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1.
Adv Exp Med Biol ; 1232: 209-214, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31893412

RESUMO

Cognitive function is reported to improve by moderate aerobic exercise. However, the effects of intermittent exercise with rest between the moderate-intensity exercise are unclear. Therefore, this study aimed to compare the effects of continuous and intermittent exercise on cerebral oxygenation and cognitive function. This study included 18 healthy adults. For the continuous exercise protocol, 5 min of rest was followed by 30 min of exercise; 5 min of rest was allowed after each exercise. For the intermittent exercise protocol, 3 sets of 10 min of exercise were completed, with 5 min of rest between the sets. Exercise intensity was 50% of maximum oxygen uptake. Oxyhemoglobin (O2Hb) in the prefrontal cortex (PFC) was measured during each protocol, and cognitive tasks (Stroop test) were performed before and after exercise. O2Hb levels for the left and right PFCs were significantly higher post-exercise than pre-exercise for both exercise protocols (p < 0.01). The average reaction time in the Stroop test was significantly shorter post-exercise than pre-exercise for both protocols (p < 0.01). There was no significant difference in the error rate pre- and post-exercise for both protocols (continuous p = 0.22; intermittent p = 0.44). There was no significant difference between both protocols in all measurement results (O2Hb: p = 0.67; average reaction time p = 0.50; error rate p = 0.24). O2Hb was higher and average reaction time was shorter after exercise than before exercise for both exercise protocols. Intermittent and continuous exercise may improve cognitive function to the same degree after exercise.


Assuntos
Cérebro , Cognição , Exercício , Oxigênio , Espectroscopia de Luz Próxima ao Infravermelho , Adulto , Cérebro/metabolismo , Cognição/fisiologia , Humanos , Oxigênio/metabolismo , Consumo de Oxigênio
2.
Adv Exp Med Biol ; 1232: 299-306, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31893424

RESUMO

Hypoxic ischemic encephalopathy (HIE) is a significant cause of death and neurological disability in newborns. Therapeutic hypothermia at 33.5 °C is one of the most common treatments in HIE and generally improves outcome; however 45-55% of injuries still result in death or severe neurodevelopmental disability. We have developed a systems biology model of cerebral oxygen transport and metabolism to model the impact of hypothermia on the piglet brain (the neonatal preclinical animal model) tissue physiology. This computational model is an extension of the BrainSignals model of the adult brain. The model predicts that during hypothermia there is a 5.1% decrease in cerebral metabolism, 1.1% decrease in blood flow and 2.3% increase in cerebral tissue oxygenation saturation. The model can be used to simulate effects of hypothermia on the brain and to help interpret bedside recordings.


Assuntos
Circulação Cerebrovascular , Cérebro , Hipotermia , Modelos Biológicos , Animais , Animais Recém-Nascidos , Circulação Cerebrovascular/fisiologia , Cérebro/metabolismo , Simulação por Computador , Humanos , Hipotermia Induzida , Hipóxia-Isquemia Encefálica , Suínos
3.
Environ Toxicol Pharmacol ; 71: 103216, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31260942

RESUMO

Methylmercury is an environmental pollutant that shows selective toxicity to the central nervous system. We previously reported that brain-specific expression of chemokine CCL3 increases in mice administered methylmercury. However, the relationship between CCL3 and methylmercury toxicity has not been elucidated. Here, we confirmed that induction of CCL3 expression occurs before pathological change by methylmercury treatment was observed in the mouse brain. This induction was also observed in C17.2 mouse neural stem cells before methylmercury-induced cytotoxicity. In addition, cells in which CCL3 was knocked-down showed higher methylmercury sensitivity than did control cells. Moreover, activation of transcription factor NF-κB was observed following methylmercury treatment, and methylmercury-mediated induction of CCL3 expression was partially suppressed by knockdown of p65, an NF-κB subunit. Our results suggest that NF-κB plays a role in the induction of methylmercury-mediated CCL3 expression and that this action may be a cellular response to methylmercury toxicity.


Assuntos
Quimiocina CCL3/biossíntese , Poluentes Ambientais/toxicidade , Compostos de Metilmercúrio/toxicidade , NF-kappa B/biossíntese , Células-Tronco Neurais/efeitos dos fármacos , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cerebelo/efeitos dos fármacos , Cerebelo/metabolismo , Cerebelo/patologia , Cérebro/efeitos dos fármacos , Cérebro/metabolismo , Cérebro/patologia , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/patologia
4.
Nat Commun ; 10(1): 2780, 2019 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-31239441

RESUMO

In the developing central nervous system, cell departure from the apical surface is the initial and fundamental step to form the 3D, organized architecture. Both delamination of differentiating cells and repositioning of progenitors to generate outer radial glial cells (oRGs) contribute to mammalian neocortical expansion; however, a comprehensive understanding of their mechanisms is lacking. Here, we demonstrate that Lzts1, a molecule associated with microtubule components, promotes both cell departure events. In neuronally committed cells, Lzts1 functions in apical delamination by altering apical junctional organization. In apical RGs (aRGs), Lzts1 expression is variable, depending on Hes1 expression levels. According to its differential levels, Lzts1 induces diverse RG behaviors: planar division, oblique divisions of aRGs that generate oRGs, and their mitotic somal translocation. Loss-of-function of lzts1 impairs all these cell departure processes. Thus, Lzts1 functions as a master modulator of cellular dynamics, contributing to increasing complexity of the cerebral architecture during evolution.


Assuntos
Cérebro/crescimento & desenvolvimento , Cérebro/metabolismo , Células Ependimogliais/metabolismo , Neurogênese , Neurônios/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Movimento Celular , Cérebro/citologia , Células Ependimogliais/citologia , Camundongos , Camundongos Transgênicos , Neurônios/citologia , Fatores de Transcrição HES-1/genética , Fatores de Transcrição HES-1/metabolismo , Proteínas Supressoras de Tumor/genética
5.
Proc Natl Acad Sci U S A ; 116(14): 7089-7094, 2019 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-30894491

RESUMO

The primate cerebrum is characterized by a large expansion of cortical surface area, the formation of convolutions, and extraordinarily voluminous subcortical white matter. It was recently proposed that this expansion is primarily driven by increased production of superficial neurons in the dramatically enlarged outer subventricular zone (oSVZ). Here, we examined the development of the parietal cerebrum in macaque monkey and found that, indeed, the oSVZ initially adds neurons to the superficial layers II and III, increasing their thickness. However, as the oSVZ grows in size, its output changes to production of astrocytes and oligodendrocytes, which in primates outnumber cerebral neurons by a factor of three. After the completion of neurogenesis around embryonic day (E) 90, when the cerebrum is still lissencephalic, the oSVZ enlarges and contains Pax6+/Hopx+ outer (basal) radial glial cells producing astrocytes and oligodendrocytes until after E125. Our data indicate that oSVZ gliogenesis, rather than neurogenesis, correlates with rapid enlargement of the cerebrum and development of convolutions, which occur concomitantly with the formation of cortical connections via the underlying white matter, in addition to neuronal growth, elaboration of dendrites, and amplification of neuropil in the cortex, which are primary factors in the formation of cerebral convolutions in primates.


Assuntos
Cérebro/crescimento & desenvolvimento , Cérebro/metabolismo , Ventrículos Laterais/crescimento & desenvolvimento , Ventrículos Laterais/metabolismo , Neurogênese/fisiologia , Neurônios/metabolismo , Animais , Astrócitos/metabolismo , Cérebro/citologia , Cérebro/embriologia , Embrião de Mamíferos , Proteínas de Homeodomínio/metabolismo , Ventrículos Laterais/citologia , Ventrículos Laterais/embriologia , Macaca , Oligodendroglia/citologia , Oligodendroglia/metabolismo , Fator de Transcrição PAX6/metabolismo , Primatas , Proteínas Supressoras de Tumor/metabolismo
6.
Mol Neurobiol ; 56(10): 6770-6776, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30919215

RESUMO

In a previous study (Mol Neurobiol 55:7476-7486, 2017), newly synthesized brain metabolic DNA (BMD) from rat subcellular fractions has been shown to behave as a DNA-RNA hybrid when analyzed in cesium gradients at early [3H] thymidine incorporation times but to assume the double-stranded configuration at later times. Conversely, BMD from purified nuclei displayed the dsDNA configuration even at early incorporation times. The results were interpreted to support the BMD origin by reverse transcription in the cytoplasm and its later acquisition of the double-stranded configuration before the partial transfer to the nuclei. This interpretation has now been confirmed by immunofluorescence analyses of newly synthesized BrdU-labeled BMD from the mouse brain that demonstrates its cytoplasmic localization and colocalization with DNA-RNA hybrids. In addition, BrdU-labeled BMD has been shown to colocalize with astroglial anti-GFAP antibodies and with presynaptic anti-synaptophysin antibodies.


Assuntos
Encéfalo/metabolismo , Citoplasma/metabolismo , DNA/metabolismo , Transcrição Genética , Animais , Anticorpos/metabolismo , Bromodesoxiuridina/metabolismo , Núcleo Celular/metabolismo , Cérebro/metabolismo , Imunofluorescência , Proteína Glial Fibrilar Ácida/metabolismo , Masculino , Mitocôndrias/metabolismo , Ratos Wistar , Sinaptofisina/metabolismo
7.
Crit Care ; 23(1): 45, 2019 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-30760295

RESUMO

BACKGROUND: Hyperventilation-induced hypocapnia (HV) reduces elevated intracranial pressure (ICP), a dangerous and potentially fatal complication of traumatic brain injury (TBI). HV decreases the arteriolar diameter of intracranial vessels, raising the risk of cerebral ischemia. The aim of this study was to characterize the effects of moderate short-term HV in patients with severe TBI by using concomitant monitoring of cerebral metabolism, brain tissue oxygen tension (PbrO2), and cerebral hemodynamics with transcranial color-coded duplex sonography (TCCD). METHODS: This prospective trial was conducted between May 2014 and May 2017 in the surgical intensive care unit (ICU) at the University Hospital of Zurich. Patients with nonpenetrating TBI older than 18 years of age with a Glasgow Coma Scale (GCS) score < 9 at presentation and with ICP monitoring, PbrO2, and/or microdialysis (MD) probes during ICU admission within 36 h after injury were included in our study. Data collection and TCCD measurements were performed at baseline (A), at the beginning of moderate HV (C), after 50 min of moderate HV (D), and after return to baseline (E). Moderate HV was defined as arterial partial pressure of carbon dioxide 4-4.7 kPa. Repeated measures analysis of variance was used to compare variables at the different time points, followed by post hoc analysis with Bonferroni adjustment as appropriate. RESULTS: Eleven patients (64% males, mean age 36 ± 14 years) with an initial median GCS score of 7 (IQR 3-8) were enrolled. During HV, ICP and mean flow velocity (CBFV) in the middle cerebral artery decreased significantly. Glucose, lactate, and pyruvate in the brain extracellular fluid did not change significantly, whereas PbrO2 showed a statistically significant reduction but remained within the normal range. CONCLUSION: Moderate short-term hyperventilation has a potent effect on the cerebral blood flow, as shown by TCCD, with a concomitant ICP reduction. Under the specific conditions of this study, this degree of hyperventilation did not induce pathological alterations of brain metabolites and oxygenation. TRIAL REGISTRATION: NCT03822026 . Registered on 30 January 2019.


Assuntos
Lesões Encefálicas Traumáticas/terapia , Cérebro/metabolismo , Hiperventilação/fisiopatologia , Adulto , Análise de Variância , Pressão Arterial/efeitos dos fármacos , Pressão Arterial/fisiologia , Cérebro/fisiopatologia , Feminino , Escala de Coma de Glasgow/estatística & dados numéricos , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Hemodinâmica/efeitos dos fármacos , Hemodinâmica/fisiologia , Humanos , Hiperventilação/complicações , Hipocapnia/etiologia , Hipocapnia/fisiopatologia , Pressão Intracraniana/efeitos dos fármacos , Pressão Intracraniana/fisiologia , Masculino , Pessoa de Meia-Idade , Oxigênio/sangue , Oxigênio/uso terapêutico , Estudos Prospectivos , Ultrassonografia Doppler Transcraniana/métodos
8.
Neurochem Int ; 125: 7-15, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30716357

RESUMO

Altered endocannabinoid (eCB) signalling is suggested as an important contributor to the pathophysiology of depression. To further elucidate this, we conducted a study using a genetic rat model of depression, the Flinders Sensitive Line (FSL), and their controls, the Flinders Resistant Line (FRL) rats. Plasma, right and left prefrontal cortex, and hippocampus were isolated from FSL and FRL rats. We analyzed each region for the eCB anandamide (AEA) and 2-arachidonoylglycerol (2-AG) levels by liquid chromatography/multiple reaction monitoring (LC/MRM), mRNA and protein levels of the cannabinoid type 1 receptor (CB1R), fatty acid amide hydrolase (FAAH) and monoacyl glycerol lipase (MAGL) by real time qPCR and Western blotting. Content of 2-AG was lower in the left side of the hippocampus and prefrontal cortex in FSL rats compared to FRL rats. Inversely, levels of AEA were higher in right hippocampus than in left hippocampus. In plasma, AEA levels were increased and 2-AG decreased. Cannabinoid receptor 1 (Cnr1), Faah and Magl mRNA levels were prominently decreased in right prefrontal cortex of FSL rats as compared to FRL rats. Protein expression of CB1R and FAAH were decreased in left hippocampus. In summary, our data suggest a decreased eCB signalling in the FSL rats, which could contribute to the depressive-like behaviour. Interestingly, the altered eCB system activity appear to be hemisphere-specific in the limbic regions. Our study support the existing literature and showed altered eCB system activity in this particular animal model of depression.


Assuntos
Depressão/metabolismo , Endocanabinoides/metabolismo , Hipocampo/metabolismo , Córtex Pré-Frontal/metabolismo , Animais , Cérebro/metabolismo , Depressão/genética , Masculino , Ratos , Ratos Transgênicos , Especificidade da Espécie
9.
Med Sci Monit ; 25: 525-531, 2019 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-30657131

RESUMO

BACKGROUND The incidence of postoperative cognitive dysfunction (POCD) after major joint arthroplasty is high. In the etiology of POCD, many factors have been cited, including thromboembolic complications. The incidence of cerebral embolization after lower extremity arthroplasty may be as high as 40-60%. The potential events of cerebral embolization could lead to a decrease in the regional cerebral oxygenation (rSO2) and increased serum levels of biochemical markers of brain damage. The objective of the study was to test whether there are any changes in the rSO2 values and serum markers of brain damage in patients who underwent total hip arthroplasty. MATERIAL AND METHODS Fifteen patients who underwent primary hip arthroplasty under spinal anesthesia were analyzed. The rSO2 was monitored using infrared spectroscopy. Biochemical analyses of S100 calcium-binding protein B (S100B) protein and fibrillary acidic protein (GFAP) serum concentrations were performed using immunoassay methods. RESULTS The values of rSO2 decreased during the surgery, but this was not related to mean arterial pressure variations or hemoglobin saturation. The concentration of S100B was increased compared to its preoperative values, and there were no changes in GFAP values. The changes in rSO2 readings correlated with the biomarkers' levels just after the surgery. CONCLUSIONS Our results suggest that S100B may be a more specific marker of astroglial damage in patients after primary total hip arthroplasty. The decrease in rSO2 readings may be due to micro-thromboembolic events that occurred during the surgery. However, the results of this study are preliminary, and further studies are needed to establish its clinical efficacy.


Assuntos
Artroplastia de Quadril/efeitos adversos , Cérebro/metabolismo , Oxigênio/metabolismo , Idoso , Idoso de 80 Anos ou mais , Artroplastia/efeitos adversos , Biomarcadores/sangue , Encéfalo/metabolismo , Lesões Encefálicas/sangue , Artérias Cerebrais/metabolismo , Cérebro/irrigação sanguínea , Feminino , Proteína Glial Fibrilar Ácida/análise , Proteína Glial Fibrilar Ácida/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Oximetria/métodos , Oxigênio/análise , Oxigênio/sangue , Período Perioperatório/métodos , Projetos Piloto , Subunidade beta da Proteína Ligante de Cálcio S100/análise , Subunidade beta da Proteína Ligante de Cálcio S100/sangue
10.
Neuropharmacology ; 149: 1-12, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30695710

RESUMO

Limited information exists on the link between purinergic class P2X7 receptors (P2X7Rs) and calcium ion channels in epilepsy; no data has been reported regarding the interaction between P2X7Rs and T-type calcium ion channels in epilepsy. Thus, this study is an evaluation of the role that T-type calcium ion channels play in the effect of P2X7Rs on penicillin-induced epileptiform activity. In the first set of experiments, P2X7R agonist BzATP (at 25-, 50-, 100- and 200-µg doses), P2X7R antagonist A-438079 (at 5-, 10-, 20- and 40-µg doses) and T-type calcium ion channel antagonist, NNC-550396 were administered for electrophysiological analyses 30 min after penicillin injection (2.5 µl, 500 IU). In the second set of experiments, the effective doses of these substances were used for biochemical analyses. Malondialdehyde (MDA), advanced oxidation protein product (AOPP), glutathione (GSH), glutathione reductase (GR), glutathione peroxide (GPx), catalase (CAT) and superoxide dismutase (SOD) levels were measured in the cerebrum, cerebellum and brainstem of rats. BzATP (100 µg, icv) increased the mean frequency of epileptiform activity, whereas A-438079 (40 µg, icv) and NNC-550396 (30 µg, ic) reduced it. Both A-438079 and NNC-550396 reversed BzATP's proconvulsant action. BzATP increased lipid peroxidation and protein oxidation; it also altered other antioxidant enzymes measured in this study, which were all then reversed via A-438079 and NNC-550396, at least in the cerebrum. The electrophysiological and biochemical analysis of present study suggest that P2X7Rs and its interaction with T-type calcium ion channels play an important role in the experimental model of epilepsy.


Assuntos
Canais de Cálcio Tipo T/efeitos dos fármacos , Canais de Cálcio Tipo T/metabolismo , Epilepsia/metabolismo , Receptores Purinérgicos P2X7/efeitos dos fármacos , Receptores Purinérgicos P2X7/metabolismo , Trifosfato de Adenosina/análogos & derivados , Trifosfato de Adenosina/farmacologia , Animais , Antioxidantes/metabolismo , Benzimidazóis/farmacologia , Tronco Encefálico/efeitos dos fármacos , Tronco Encefálico/metabolismo , Cerebelo/efeitos dos fármacos , Cerebelo/metabolismo , Cérebro/efeitos dos fármacos , Cérebro/metabolismo , Ciclopropanos/farmacologia , Modelos Animais de Doenças , Epilepsia/induzido quimicamente , Naftalenos/farmacologia , Penicilinas/farmacologia , Agonistas do Receptor Purinérgico P2X/farmacologia , Antagonistas do Receptor Purinérgico P2X/farmacologia , Piridinas/farmacologia , Ratos , Ratos Wistar , Tetrazóis/farmacologia
11.
Bull Exp Biol Med ; 166(3): 317-320, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30627909

RESUMO

The in vitro and in vivo models of ethanol-induced neurodegeneration were used to evaluate the content and functional activity of various types of regeneration-competent cells in subventricular zone of the cerebral hemispheres in C57Bl/6JY mice. In nervous tissue culture, ethanol (65 mM) produced no effect on formation of neurospheres. When administered per os in a daily dose of 3 g/kg for 8 weeks, ethanol produced no effect on the number of neural CFU in situ. In both cases, ethanol reduced proliferative activity of neural CFU. Long-term administration of ethanol in vivo suppressed differentiation of neural stem cells and decreased the number of committed precursors (neural cluster-forming units) in the subventricular zone of cerebral hemispheres. In vitro application of ethanol stimulated secretion of humoral growth factors by the cluster-forming neural glial cells. In contrast, in vivo administration of ethanol suppressed this secretion.


Assuntos
Alcoolismo/patologia , Cérebro/efeitos dos fármacos , Etanol/farmacologia , Ventrículos Laterais/efeitos dos fármacos , Doenças Neurodegenerativas/patologia , Neurônios/efeitos dos fármacos , Alcoolismo/metabolismo , Animais , Contagem de Células , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cérebro/metabolismo , Cérebro/patologia , Cérebro/fisiopatologia , Modelos Animais de Doenças , Peptídeos e Proteínas de Sinalização Intercelular/agonistas , Peptídeos e Proteínas de Sinalização Intercelular/biossíntese , Ventrículos Laterais/metabolismo , Ventrículos Laterais/patologia , Ventrículos Laterais/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/patologia , Doenças Neurodegenerativas/metabolismo , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Neuroglia/patologia , Neurônios/patologia , Cultura Primária de Células , Esferoides Celulares/efeitos dos fármacos
12.
Neurocrit Care ; 30(3): 590-600, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30430381

RESUMO

BACKGROUND: Cerebral microdialysis (CMD) is a valuable tool for monitoring compounds in the cerebral extracellular fluid (ECF). Glycerol is one such compound which is regarded as a marker of cell membrane decomposition. Notably, in some acutely brain-injured patients, CMD-glycerol levels rise without any other apparent indication of cerebral deterioration. The aim of this study was to investigate whether this could be due to an association between CMD-glycerol levels and the administration of glycerol-containing drugs. METHODS: Microdialysis data were retrospectively retrieved from the hospital's intensive care unit patient data management system (PDMS). All patients who were monitored with CMD for ≥ 96 h were included. Administered drug doses were retrieved from the PDMS and converted to exact doses of glycerol. Cross-correlation analyses were performed between the free, metabolized as well as total administered dose of glycerol and the detrended and differenced CMD-glycerol concentration. These analyses were repeated for two sets of subgroups based upon the individual catheter's graphical trend and its location in relation to the lesion. RESULTS: There was no significant correlation between the differenced CMD-glycerol levels and drug-administered glycerol. Furthermore, there was no significant correlation between CMD-glycerol and catheter location or graphical trend. However, if the CMD-glycerol levels were detrended, significant but clinically non-relevant correlations were identified (maximum correlation coefficient of 0.1 (0.04-0.15, 95% CI) at a lag of 7 h using the total administered dose of glycerol). CONCLUSIONS: Glycerol-containing drugs routinely administered intravenously in the clinical setting appear to have a minimal and clinically insignificant effect on levels of glycerol in the cerebral ECF.


Assuntos
Lesões Encefálicas Traumáticas/diagnóstico , Cérebro/metabolismo , Cuidados Críticos , Líquido Extracelular/metabolismo , Glicerol/administração & dosagem , Glicerol/metabolismo , Meningites Bacterianas/diagnóstico , Microdiálise , Hemorragia Subaracnóidea/diagnóstico , Administração Intravenosa , Adulto , Lesões Encefálicas Traumáticas/tratamento farmacológico , Lesões Encefálicas Traumáticas/metabolismo , Feminino , Humanos , Unidades de Terapia Intensiva , Masculino , Sistemas Computadorizados de Registros Médicos , Meningites Bacterianas/tratamento farmacológico , Meningites Bacterianas/metabolismo , Pessoa de Meia-Idade , Monitorização Neurofisiológica , Estudos Retrospectivos , Hemorragia Subaracnóidea/tratamento farmacológico , Hemorragia Subaracnóidea/metabolismo
13.
Mol Pharm ; 16(1): 247-257, 2019 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-30495961

RESUMO

Certain proteins, such as inflammatory cytokines, that are released from injured or diseased organs are transported from the circulating blood through the blood-brain barrier (BBB) into the brain and contribute to the pathogenesis of related central nervous system dysfunctions. However, little is known about the protein transport mechanisms involved in the central nervous system dysfunctions. The aims of the present study were to identify BBB-permeable protein(s) derived from liver and to clarify their transport characteristics at the BBB. After administration of biotin-labeled liver cytosolic protein fraction to mice in vivo, we identified 9 biotin-labeled proteins in the brain. Among them, we focused here on creatine kinase (CK). In vitro uptake studies with human brain microvessel endothelial cells (hCMEC/D3 cells) showed preferential uptake of muscle-type CK (CK-MM) compared with brain-type CK (CK-BB) at the BBB. Integration plot analysis revealed that CK-MM readily penetrated into brain parenchyma from the circulating blood across the BBB. The uptake of CK-MM by hCMEC/D3 cells was decreased at 4 °C and in the presence of clathrin- and caveolin-dependent endocytosis inhibitors. These results indicate that entry of CK into the brain is mediated by a transport system(s) at the BBB.


Assuntos
Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Creatina Quinase/metabolismo , Animais , Transporte Biológico/fisiologia , Linhagem Celular , Cérebro/metabolismo , Humanos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteômica , Coelhos
14.
Aerosp Med Hum Perform ; 89(12): 1045-1049, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30487024

RESUMO

INTRODUCTION: Clinical accuracy of pulse oximeters (giving Spo2) is routinely tested down to an Sao2 of 70%, but lower oxygen saturations are often experienced during hypobaric hypoxia. Cerebral (Sco2) and peripheral tissue (Sto2) oxygen saturations can be measured using near infra-red spectroscopy. In a project simulating oxygen system failure during high altitude-high opening parachuting (HAHO), Sao2, Spo2, Sco2, and forearm Sto2 were measured. The aim of the present analysis was to explore the agreement between Sao2 and the three noninvasive measurements of hypoxemia (Spo2, Sco2, and Sto2).METHODS: Healthy volunteers from the Norwegian Special Operations Commando were studied in a hypobaric chamber as supplemental oxygen was removed at 301 hPa ambient pressure (30,000 ft) and recompressed at 25 hPa · min-1 (1000 ft · min-1) to ground level simulating a HAHO parachute flight. Sao2 was compared with Spo2, Sco2, and Sto2 in scatterplots and Bland-Altman plots, calculating bias and limits of agreement (LOA).RESULTS: The bias ± LOA were: Sao2 vs. Spo2: -5.8% ± 16, Sao2 vs. Sco2: -3.4% ± 11, and Sao2 vs. Sto2: 17% ± 30. The bias for Sao2 vs. Spo2 was dependent on the range of values, and correcting for this with a sloped bias line reduced the LOA to ± 8.2%.DISCUSSION: There were wide limits of agreement between Sao2 and Spo2. Sao2 and Sco2 agreed better, whereas Sao2 and forearm Sto2 had wide LOA. The agreement between Sao2 and Spo2 improved when correcting for the underestimation of Spo2 at low values. There is a poor agreement between Spo2 and the gold standard Sao2 during extreme hypobaric hypoxemia.Ottestad W, Kåsin JI, Høiseth LØ. Arterial oxygen saturation, pulse oximetery, and cerebral and tissue oximetry in hypobaric hypoxia. Aerospace Med Hum Perform. 2018; 89(12):1045-1049.


Assuntos
Cérebro/metabolismo , Hipóxia/fisiopatologia , Oxigênio/sangue , Adulto , Medicina Aeroespacial , Altitude , Pressão Atmosférica , Gasometria , Feminino , Humanos , Hipóxia/sangue , Masculino , Pessoa de Meia-Idade , Oximetria
15.
Transl Psychiatry ; 8(1): 238, 2018 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-30375373

RESUMO

Accumulating research has linked Mediterranean diet (MeDi) adherence with slower cognitive decline and reduced Alzheimer's disease (AD) risk. However, no study to-date has examined the relationship between MeDi adherence and accumulation of cerebral Aß-amyloid (Aß; a pathological hallmark of AD) in older adults. Cognitively normal healthy control participants of the Australian Imaging, Biomarkers and Lifestyle (AIBL) Study of Ageing completed the Cancer Council of Victoria Food Frequency Questionnaire at baseline, which was used to construct a MeDi score for each participant (score range 0-9; higher score indicating higher adherence). Cerebral Aß load was quantified by Pittsburgh Compound B positron emission tomography at baseline, 18 and 36 months: Only individuals categorised as "Aß accumulators", and thus considered to be on the AD pathway, were included in the analysis (N = 77). The relationship between MeDi adherence, MeDi components, and change in cerebral Aß load (baseline to 36 months) was evaluated using Generalised Linear Modelling, accounting for age, gender, education, Apolipoprotein E ε4 allele status, body mass index and total energy intake. Higher MeDi score was associated with less Aß accumulation in our cohort (ß = -0.01 ± 0.004, p = 0.0070). Of the individual MeDi score components, a high intake of fruit was associated with less accumulation of Aß (ß = -0.04 ± 0.01, p = 0.00036). Our results suggest MeDi adherence is associated with reduced cerebral AD pathology accumulation over time. When our results are considered collectively with previous data linking the MeDi to slower cognitive decline, it is apparent that MeDi adherence warrants further investigation in the quest to delay AD onset.


Assuntos
Envelhecimento/metabolismo , Peptídeos beta-Amiloides/metabolismo , Cérebro/metabolismo , Dieta Mediterrânea , Idoso , Idoso de 80 Anos ou mais , Austrália , Biomarcadores/metabolismo , Cérebro/diagnóstico por imagem , Feminino , Seguimentos , Humanos , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons
16.
Nat Commun ; 9(1): 4167, 2018 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-30301888

RESUMO

Cerebral organoids are 3D stem cell-derived models that can be utilized to study the human brain. The current consensus is that cerebral organoids consist of cells derived from the neuroectodermal lineage. This limits their value and applicability, as mesodermal-derived microglia are important players in neural development and disease. Remarkably, here we show that microglia can innately develop within a cerebral organoid model and display their characteristic ramified morphology. The transcriptome and response to inflammatory stimulation of these organoid-grown microglia closely mimic the transcriptome and response of adult microglia acutely isolated from post mortem human brain tissue. In addition, organoid-grown microglia mediate phagocytosis and synaptic material is detected inside them. In all, our study characterizes a microglia-containing organoid model that represents a valuable tool for studying the interplay between microglia, macroglia, and neurons in human brain development and disease.


Assuntos
Cérebro/metabolismo , Microglia/metabolismo , Organoides/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Camadas Germinativas/citologia , Humanos , Imunidade , Masculino , Mesoderma/citologia , Microglia/citologia , Pessoa de Meia-Idade , Neurônios/metabolismo , Células-Tronco/citologia , Células-Tronco/metabolismo , Transcriptoma/genética , Adulto Jovem
17.
BMC Neurosci ; 19(1): 55, 2018 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-30208879

RESUMO

BACKGROUND: The long-term effects of psychotropic drugs are associated with the reversal of disease-related alterations through the reorganization and normalization of neuronal connections. Molecular factors that trigger drug-induced brain plasticity remain only partly understood. Doublecortin-like kinase 1 (Dclk1) possesses microtubule-polymerizing activity during synaptic plasticity and neurogenesis. However, the Dclk1 gene shows a complex profile of transcriptional regulation, with two alternative promoters and exon splicing patterns that suggest the expression of multiple isoforms with different kinase activities. RESULTS: Here, we applied next-generation sequencing to analyze changes in the expression of Dclk1 gene isoforms in the brain in response to several psychoactive drugs with diverse pharmacological mechanisms of action. We used bioinformatics tools to define the range and levels of Dclk1 transcriptional regulation in the mouse nucleus accumbens and prefrontal cortex. We also sought to investigate the presence of DCLK1-derived peptides using mass spectrometry. We detected 15 transcripts expressed from the Dclk1 locus (FPKM > 1), including 2 drug-regulated variants (fold change > 2). Drugs that act on serotonin receptors (5-HT2A/C) regulate a subset of Dclk1 isoforms in a brain-region-specific manner. The strongest influence was observed for the mianserin-induced expression of an isoform with intron retention. The drug-activated expression of novel alternative Dclk1 isoforms was validated using qPCR. The drug-regulated isoform contains genetic variants of DCLK1 that have been previously associated with schizophrenia and hyperactivity disorder in humans. We identified a short peptide that might originate from the novel DCLK1 protein product. Moreover, protein domains encoded by the regulated variant indicate their potential involvement in the negative regulation of the canonical DCLK1 protein. CONCLUSIONS: In summary, we identified novel isoforms of the neuroplasticity-related gene Dclk1 that are expressed in the brain in response to psychotropic drug treatments.


Assuntos
Processamento Alternativo/efeitos dos fármacos , Cérebro/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/metabolismo , Psicotrópicos/farmacologia , Transcrição Genética/efeitos dos fármacos , Animais , Cérebro/metabolismo , Biologia Computacional , Masculino , Proteínas de Membrana , Camundongos Endogâmicos C57BL , Isoformas de Proteínas/efeitos dos fármacos , Isoformas de Proteínas/metabolismo , RNA Mensageiro/metabolismo , Proteínas de Saccharomyces cerevisiae
18.
Vascul Pharmacol ; 111: 26-35, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30114508

RESUMO

We assessed the ability of poststroke losartan and captopril treatment to attenuate hematoma expansion and plasma extravasation after intracerebral hemorrhagic stroke in Kyoto-Wistar stroke-prone hypertensive rats (SHRsp). Cerebrum volume, herniation and surface areas exhibiting new and old hemorrhages and albumin extravasation were measured prior to and after stroke and following 30 and 60 days of post-stroke losartan or captopril treatment in Evans Blue dye perfused brains. Lesion morphology was studied in serial sections. Losartan or captopril treatment initiated at stroke prevented death for 60 days without lowering BP. Stroke onset was associated with the development and subsequent expansion of cerebrum volume, herniation, hematoma and plasma albumin extravasation. Losartan arrested cerebral volume expansion and herniation, and produced the virtual disappearance of hematoma and plasma albumin extravasation after 60 days. Captopril treatment equally attenuated cerebral herniation and hematoma expansion but was less effective in stopping albumin extravasation and allowed cerebrum volume to increase to post-stroke levels after 60 days of treatment. Both treatments resolved hematomas into cortical fluid filled spaces and prevented new hemorrhage formation. We believe that the treatments attenuated death after stroke by inhibiting hemorrhagic expansion through non-pressure related physiological changes mediated by the inhibition of the renin-angiotensin system.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Captopril/farmacologia , Hemorragia Cerebral/tratamento farmacológico , Cérebro/efeitos dos fármacos , Losartan/farmacologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Acidente Vascular Cerebral/tratamento farmacológico , Animais , Edema Encefálico/metabolismo , Edema Encefálico/patologia , Edema Encefálico/fisiopatologia , Edema Encefálico/prevenção & controle , Hemorragia Cerebral/metabolismo , Hemorragia Cerebral/patologia , Hemorragia Cerebral/fisiopatologia , Cérebro/metabolismo , Cérebro/patologia , Cérebro/fisiopatologia , Modelos Animais de Doenças , Progressão da Doença , Masculino , Ratos Endogâmicos WKY , Albumina Sérica/metabolismo , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/fisiopatologia , Fatores de Tempo
19.
Mamm Genome ; 29(9-10): 619-631, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30008145

RESUMO

Glutathione is a ubiquitous antioxidant that protects cells against reactive oxygen species and other chemical stressors. Despite its functional importance, the impact of genetics on the glutathione system has yet to be fully appreciated. Here, we investigated the heritability of glutathione levels and redox status in a disease-relevant condition: advanced age. We assembled a panel of 18-21-month-old mice representing 19 inbred strains and quantified the levels of reduced and oxidized glutathione, and their sums and ratios, in liver, kidney, heart, pancreas, cerebral cortex, and striatum. Heritability values were calculated for each phenotype and the results varied by tissue of origin. Cardiac glutathione phenotypes exhibited the highest heritabilities (G2 = 0.44-0.67), while striatal glutathione was least heritable (G2 = 0.11-0.29). Statistical relationships between tissues were evaluated, and the emergence of significant correlations suggested that despite tissue-specific heritabilities, at least some shared regulatory mechanisms may exist. Overall, these data highlight another mechanism by which genetic background determines antioxidant protection and stress resistance.


Assuntos
Glutationa/genética , Glutationa/metabolismo , Animais , Cérebro/metabolismo , Feminino , Glutationa/análise , Dissulfeto de Glutationa/análise , Dissulfeto de Glutationa/genética , Dissulfeto de Glutationa/metabolismo , Rim/metabolismo , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos , Miocárdio/metabolismo , Especificidade de Órgãos , Pâncreas/metabolismo , Fenótipo , Característica Quantitativa Herdável , Especificidade da Espécie
20.
J Agric Food Chem ; 66(25): 6402-6413, 2018 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-29865786

RESUMO

The residues from the widely used broad-spectrum environmental herbicide, atrazine (ATR), result in the exposure of nontarget organisms and persist as a global major public health hazard. ATR is neurotoxic and may cause adverse health effects in mammals, birds, and fishes. Nevertheless, the molecular mechanism of ATR induced neurotoxicity remains unclear. To assess the molecular mechanisms of ATR-induced cerebral toxicity through potential oxidative damage, quail were treated with ATR by oral gavage administration at doses of 0, 50, 250, and 500 mg/kg body weight daily for 45 days. Markedly, increases in the amount of swelling of neuronal cells, the percentage of mean damaged mitochondria, mitochondrial malformation, and mitochondrial vacuolar degeneration as well as decreases in the mitochondrial cristae and mitochondrial volume density were observed by light and electron microscopy in the cerebrum of quail. ATR induced toxicities in the expression of mitochondrial function-related genes and promoted oxidative damage, as indicated by effects on oxidative stress indices. These results indicated that ATR exposure can cause neurological disorders and cerebral injury. ATR may initiate apoptosis by activating Bcl-2, Bax, and Caspase3 protein expression but failed to induce autophagy (LC3B has not cleaved to LC3BI/II). Furthermore, ATR induced CYP-related enzymes metabolism disorders by activating the nuclear xenobiotic receptors response (NXRs including AHR, CAR, and PXR) and increased expression of several CYP isoforms (including CYP1B1 and CYP2C18) and thereby producing mitochondrial dysfunction. In this study, we observed ATR exposure resulted in oxidative stress and mitochondrial dysfunction by activating the NXR response and interfering the CYP450s homeostasis in quail cerebrum that supported the molecular mechanism of ATR induced cerebrum toxicity. In conclusion, these results provided new evidence on molecular mechanism of ATR induced neurotoxicity.


Assuntos
Atrazina/toxicidade , Proteínas Aviárias/metabolismo , Cérebro/efeitos dos fármacos , Coturnix/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Herbicidas/toxicidade , Receptores Citoplasmáticos e Nucleares/metabolismo , Xenobióticos/toxicidade , Animais , Apoptose/efeitos dos fármacos , Proteínas Aviárias/genética , Cérebro/metabolismo , Coturnix/genética , Sistema Enzimático do Citocromo P-450/genética , Homeostase/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Receptores Citoplasmáticos e Nucleares/genética
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