non-specific inhibitors of aquaporin-4 stimulate S100B secretion in acute hippocampal slices of rats. Brain Res 2013; 1491:14-22. [DOI: 10.1016/j.brainres.2012.10.065] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2012] [Revised: 10/29/2012] [Accepted: 10/31/2012] [Indexed: 10/27/2022]
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Hermann A, Donato R, Weiger TM, Chazin WJ. S100 calcium binding proteins and ion channels. Front Pharmacol 2012; 3:67. [PMID: 22539925 PMCID: PMC3336106 DOI: 10.3389/fphar.2012.00067] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2012] [Accepted: 04/03/2012] [Indexed: 12/23/2022] Open
Abstract
S100 Ca(2+)-binding proteins have been associated with a multitude of intracellular Ca(2+)-dependent functions including regulation of the cell cycle, cell differentiation, cell motility and apoptosis, modulation of membrane-cytoskeletal interactions, transduction of intracellular Ca(2+) signals, and in mediating learning and memory. S100 proteins are fine tuned to read the intracellular free Ca(2+) concentration and affect protein phosphorylation, which makes them candidates to modulate certain ion channels and neuronal electrical behavior. Certain S100s are secreted from cells and are found in extracellular fluids where they exert unique extracellular functions. In addition to their neurotrophic activity, some S100 proteins modulate neuronal electrical discharge activity and appear to act directly on ion channels. The first reports regarding these effects suggested S100-mediated alterations in Ca(2+) fluxes, K(+) currents, and neuronal discharge activity. Recent reports revealed direct and indirect interactions with Ca(2+), K(+), Cl(-), and ligand activated channels. This review focuses on studies of the physical and functional interactions of S100 proteins and ion channels.
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Affiliation(s)
- Anton Hermann
- Division of Cellular and Molecular Neurobiology, Department of Cell Biology, University of SalzburgSalzburg, Austria
| | - Rosario Donato
- Department of Experimental Medicine and Biochemical Sciences, University of PerugiaPerugia, Italy
| | - Thomas M. Weiger
- Division of Cellular and Molecular Neurobiology, Department of Cell Biology, University of SalzburgSalzburg, Austria
| | - Walter J. Chazin
- Departments of Biochemistry and Chemistry, Center for Structural Biology, Vanderbilt UniversityNashville, TN, USA
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Lipopolysaccharide modulates astrocytic S100B secretion: a study in cerebrospinal fluid and astrocyte cultures from rats. J Neuroinflammation 2011; 8:128. [PMID: 21970823 PMCID: PMC3198930 DOI: 10.1186/1742-2094-8-128] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2010] [Accepted: 10/04/2011] [Indexed: 02/07/2023] Open
Abstract
Background Inflammatory responses in brain are primarily mediated by microglia, but growing evidence suggests a crucial importance of astrocytes. S100B, a calcium-binding protein secreted by astrocytes, has properties of a neurotrophic or an inflammatory cytokine. However, it is not known whether primary signals occurring during induction of an inflammatory response (e.g. lipopolysaccharide, LPS) directly modulate S100B. Methods In this work, we evaluated whether S100B levels in cerebrospinal fluid (CSF) and serum of Wistar rats are affected by LPS administered by intraperitoneal (IP) or intracerebroventricular (ICV) injection, as well as whether primary astrocyte cultures respond directly to lipopolysaccharide. Results Our data suggest that S100B secretion in brain tissue is stimulated rapidly and persistently (for at least 24 h) by ICV LPS administration. This increase in CSF S100B was transient when LPS was IP administered. In contrast to these S100B results, we observed an increase in in TNFα levels in serum, but not in CSF, after IP administration of LPS. In isolated astrocytes and in acute hippocampal slices, we observed a direct stimulation of S100B secretion by LPS at a concentration of 10 μg/mL. An involvement of TLR4 was confirmed by use of specific inhibitors. However, lower levels of LPS in astrocyte cultures were able to induce a decrease in S100B secretion after 24 h, without significant change in intracellular content of S100B. In addition, after 24 h exposure to LPS, we observed a decrease in astrocytic glutathione and an increase in astrocytic glial fibrillary acidic protein. Conclusions Together, these data contribute to the understanding of the effects of LPS on astrocytes, particularly on S100B secretion, and help us to interpret cerebrospinal fluid and serum changes for this protein in neuroinflammatory diseases. Moreover, non-brain S100B-expressing tissues may be differentially regulated, since LPS administration did not lead to increased serum levels of S100B.
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Nardin P, Tramontina AC, Quincozes-Santos A, Tortorelli LS, Lunardi P, Klein PR, Wartchow KM, Bobermin LD, Gottfried C, Elisabetsky E, Gonçalves CA. In vitro S100B secretion is reduced by apomorphine: effects of antipsychotics and antioxidants. Prog Neuropsychopharmacol Biol Psychiatry 2011; 35:1291-6. [PMID: 21513766 DOI: 10.1016/j.pnpbp.2011.04.004] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2010] [Revised: 04/06/2011] [Accepted: 04/06/2011] [Indexed: 02/06/2023]
Abstract
Astrocytes express dopamine receptors and respond to dopamine stimulation. However, the role of astrocytes in psychiatric disorders and the effects of antipsychotics on astroglial cells have only been investigated recently. S100B is a glial-derived protein, commonly used as a marker of astroglial activation in psychiatric disorders, particularly schizophrenia. We investigated S100B secretion in three different rat brain preparations (fresh hippocampal slices, C6 glioma cells and primary astrocyte cultures) exposed to apomorphine and antipsychotics (haloperidol and risperidone), aiming to evaluate, ex vivo and in vitro, whether dopamine activation and dopaminergic antagonists modulate astroglial activation, as measured by changes in the extracellular levels of S100B. The serum S100B elevation observed in schizophrenic patients is not reflected by the in vitro decrease of S100B secretion that we observed in hippocampal slices, cortical astrocytes and C6 glioma cells treated with apomorphine, which mimics dopaminergic hyperactivation. This decrease in S100B secretion can be explained by a stimulation of D2 receptors negatively coupled to adenyl cyclase. Antipsychotic medications and antioxidant supplementation were able to prevent the decline in S100B secretion. Findings reinforce the benefits of antioxidant therapy in psychiatric disorders. Based on our results, in hippocampal slices exposed to apomorphine, it may be suggested that antipsychotics could help to normalize S100B secretion by astrocytes.
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Affiliation(s)
- Patrícia Nardin
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
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Sorci G, Bianchi R, Riuzzi F, Tubaro C, Arcuri C, Giambanco I, Donato R. S100B Protein, A Damage-Associated Molecular Pattern Protein in the Brain and Heart, and Beyond. Cardiovasc Psychiatry Neurol 2010; 2010:656481. [PMID: 20827421 PMCID: PMC2933911 DOI: 10.1155/2010/656481] [Citation(s) in RCA: 115] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2010] [Accepted: 06/08/2010] [Indexed: 12/15/2022] Open
Abstract
S100B belongs to a multigenic family of Ca(2+)-binding proteins of the EF-hand type and is expressed in high abundance in the brain. S100B interacts with target proteins within cells thereby altering their functions once secreted/released with the multiligand receptor RAGE. As an intracellular regulator, S100B affects protein phosphorylation, energy metabolism, the dynamics of cytoskeleton constituents (and hence, of cell shape and migration), Ca(2+) homeostasis, and cell proliferation and differentiation. As an extracellular signal, at low, physiological concentrations, S100B protects neurons against apoptosis, stimulates neurite outgrowth and astrocyte proliferation, and negatively regulates astrocytic and microglial responses to neurotoxic agents, while at high doses S100B causes neuronal death and exhibits properties of a damage-associated molecular pattern protein. S100B also exerts effects outside the brain; as an intracellular regulator, S100B inhibits the postinfarction hypertrophic response in cardiomyocytes, while as an extracellular signal, (high) S100B causes cardiomyocyte death, activates endothelial cells, and stimulates vascular smooth muscle cell proliferation.
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Affiliation(s)
- Guglielmo Sorci
- Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Via del Giochetto, 06122 Perugia, Italy
| | - Roberta Bianchi
- Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Via del Giochetto, 06122 Perugia, Italy
| | - Francesca Riuzzi
- Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Via del Giochetto, 06122 Perugia, Italy
| | - Claudia Tubaro
- Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Via del Giochetto, 06122 Perugia, Italy
| | - Cataldo Arcuri
- Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Via del Giochetto, 06122 Perugia, Italy
| | - Ileana Giambanco
- Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Via del Giochetto, 06122 Perugia, Italy
| | - Rosario Donato
- Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Via del Giochetto, 06122 Perugia, Italy
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Oades RD, Dauvermann MR, Schimmelmann BG, Schwarz MJ, Myint AM. Attention-deficit hyperactivity disorder (ADHD) and glial integrity: S100B, cytokines and kynurenine metabolism--effects of medication. BEHAVIORAL AND BRAIN FUNCTIONS : BBF 2010; 6:29. [PMID: 20509936 PMCID: PMC2889842 DOI: 10.1186/1744-9081-6-29] [Citation(s) in RCA: 103] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/17/2009] [Accepted: 05/28/2010] [Indexed: 12/30/2022]
Abstract
BACKGROUND Children with attention-deficit/hyperactivity disorder (ADHD) show a marked temporal variability in their display of symptoms and neuropsychological performance. This could be explained in terms of an impaired glial supply of energy to support neuronal activity. METHOD We pursued one test of the idea with measures of a neurotrophin reflecting glial integrity (S100B) and the influences of 8 cytokines on the metabolism of amino-acids, and of tryptophan/kynurenine to neuroprotective or potentially toxic products that could modulate glial function. Serum samples from 21 medication-naïve children with ADHD, 21 typically-developing controls, 14 medicated children with ADHD and 7 healthy siblings were analysed in this preliminary exploration of group differences and associations. RESULTS There were no marked group differences in levels of S100B, no major imbalance in the ratios of pro- to anti-inflammatory interleukins nor in the metabolism of kynurenine to toxic metabolites in ADHD. However, four trends are described that may be worthy of closer examination in a more extensive study. First, S100B levels tended to be lower in ADHD children that did not show oppositional/conduct problems. Second, in medicated children raised interleukin levels showed a trend to normalisation. Third, while across all children the sensitivity to allergy reflected increased levels of IL-16 and IL-10, the latter showed a significant inverse relationship to measures of S100B in the ADHD group. Fourthly, against expectations healthy controls tended to show higher levels of toxic 3-hydroxykynurenine (3 HK) than those with ADHD. CONCLUSIONS Thus, there were no clear signs (S100B) that the glial functions were compromised in ADHD. However, other markers of glial function require examination. Nonetheless there is preliminary evidence that a minor imbalance of the immunological system was improved on medication. Finally, if lower levels of the potentially toxic 3 HK in ADHD children were confirmed this could reflect a reduction of normal pruning processes in the brain that would be consistent with delayed maturation (supported here by associations with amino-acid metabolism) and a reduced metabolic source of energy.
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Affiliation(s)
- Robert D Oades
- Clinic for Child and Adolescent Psychiatry and Psychotherapy, University of Duisburg-Essen, 45147 Essen Germany
| | - Maria R Dauvermann
- Clinic for Child and Adolescent Psychiatry and Psychotherapy, University of Duisburg-Essen, 45147 Essen Germany
| | - Benno G Schimmelmann
- Child and Adolescent Psychiatry, University of Bern, Effingerstr. 12, 3011 Bern, Switzerland
| | - Markus J Schwarz
- Laboratory for Psychoneuroimmunology, Ludwig Maximillian's University Psychiatric Hospital, 8036 Munich, Germany
| | - Aye-Mu Myint
- Laboratory for Psychoneuroimmunology, Ludwig Maximillian's University Psychiatric Hospital, 8036 Munich, Germany
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Mechanism of S100b release from rat cortical slices determined under basal and stimulated conditions. Neurochem Res 2009; 35:429-36. [PMID: 19823932 DOI: 10.1007/s11064-009-0075-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/25/2009] [Indexed: 10/20/2022]
Abstract
Incubation of rat cortical slices in a medium that was not containing oxygen and glucose (oxygen-glucose deprivation, OGD) caused a 200% increase in the release of S100B. However, when slices were transferred to a medium containing oxygen and glucose (reoxygenation conditions, or REO), S100B release reached 500% of its control value. Neither inhibition of nitric oxide (NO) synthase by L-NAME nor addition of the NO donors sodium nitroprussid (SNP) or hydroxylamine (HA) to the medium altered basal S100B release. Similarly, the presence of SNP, HA or NO precursor L: -arginine in the medium, or inhibition of NO synthase by L-NAME also failed to alter OGD- and REO-induced S100B outputs. Moreover, individual inhibition of PKC, PLA(2) or PLC all failed to attenuate the S100B release determined under control condition or enhanced by either OGD or REO. Blockade of calcium channels with verapamil, chelating the Ca(+2) ions with BAPTA or blockade of sodium channels with tetrodotoxin (TTX) did not alter OGD- and REO-induced S100B release. In contrast to the pharmacologic manipulations mentioned above, glutamate and alpha-ketoglutarate added at high concentrations to the medium prevented both OGD- and REO-induced S100B outputs. These results indicate that neither NO nor the activation of PKC, PLA(2) or PLC seem to be involved in basal or OGD- and REO-induced S100B outputs. Additionally, calcium and sodium currents that are sensitive to verapamil and TTX, respectively, are unlikely to contribute to the enhanced S100B release observed under these conditions.
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Leite MC, Galland F, de Souza DF, Guerra MC, Bobermin L, Biasibetti R, Gottfried C, Gonçalves CA. Gap junction inhibitors modulate S100B secretion in astrocyte cultures and acute hippocampal slices. J Neurosci Res 2009; 87:2439-46. [PMID: 19360884 DOI: 10.1002/jnr.22083] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Astrocytes sense, integrate, and respond to stimuli generated by neurons or neural injury; this response involves gap junction (GJ) communication. Neuronal vulnerability to injury increased when cocultures of astrocytes and neurons were exposed to GJ inhibitors. However, GJ uncoupling could limit the extension of a lesion. We investigated a possible link between GJ communication and S100B secretion. S100B is a calcium-binding protein of 21 kDa that is predominantly expressed and secreted by astrocytes, which has trophic paracrine activity on neurite growth, glial proliferation, and neuronal survival. GJ inhibitors were analyzed in isolated astrocytes in primary cultures from hippocampus, acute hippocampal slices, and C6 glioma cells, which were used as a negative control. Our data indicate that GJ blocking stimulates S100B secretion in astrocyte cultures and acute hippocampal slices. Different assays were used to confirm cell integrity during exposure to GJ inhibitors. S100B secretion was observed with different types of GJ inhibitors; the resulting event was dependent on time, the nature of the inhibitor, its putative molecular target of GJ blocking, and/or the cell preparation used. Only carbenoxolone induced a fast and persistent increase in S100B secretion in both preparations. Endothelin-1 increased S100B secretion in astrocyte cultures at 1 hr, but a decrease was observed at 6 hr or in acute hippocampal slices. Physiologically, a local GJ closure associated with release of S100B in injury conditions favors the idea of a common mechanism available to limit the extension of lesion and increase the chances of cell survival.
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Affiliation(s)
- Marina Concli Leite
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
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Mello ADS, Santos AQ, Funchal C. Correlação entre Hiperglicemia e Células do SNC, com Enfoque na Atividade Glial. ACTA ACUST UNITED AC 2001. [DOI: 10.34024/rnc.2012.v20.8284] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Introdução. Entre os mecanismos biológicos que originam o quadro hiperglicêmico a predominância é do diabetes melittus (DM). O DM representa um grupo de desordens metabólicas caracterizadas por hiperglicemia crônica que ocasiona severas alterações celulares e teciduais. Objetivo. O presente trabalho analisou através de revisão da literatura o comportamento de células gliais expostas a elevadas concentrações de glicose, similares às observadas no DM. Método. Foi realizada uma revisão literária através de artigos científicos das bases de dados Pubmed, Science Direct, Scopus e Scielo. Resultados. Foram selecionados artigos e livros entre 1988 e 2009 que discutiam hiperglicemia, sistema nervoso central e que relacionavam hiperglicemia e células gliais. Conclusão. A hiperglicemia crônica proporcionada pelo DM pode influenciar de maneira danosa o metabolismo cerebral exercendo ações sobre a atividade glial. Podendo afetar a sobrevivência neuronal através da excitotoxicidade glutamatérgica e da produção de espécies reativas de oxigênio (ERO) e de espécies reativas de nitrogênio (ERN) que geram como consequência o processo de neuroinflamação. Tal processo inflamatório pode resultar em dano e morte neural caracterizando um processo neurodegerativo.
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