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1.
J Neurovirol ; 29(5): 577-587, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37501054

RESUMO

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.


Assuntos
COVID-19 , Humanos , Animais , Ratos , COVID-19/genética , Doenças Neuroinflamatórias , Síndrome de COVID-19 Pós-Aguda , SARS-CoV-2 , Homeostase , Hipocampo
2.
Toxicol Appl Pharmacol ; 264(2): 143-52, 2012 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-22885153

RESUMO

In the present report 15day-old Wistar rats were injected with 0.3µmol of diphenyl ditelluride (PhTe)(2)/kg body weight and parameters of neurodegeneration were analyzed in slices from striatum 6days afterwards. We found hyperphosphorylation of intermediate filament (IF) proteins from astrocyte (glial fibrillary acidic protein-GFAP and vimentin) and from neuron (low-, medium- and high molecular weight neurofilament subunits: NF-L, NF-M and NF-H, respectively) and increased MAPK (Erk, JNK and p38MAPK) as well as PKA activities. The treatment induced reactive astrogliosis in the striatum, evidenced by increased GFAP and vimentin immunocontent as well as their mRNA overexpression. Also, (PhTe)(2) significantly increased the propidium iodide (PI) positive cells in NeuN positive population without altering PI incorporation into GFAP positive cells, indicating that in vivo exposure to (PhTe)(2) provoked neuronal damage. Immunohistochemistry showed a dramatic increase of GFAP staining characteristic of reactive astrogliosis. Moreover, increased caspase 3 in (PhTe)(2) treated striatal slices suggested apoptotic cell death. (PhTe)(2) exposure decreased Akt immunoreactivity, however phospho-GSK-3-ß (Ser9) was unaltered, suggesting that this kinase is not directly implicated in the neurotoxicity of this compound. Therefore, the present results shed light into the mechanisms of (PhTe)(2)-induced neurodegeneration in rat striatum, evidencing a critical role for the MAPK and Akt signaling pathways and disruption of cytoskeletal homeostasis, which could be related with apoptotic neuronal death and astrogliosis.


Assuntos
Derivados de Benzeno/toxicidade , Proteínas Quinases Ativadas por Mitógeno/fisiologia , Neostriado/patologia , Doenças Neurodegenerativas/induzido quimicamente , Doenças Neurodegenerativas/patologia , Síndromes Neurotóxicas/patologia , Proteína Oncogênica v-akt/fisiologia , Compostos Organometálicos/toxicidade , Animais , Apoptose/efeitos dos fármacos , Western Blotting , Proteínas do Citoesqueleto/metabolismo , Eletroforese em Gel de Poliacrilamida , Feminino , Citometria de Fluxo , Gliose/induzido quimicamente , Gliose/patologia , Homeostase/efeitos dos fármacos , Imuno-Histoquímica , Masculino , Neurônios/efeitos dos fármacos , Radioisótopos de Fósforo , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real
3.
Behav Brain Res ; 428: 113880, 2022 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-35390432

RESUMO

Transcranial direct current stimulation (tDCS) has demonstrated clinical benefits such as analgesia, anti-inflammatory, and neuroprotective effects. However, the mechanisms of action of a single tDCS session are poorly characterized. The present study aimed to evaluate the effects of a single tDCS session on pain sensitivity, inflammatory parameters, and astrocyte activity in naive rats. In the first experiment, sixty-day-old male Wistar rats (n = 95) were tested for mechanical pain threshold (von Frey test). Afterward, animals were submitted to a single bimodal tDCS (0.5 mA, 20 min) or sham-tDCS session. According to the group, animals were re-tested at different time intervals (30, 60, 120 min, or 24 h) after the intervention, euthanized, and the cerebral cortex collected for biochemical analysis. A second experiment (n = 16) was performed using a similar protocol to test the hypotheses that S100B levels in the cerebrospinal fluid (CSF) are altered by tDCS. Elisa assay quantified the levels of tumor necrosis factor-alfa (TNF-α), interleukin-10 (IL10), S100 calcium-binding protein B (S100B), and Glial fibrillary acidic protein (GFAP). Data were analyzed using ANOVA and independent t-test (P < 0.05). Results showed that tDCS decreased pain sensitivity (30 and 60 min), cerebral TNF-α and S100B levels (30 min). CSF S100B levels increased 30 min after intervention. There were no differences in IL10 and GFAP levels. TCDS showed analgesic, anti-inflammatory, and neuroprotective effects in naive animals. Therefore, this non-invasive and inexpensive therapy may potentially be a preemptive alternative to reduce pain, inflammation, and neurodegeneration in situations where patients will undergo medical procedures (e.g., surgery).


Assuntos
Fármacos Neuroprotetores , Estimulação Transcraniana por Corrente Contínua , Animais , Astrócitos/metabolismo , Humanos , Interleucina-10/metabolismo , Masculino , Dor , Limiar da Dor , Ratos , Ratos Wistar , Estimulação Transcraniana por Corrente Contínua/métodos , Fator de Necrose Tumoral alfa/metabolismo
4.
Neural Regen Res ; 13(11): 1945-1952, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30233068

RESUMO

Emerging evidence has suggested global histone H4 acetylation status plays an important role in neural plasticity. For instance, the imbalance of this epigenetic marker has been hypothesized as a key factor for the development and progression of several neurological diseases. Likewise, astrocytic reactivity - a well-known process that markedly influences the tissue remodeling after a central nervous system injury - is crucial for tissue remodeling after spinal cord injury (SCI). However, the linkage between the above-mentioned mechanisms after SCI remains poorly understood. We sought to investigate the relation between both glial fibrillary acidic protein (GFAP) and S100 calcium-binding protein B (S100B) (astrocytic reactivity classical markers) and global histone H4 acetylation levels. Sixty-one male Wistar rats (aged ~3 months) were divided into the following groups: sham; 6 hours post-SCI; 24 hours post-SCI; 48 hours post-SCI; 72 hours post-SCI; and 7 days post-SCI. The results suggested that GFAP, but not S100B was associated with global histone H4 acetylation levels. Moreover, global histone H4 acetylation levels exhibited a complex pattern after SCI, encompassing at least three clearly defined phases (first phase: no changes in the 6, 24 and 48 hours post-SCI groups; second phase: increased levels in the 72 hours post-SCI group; and a third phase: return to levels similar to control in the 7 days post-SCI group). Overall, these findings suggest global H4 acetylation levels exhibit distinct patterns of expression during the first week post-SCI, which may be associated with GFAP levels in the perilesional tissue. Current data encourage studies using H4 acetylation as a possible biomarker for tissue remodeling after spinal cord injury.

5.
Mol Neurobiol ; 55(5): 4068-4077, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-28585188

RESUMO

Although many studies show the toxic effects of proline, recently it has been reported some anti-inflammatory effect of this amino acid. Our principal objective was to investigate the effects of proline on the alterations caused by LPS (lipopolysaccharide) administration in the cerebral cortex and cerebellum of young Wistar rats. The animals were divided into four groups: control (0.85% saline); proline, (12.8 µmol of proline/g body weight from day 7 to 13; 14.6 µmol of proline/g body weight from day 14 to 17 and 16.4 µmol of proline/g body weight from day 18 to 21); LPS (1 mg/g body weight); LPS plus proline. The animals were killed at 22 days of age, 12 h after the last injection, by decapitation without anesthesia. The brain cortex and cerebellum were separated for chemical determinations. The effects of proline and LPS in the cerebral cortex and cerebellum on the expression of S100B and GFAP, oxidative stress parameters, enzymes of phosphoryl transfer network activity, and mitochondrial respiration chain complexes were investigated. Two-way ANOVA showed that the administration of proline did not alter the analyzed parameter in cerebral cortex and cerebellum. On the other hand, LPS administration caused a change in these parameters. Besides, the co-administration of proline and LPS showed the ability of Pro in preventing the effects of LPS. These results indicated that LPS induces inflammation, oxidative stress, and alters energy parameters in cerebral cortex and cerebellum of the rats. Moreover, co-administration of Pro was able to prevent these harmful effects of LPS.


Assuntos
Anti-Inflamatórios/farmacologia , Cerebelo/patologia , Córtex Cerebral/patologia , Prolina/farmacologia , Animais , Cerebelo/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Transporte de Elétrons/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/metabolismo , Lipopolissacarídeos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Proteínas S100/metabolismo
6.
Behav Brain Res ; 334: 78-85, 2017 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-28756215

RESUMO

Clinical and pre-clinical studies indicate that exercise is beneficial to many aspects of brain function especially during aging. The present study investigated the effects of a treadmill running protocol in young (3month-old) and aged (22month-old) male Wistar rats, on: I) cognitive function, as assessed by spatial reference memory in the Morris water maze; II) oxidative stress parameters and the expression of neurotrophic factors BDNF, NT-3, IGF-1 and VEGF in the hippocampus. Animals of both ages were assigned to sedentary (non-exercised) and exercised (20min of daily running sessions, 3 times per week for 4weeks) groups. Cognition was assessed by a reference memory task run in the Morris water maze; twenty four hours after last session of behavioral testing hippocampi were collected for biochemical analysis. Results demonstrate that the moderate treadmill running exercise: I) prevented age-related deficits in reference memory in the Morris water maze; II) prevented the age-related increase of reactive oxygen species levels and lipid peroxidation in the hippocampus; III) caused an increase of BDNF, NT-3 and IGF-1 expression in the hippocampus of aged rats. Taken together, results suggest that both exercise molecular effects, namely the reduction of oxidative stress and the increase of neurotrophic factors expression in the hippocampus, might be related to its positive effect on memory performance in aged rats.


Assuntos
Envelhecimento/fisiologia , Envelhecimento/psicologia , Hipocampo/metabolismo , Transtornos da Memória/prevenção & controle , Corrida/fisiologia , Corrida/psicologia , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Catalase/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Peroxidação de Lipídeos/fisiologia , Masculino , Aprendizagem em Labirinto/fisiologia , Transtornos da Memória/metabolismo , Fatores de Crescimento Neural/metabolismo , Estresse Oxidativo/fisiologia , Distribuição Aleatória , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Memória Espacial/fisiologia , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
7.
Eur J Med Chem ; 121: 758-772, 2016 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-27392529

RESUMO

Tianeptine was linked to various 9-aminoalkylamino-1,2,3,4-tetrahydroacridines using EDC·HCl/HOBt to afford a series of tacrine-tianeptine hybrids. The hybrids were tested for their ability to inhibit AChE and BuChE and IC50 values in the nanomolar concentration scale were obtained. AChE molecular modeling studies of these hybrids indicated that tacrine moiety interacts in the bottom of the gorge with the catalytic active site (CAS) while tianeptine binds to peripheral anionic site (PAS). Furthermore, the compounds 2g and 2e were able to reduce the in vitro basal secretion of S100B, suggesting its therapeutic action in some cases or stages of Alzheimer's disease.


Assuntos
Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Tacrina/química , Tiazepinas/química , Tiazepinas/farmacologia , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Domínio Catalítico , Técnicas de Química Sintética , Electrophorus , Humanos , L-Lactato Desidrogenase/metabolismo , Modelos Moleculares , Subunidade beta da Proteína Ligante de Cálcio S100/metabolismo , Tiazepinas/síntese química
8.
PLoS One ; 11(4): e0154612, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27123999

RESUMO

Glioblastoma is the most frequent and malignant brain tumor. Treatment includes chemotherapy with temozolomide concomitant with surgical resection and/or irradiation. However, a number of cases are resistant to temozolomide, as well as the human glioblastoma cell line U138-MG. We investigated doxazosin's (an antihypertensive drug) activity against glioblastoma cells (C6 and U138-MG) and its neurotoxicity on primary astrocytes and organoptypic hippocampal cultures. For this study, the following methods were used: citotoxicity assays, flow cytometry, western-blotting and confocal microscopy. We showed that doxazosin induces cell death on C6 and U138-MG cells. We observed that doxazosin's effects on the PI3K/Akt pathway were similar as LY294002 (PI3K specific inhibitor). In glioblastoma cells treated with doxasozin, Akt levels were greatly reduced. Upon examination of activities of proteins downstream of Akt we observed upregulation of GSK-3ß and p53. This led to cell proliferation inhibition, cell death induction via caspase-3 activation and cell cycle arrest at G0/G1 phase in glioblastoma cells. We used in this study Lapatinib, a tyrosine kinase inhibitor, as a comparison with doxazosin because they present similar chemical structure. We also tested the neurocitotoxicity of doxazosin in primary astrocytes and organotypic cultures and observed that doxazosin induced cell death on a small percentage of non-tumor cells. Aggressiveness of glioblastoma tumors and dismal prognosis require development of new treatment agents. This includes less toxic drugs, more selective towards tumor cells, causing less damage to the patient. Therefore, our results confirm the potential of doxazosin as an attractive therapeutic antiglioma agent.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias Encefálicas/tratamento farmacológico , Doxazossina/farmacologia , Glioblastoma/tratamento farmacológico , Inibidores de Fosfoinositídeo-3 Quinase , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteína Supressora de Tumor p53/biossíntese , Animais , Astrócitos/efeitos dos fármacos , Caspase 3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cromonas/farmacologia , Doxazossina/toxicidade , Ativação Enzimática/efeitos dos fármacos , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/biossíntese , Hipocampo/efeitos dos fármacos , Humanos , Lapatinib , Morfolinas/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Quinazolinas/farmacologia , Ratos , Ratos Wistar
9.
Brain Res Bull ; 65(5): 443-50, 2005 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-15833599

RESUMO

Several studies have shown that high corticosteroid hormone levels increase neuronal vulnerability. Here we evaluate the consequences of in vivo acute or repeated restraint stress on cellular viability in rat hippocampal slices suffering an in vitro model of ischemia. Cellular injury was quantified by measuring lactate dehydrogenase (LDH) and neuron-specific enolase released into the medium. Acute stress did not affect cellular death when oxygen and glucose deprivation (OGD) was applied both immediately or 24h after restraint. The exposure to OGD, followed by reoxygenation, resulted in increased LDH in the medium. Repeated stress potentiated the effect of OGD both, on LDH and neuron-specific enolase released to the medium. There was no effect of repeated stress on the release of S100B, an astrocytic protein. Additionally, no effect of repeated stress was observed on glutamate uptake by the tissue. These results suggest that repeated stress increases the vulnerability of hippocampal cells to an in vitro model of ischemia, potentiating cellular damage, and that the cells damaged by the exposure to repeated stress+OGD are mostly neurons. The uptake of glutamate was not observed to participate in the mechanisms responsible for rendering the neurons more susceptible to ischemic damage after repeated stress.


Assuntos
Glucose/deficiência , Hipocampo/metabolismo , Hipóxia , Estresse Fisiológico/metabolismo , Análise de Variância , Animais , Ensaio de Imunoadsorção Enzimática/métodos , Ácido Glutâmico/metabolismo , Hipocampo/patologia , Técnicas In Vitro , L-Lactato Desidrogenase/metabolismo , Masculino , Fatores de Crescimento Neural/metabolismo , Fosfopiruvato Hidratase/metabolismo , Ratos , Ratos Wistar , Restrição Física/métodos , Subunidade beta da Proteína Ligante de Cálcio S100 , Proteínas S100/metabolismo , Sódio/farmacologia , Fatores de Tempo
10.
Eur J Med Chem ; 62: 556-63, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23422935

RESUMO

A novel series of tacrine-lophine hybrids was synthesized and tested for their ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) with IC50 in the nanomolar concentration scale. The key step is the one-pot four component condensation reaction of 9-aminoalkylamino-1,2,3,4-tetrahydroacridines, benzil, different substituted aromatic aldehydes and NH4OAc, using InCl3 as the best catalyst. Tacrine-lophine hybrids were found to be potent and selective inhibitors of cholinesterases. As an extension of the four component approach to tetrasubstituted imidazoles, a new series of bis-(2,4,5-triphenyl-1H-imidazoles) or bis(n)-lophines was tested against AChE and BuChE.


Assuntos
Acetilcolinesterase/metabolismo , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Imidazóis/química , Tacrina/química , Animais , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Humanos , Masculino , Estrutura Molecular , Ratos , Ratos Wistar , Relação Estrutura-Atividade
11.
Nutrire Rev. Soc. Bras. Aliment. Nutr ; 41: 1-7, Dec. 2016. ilus, tab, graf
Artigo em Inglês | LILACS | ID: biblio-880482

RESUMO

BACKGROUND: The benefits of caloric restriction (CR) on the protection against age-related neurodegenerative diseases have been the subject of several studies. However, the effects of CR on the central nervous system are still poorl y understood since most studies were carried out in mature animals. The present study aimed to investigate whether the age at onset of CR could differently affect the redox status of the rat hippocampus. METHODS: Thirty-two male Wistar rats at 35 days old (35d;n= 16) and 65 days old (65d;n= 16) were fed ad libitum or subjected to 30 % CR (n= 8 group/age) for 12 weeks. At the end of the experiment, the rats were euthanized, blood was collected, and the hippocampus was dissected for measuring the redox status. RESULTS: CR in 35d and 65d rats induced a 16 and 21% reduction in body weight gain, respectively, compared to controls (p< 0.05). Urea, total cholesterol, triacylglycerol, HDL cholesterol, and LDL cholesterol concentrations were lower in CR 35d rats than in 35d controls (p< 0.05). No differences were detected between the CR groups and controls in the object recognition test (p> 0.05) and in superoxide dismutase activity, nitric oxide content, and lipid peroxidation levels(p> 0.05). However, glutathione peroxidase activity was higher (p< 0.0001) in 65d rats compared to that in 35d rats, and GSH content was higher (p< 0.05) in CR-fed rats compared to that in controls at both ages. CONCLUSIONS: In conclusion, CR increased GSH content when started at both ages but did not affect the activity of antioxidant enzymes and the level of ROS in the hippocampus. In addition, CR did not induce any detrimental effects on memory and nutritional status when started in both 35d and 65d rats


Assuntos
Cobaias , Camundongos , Ratos , Restrição Calórica , Oxirredução , Estresse Oxidativo , Doenças Neurodegenerativas/dietoterapia
12.
Brain Res ; 1247: 188-95, 2009 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-18992724

RESUMO

Environmental enrichment recovers memory deficits without affecting atrophy of the hippocampus adult rats submitted to neonatal hypoxia-ischemia (HI). The present study was designed to investigate whether the modulation of brain oxidative status and/or BDNF content, as assessed in adulthood, are involved with the functional neuroprotection caused by environmental enrichment in animals receiving neonatal HI. Male Wistar rats, in the 7th postnatal day, were submitted to the Levine-Rice model of neonatal hypoxia-ischemia, comprising permanent occlusion of the right common carotid artery and a 90 min period of hypoxia (8% O(2)-92% N(2)). Starting 2 weeks after the HI event, animals were stimulated by the enriched environment (1 h/day for 9 weeks). Rats were sacrificed approximately 24 h after the end of enrichment period and some oxidative stress parameters, specifically the free radical levels, macromolecules damage and superoxide dismutase activity, in hippocampus and frontal cortex samples were determined. BDNF levels were also measured in the same encephalic structures. Indexes of macromolecules damage, TBARS levels and total cellular thiols, as well as free radical levels were unchanged in both studied structures. An increased SOD activity in the right hippocampus of HI group maintained in standard environment was found, this effect was reversed in HI enriched group. Moreover, BDNF levels were increased only in the hippocampus of non-stimulated HI group. These results suggest that the environmental enrichment protocol bearing cognitive protection is not associated to increases in BDNF expression nor SOD activity in hippocampus of the rats, as assessed in adulthood, submitted to neonatal hypoxia-ischemia.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Encéfalo/metabolismo , Citoproteção/fisiologia , Hipóxia-Isquemia Encefálica/metabolismo , Hipóxia-Isquemia Encefálica/terapia , Estresse Oxidativo/fisiologia , Animais , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Metabolismo Energético/fisiologia , Meio Ambiente , Radicais Livres/metabolismo , Lobo Frontal/metabolismo , Lobo Frontal/fisiopatologia , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Hipóxia-Isquemia Encefálica/fisiopatologia , Masculino , Degeneração Neural/etiologia , Degeneração Neural/fisiopatologia , Degeneração Neural/terapia , Ratos , Ratos Wistar , Compostos de Sulfidrila/metabolismo , Superóxido Dismutase/metabolismo , Superóxido Dismutase-1 , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Tempo
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