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1.
Cardiol Young ; 29(7): 893-897, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31218973

RESUMO

BACKGROUND: Vascular endothelial growth factor is critically involved in ductus arteriosus closure. Polymorphisms in the vascular endothelial growth factor gene have been associated with several diseases in neonates and adults. AIM: Herein, we investigated if vascular endothelial growth factor polymorphism rs2010963 status is associated with patent ductus arteriosus incidence and/or pharmacological treatment success. METHODS: We assessed rs2010963 status in 814 preterm infants (<1500 g birth weight) by means of restriction fragment length polymorphism analysis. DNA samples were obtained from dry-spot cards used for the German national newborn screening program. Clinical data were obtained by retrospective chart review. RESULTS: We could not find any statistically significant difference in the incidence of patent ductus arteriosus depending on vascular endothelial growth factor rs2010963 polymorphism status. Furthermore, no statistically significant associations between vascular endothelial growth factor polymorphism rs2010963 status and cyclooxygenase inhibitor treatment success were observed. CONCLUSION: Our results indicate that there is no association between vascular endothelial growth factor polymorphism rs2010963 status and the occurrence of patent ductus arteriosus or the response to cyclooxygenase inhibitor treatment in a large cohort of preterm infants. Additional studies are needed to determine the role of genetic factors on patent ductus arteriosus incidence and treatment response.


Assuntos
Inibidores de Ciclo-Oxigenase/uso terapêutico , Permeabilidade do Canal Arterial/tratamento farmacológico , Permeabilidade do Canal Arterial/genética , Doenças do Prematuro/genética , Polimorfismo Genético/genética , Fator A de Crescimento do Endotélio Vascular/genética , Estudos de Casos e Controles , Permeabilidade do Canal Arterial/epidemiologia , Feminino , Humanos , Ibuprofeno/uso terapêutico , Incidência , Indometacina/uso terapêutico , Recém-Nascido , Recém-Nascido Prematuro , Doenças do Prematuro/tratamento farmacológico , Doenças do Prematuro/epidemiologia , Masculino , Resultado do Tratamento
2.
Respir Res ; 20(1): 88, 2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-31077204

RESUMO

BACKGROUND: While additional oxygen supply is often required for the survival of very premature infants in intensive care, this also brings an increasing risk of progressive lung diseases and poor long-term lung outcomes. Caffeine is administered to neonates in neonatal intensive care for the prevention and treatment of apneas and has been shown to reduce BPD incidence and the need for mechanical ventilation, although it is still unclear whether this is due to a direct pulmonary action via antagonism of adenosine receptors and/or an indirect action. This experimental study aims to investigate the action of caffeine on the oxidative stress response in pulmonary tissue in a hyperoxia-based model of bronchopulmonary dysplasia in newborn rats. METHODS: Newborn Wistar rats were exposed to 21% or 80% oxygen for 3 (P3) or 5 (P5) postnatal days with or without recovery on room air until postnatal day 15 (P15) and treated with vehicle or caffeine (10 mg/kg) every 48 h beginning on the day of birth. The lung tissue of the rat pups was examined for oxidative stress response at P3 and P5 immediately after oxygen exposure or after recovery in ambient air (P15) by immunohistological staining and analysis of lung homogenates by ELISA and qPCR. RESULTS: Lungs of newborn rats, corresponding to the saccular stage of lung development and to the human lung developmental stage of preterms, showed increased rates of total glutathione and hydrogen peroxide, oxidative damage to DNA and lipids, and induction of second-phase mediators of antioxidative stress response (superoxide dismutase, heme oxygenase-1, and the Nrf2/Keap1 system) in response to hyperoxia. Caffeine reduced oxidative DNA damage and had a protective interference with the oxidative stress response. CONCLUSION: In addition to the pharmacological antagonism of adenosine receptors, caffeine appears to be a potent antioxidant and modulates the hyperoxia-induced pulmonary oxidative stress response and thus protective properties in the BPD-associated animal model. Free-radical-induced damage caused by oxidative stress seems to be a biological mechanism progress of newborn diseases. New aspects of antioxidative therapeutic strategies to passivate oxidative stress-related injury should be in focus of further investigations.


Assuntos
Antioxidantes/uso terapêutico , Displasia Broncopulmonar/tratamento farmacológico , Cafeína/uso terapêutico , Modelos Animais de Doenças , Hiperóxia/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Antioxidantes/farmacologia , Displasia Broncopulmonar/sangue , Cafeína/sangue , Cafeína/farmacologia , Feminino , Hiperóxia/sangue , Estresse Oxidativo/fisiologia , Gravidez , Distribuição Aleatória , Ratos , Ratos Wistar , Resultado do Tratamento
3.
Dev Neurobiol ; 79(3): 222-235, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30674088

RESUMO

In preterm infants, the changes from fetal life to ex-utero conditions often coincide with reduced growth and white matter damage of the cerebellum. The premature increase in arterial oxygen tension caused by preterm birth may dysregulate cerebellar development. In a hyperoxia rat model of white matter damage to mimic a steep increase in oxygen levels by 24 h exposure to 80% O2 from postnatal day 6 (P6) to day 7, we analyzed growth factor (GF) synthesis of cerebellar astrocytes. Determination of GF production was performed in astrocytes after Magnetic-activated cell sorting (MACS) isolation from cerebelli after hyperoxia exposure ex vivo, and also in astroglial cultures. Oligodendrocyte progenitor cell (OPC) function was analyzed in cerebellar OPCs isolated by MACS after hyperoxia. Administration of PDGFA from P6 to P11, during hyperoxia and during 4 days recovery, was finally tested for protection of oligodendroglia and myelination. As a result, expression of the GFs Pdgfa, Fgf2, and Bdnf was diminished in cerebellar astrocytes in vitro and in vivo. Gene expression of Olig1, Olig2, Sox9, Sox10, and Cnp was reduced in OPCs in vivo. Nasal PDGFA application improved oligodendroglial proliferation after hyperoxia at P7. However, this treatment effect vanished until P9. Impaired MBP expression after hyperoxia was attenuated by PDGFA treatment until P11, but not beyond when PDGFA supply was stopped. In this study on neonatal cerebellar injury, it is documented for the first time that improvement of oligodendroglial proliferation and of myelination can be achieved by PDGFA treatment. However, the treatment benefit is not maintained long term.


Assuntos
Cerebelo/efeitos dos fármacos , Hiperóxia/metabolismo , Oligodendroglia/efeitos dos fármacos , Fator de Crescimento Derivado de Plaquetas/farmacologia , Animais , Animais Recém-Nascidos , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Proliferação de Células/efeitos dos fármacos , Cerebelo/crescimento & desenvolvimento , Recém-Nascido Prematuro , Fibras Nervosas Mielinizadas/metabolismo , Neurogênese/efeitos dos fármacos , Oligodendroglia/metabolismo , Ratos Wistar , Substância Branca/efeitos dos fármacos , Substância Branca/crescimento & desenvolvimento
4.
J Neuroimmune Pharmacol ; 13(3): 383-395, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29790105

RESUMO

Tissue damage and pathogen invasion during surgical trauma have been identified as contributing factors leading to neuroinflammation in the hippocampus, which can be protected by stimulation of the cholinergic anti-inflammatory pathway using the acetylcholinesterase inhibitor physostigmine. Macroautophagy, an intracellular degradation pathway used to recycle and eliminate damaged proteins and organelles by lysosomal digestion, seems to be important for cell survival under stress conditions. This study aimed to examine the role of autophagy in physostigmine-mediated hippocampal cell protection in a rat model of surgery stress. In the presence or absence of physostigmine, adult Wistar rats underwent surgery in combination with lipopolysaccharide (LPS). Activated microglia, apoptosis-, autophagy-, and anti-inflammatory-related genes and -proteins in the hippocampus were determined by Real-Time PCR, Western blot and fluorescence microscopy after 1 h, 24 h and 3 d. Surgery combined with LPS-treatment led to microglia activation after 1 h and 24 h which was accompanied by apoptotic cell death after 24 h in the hippocampus. Furthermore, it led to a decreased expression of ATG-3 after 24 h and an increased expression of p62/ SQSTM1 after 1 h and 24 h. Administration of physostigmine significantly increased autophagy related markers and restored the autophagic flux after surgery stress, detected by increased degradation of p62/ SQSTM1 in the hippocampus after 1 h and 24 h. Furthermore, physostigmine reduced activated microglia and apoptosis relevant proteins and elevated the increased expression of TGF-beta1 and MFG-E8 after surgery stress. In conclusion, activation of autophagy may be essential in physostigmine-induced neuroprotection against surgery stress.


Assuntos
Autofagia/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Lipopolissacarídeos/antagonistas & inibidores , Fármacos Neuroprotetores/farmacologia , Fisostigmina/farmacologia , Estresse Fisiológico , Animais , Apoptose/efeitos dos fármacos , Proteínas Relacionadas à Autofagia/biossíntese , Proteína Beclina-1/metabolismo , Inflamação/genética , Inflamação/patologia , Inflamação/psicologia , Lipopolissacarídeos/toxicidade , Ativação de Macrófagos/efeitos dos fármacos , Masculino , Microglia/efeitos dos fármacos , Proteínas Associadas aos Microtúbulos/metabolismo , Peptídeo Sintases/biossíntese , Período Pós-Operatório , Ratos , Ratos Wistar , Proteína Sequestossoma-1/biossíntese
5.
Neurotox Res ; 34(2): 173-187, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29417440

RESUMO

In preterm infants, phenobarbital is the first-line antiepileptic drug for neonatal seizures while caffeine is used for the treatment of apnea. Data from experimental animals suggest that phenobarbital and other anticonvulsants are toxic for the developing brain, while neuroprotective effects have been reported for caffeine both in newborn rodents and preterm human infants. To characterize the interaction of phenobarbital and caffeine in the hippocampus of the developing rodent brain, we examined the effects of both drugs given separately or together on postnatal neurogenesis after administration to neonatal rats throughout postnatal day (P) 4 to P6. Phenobarbital treatment (50 mg/kg) resulted in a significant decrease of proliferative capacity in the dentate gyrus. Phenobarbital also reduced expression of neuronal markers (doublecortin (DCX), calretinin, NeuN), neuronal transcription factors (Pax6, Sox2, Tbr1/2, Prox1), and neurotrophins (NGF, BDNF, NT-3) up to 24 h after the last administration. The phenobarbital-mediated impairment of neurogenesis was largely ameliorated by preconditioning with caffeine (10 mg/kg). In contrast, caffeine alone reduced proliferative capacity and expression of the neuronal markers DCX and NeuN at 6 h, but increased expression of neurotrophins and neuronal transcription factors at 6 and 12 h. These results indicate that administration of phenobarbital during the vulnerable phase of brain development negatively interferes with neuronal development, which can be prevented in part by co-administration of caffeine.


Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/crescimento & desenvolvimento , Cafeína/farmacologia , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Análise de Variância , Animais , Animais Recém-Nascidos , Anticonvulsivantes/toxicidade , Encéfalo/citologia , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proliferação de Células/efeitos dos fármacos , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Feminino , Hipoxantina Fosforribosiltransferase/genética , Hipoxantina Fosforribosiltransferase/metabolismo , Masculino , Fator de Crescimento Neural/genética , Fator de Crescimento Neural/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurotrofina 3/genética , Neurotrofina 3/metabolismo , Fator de Transcrição PAX6/genética , Fator de Transcrição PAX6/metabolismo , Fenobarbital/toxicidade , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Fatores de Tempo
6.
Mol Neurobiol ; 55(5): 3901-3915, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-28547531

RESUMO

Impaired postnatal brain development of preterm infants often results in neurological deficits. Besides pathologies of the forebrain, maldeveolopment of the cerebellum is increasingly recognized to contribute to psychomotor impairments of many former preterm infants. However, causes are poorly defined. We used a hyperoxia model to define neonatal damage in cerebellar granule cell precursors (GCPs) and in Purkinje cells (PCs) known to be essential for interaction with GCPs during development. We exposed newborn rats to 24 h 80% O2 from age P6 to P7 to identify postnatal and long-term damage in cerebellar GCPs at age P7 after hyperoxia and also after recovery in room air thereafter until P11 and P30. We determined proliferation and apoptosis of GCPs and immature neurons by immunohistochemistry, quantified neuronal damage by qPCR and Western blots for neuronal markers, and measured dendrite outgrowth of PCs by CALB1 immunostainings and by Sholl analysis of Golgi stainings. After hyperoxia, proliferation of PAX6+ GCPs was decreased at P7, while DCX + CASP3+ cells were increased at P11. Neuronal markers Pax6, Tbr2, and Prox1 were downregulated at P11 and P30. Neuronal damage was confirmed by reduced NeuN protein expression at P30. Sonic hedgehog (SHH) was significantly decreased at P7 and P11 after hyperoxia and coincided with lower CyclinD2 and Hes1 expression at P7. The granule cell injury was accompanied by hampered PC maturation with delayed dendrite formation and impaired branching. Neonatal injury induced by hyperoxia inhibits PC functioning and impairs granule cell development. As a conclusion, maldevelopment of the cerebellar neurons found in preterm infants could be caused by postnatal oxygen toxicity.


Assuntos
Cerebelo/crescimento & desenvolvimento , Cerebelo/patologia , Hiperóxia/patologia , Neurogênese , Neurônios/patologia , Animais , Animais Recém-Nascidos , Contagem de Células , Morte Celular/genética , Proliferação de Células/genética , Dendritos/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Proteínas Hedgehog/metabolismo , Hiperóxia/genética , Neurônios/metabolismo , Células de Purkinje/metabolismo , Ratos Wistar
7.
Int J Mol Sci ; 18(9)2017 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-28832497

RESUMO

During surgery or infection, peripheral inflammation can lead to neuroinflammation, which is associated with cognitive impairment, neurodegeneration, and several neurodegenerative diseases. Dexmedetomidine, an α-2-adrenoceptor agonist, is known to exert anti-inflammatory and neuroprotective properties and reduces the incidence of postoperative cognitive impairments. However, on the whole the molecular mechanisms are poorly understood. This study aims to explore whether dexmedetomidine influences microRNAs (miRNAs) in a rat model of lipopolysaccharide (LPS)-induced neuroinflammation. Adult Wistar rats were injected with 1 mg/kg LPS intraperitoneal (i.p.) in the presence or absence of 5 µg/kg dexmedetomidine. After 6 h, 24 h, and 7 days, gene expressions of interleukin 1-ß (IL1-ß), tumor necrosis factor-α (TNF-α), and microRNA expressions of miR 124, 132, 134, and 155 were measured in the hippocampus, cortex, and plasma. Dexmedetomidine decreased the LPS-induced neuroinflammation in the hippocampus and cortex via significant reduction of the IL1-ß and TNF-α gene expressions after 24 h. Moreover, the LPS-mediated increased expressions of miR 124, 132, 134, and 155 were significantly decreased after dexmedetomidine treatment in both brain regions. In plasma, dexmedetomidine significantly reduced LPS-induced miR 155 after 6 h. Furthermore, there is evidence that miR 132 and 134 may be suitable as potential biomarkers for the detection of neuroinflammation.


Assuntos
Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Anti-Inflamatórios/farmacologia , Encéfalo/metabolismo , Dexmedetomidina/farmacologia , MicroRNAs/genética , Animais , Encéfalo/efeitos dos fármacos , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Lipopolissacarídeos/toxicidade , Masculino , MicroRNAs/metabolismo , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
8.
Neurotox Res ; 32(3): 460-472, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28643232

RESUMO

Phenobarbital is the most commonly used drug for the treatment of neonatal seizures but may induce neurodegeneration in the developing brain. Methylxanthine caffeine is used for the treatment of apnea in newborn infants and appears to be neuroprotective, as shown by antiapoptotic and anti-inflammatory effects in oxidative stress models in newborn rodents and reduced rates of cerebral palsy in human infants treated with caffeine. We hypothesized that caffeine may counteract the proapoptotic effects of phenobarbital in newborn rats. Postnatal day 4 (P4) rats received phenobarbital (50 mg/kg) +/- caffeine (10 mg/kg) for three consecutive days. Brains examined at 6, 12, and 24 h after last injection of phenobarbital showed a drastic increase of apoptotic cell death (TUNEL+), which was attenuated by co-treatment with caffeine at 6 and 24 h but not at 12 h. Phenobarbital also increased protein levels of apoptosis inducing factor (AIF) and cleaved caspase-3, which was reduced by caffeine co-administration at all time points investigated. RNA expression of the pro-inflammatory cytokines TNFα, IFNγ, and IL-1ß, but not IL-18, was upregulated by phenobarbital. Co-treatment with caffeine significantly decreased these upregulations at all time points investigated, while caffeine without phenobarbital resulted in increased expression of TNFα, IL-1ß, and IL-18, but not IFNγ at 6 h. Downregulation of the adenosine A1 and A2a receptors, both of which bind caffeine, by 24 h of phenobarbital exposure was partly antagonized by caffeine. These results raise the possibility that the phenobarbital-induced adverse effects could be reduced by a co-treatment with caffeine.


Assuntos
Anticonvulsivantes/toxicidade , Encéfalo/efeitos dos fármacos , Encéfalo/crescimento & desenvolvimento , Cafeína/farmacologia , Fármacos Neuroprotetores/farmacologia , Fenobarbital/toxicidade , Animais , Animais Recém-Nascidos , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Encéfalo/metabolismo , Encéfalo/patologia , Citocinas/metabolismo , Expressão Gênica/efeitos dos fármacos , Degeneração Neural/induzido quimicamente , Degeneração Neural/tratamento farmacológico , Degeneração Neural/metabolismo , Degeneração Neural/patologia , Distribuição Aleatória , Ratos Wistar , Receptores Purinérgicos P1/metabolismo , Fatores de Tempo , Ácido gama-Aminobutírico/metabolismo
10.
PLoS One ; 12(2): e0171498, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28158247

RESUMO

Dexmedetomidine (DEX) is a highly selective agonist of α2-receptors with sedative, anxiolytic, and analgesic properties. Neuroprotective effects of dexmedetomidine have been reported in various brain injury models. In the present study, we investigated the effects of dexmedetomidine on hippocampal neurogenesis, specifically the proliferation capacity and maturation of neurons and neuronal plasticity following the induction of hyperoxia in neonatal rats. Six-day old sex-matched Wistar rats were exposed to 80% oxygen or room air for 24 h and treated with 1, 5 or 10 µg/kg of dexmedetomidine or normal saline. A single pretreatment with DEX attenuated the hyperoxia-induced injury in terms of neurogenesis and plasticity. In detail, both the proliferation capacity (PCNA+ cells) as well as the expression of neuronal markers (Nestin+, PSA-NCAM+, NeuN+ cells) and transcription factors (SOX2, Tbr1/2, Prox1) were significantly reduced under hyperoxia compared to control. Furthermore, regulators of neuronal plasticity (Nrp1, Nrg1, Syp, and Sema3a/f) were also drastically decreased. A single administration of dexmedetomidine prior to oxygen exposure resulted in a significant up-regulation of expression-profiles compared to hyperoxia. Our results suggest that dexmedetomidine may have neuroprotective effects in an acute hyperoxic model of the neonatal rat.


Assuntos
Lesões Encefálicas/prevenção & controle , Hipóxia Celular , Dexmedetomidina/farmacologia , Hipocampo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Animais , Lesões Encefálicas/induzido quimicamente , Diferenciação Celular/efeitos dos fármacos , Feminino , Hipocampo/citologia , Hipocampo/crescimento & desenvolvimento , Masculino , Neurogênese/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Oxigênio/fisiologia , Ratos , Ratos Wistar , Transcrição Genética/efeitos dos fármacos
11.
Sci Rep ; 7: 43000, 2017 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-28230075

RESUMO

The premature increase of oxygen tension may contribute to oligodendroglial precursor cell (OPC) damage in preterm infants. Fetal OPCs are exposed to low oxygen tissue tensions not matched when cells are cultured in room air. Maturation (A2B5, O4, O1, MBP, CNP, arborization), oxidative stress (nitrotyrosine Western blot, NRF2 and SOD2 expression), apoptosis (TUNEL), proliferation (Ki67), and expression of transcription factors regulated by Hypoxia-Inducible-Factor-1-alpha (Hif-1α) expressed in OPCs (Olig1, Olig2, Sox9, Sox10) were assessed in rat OPCs and OLN93 cells cultured at 5% O2 and 21% O2. Influences of Hif-1α were investigated by Hif-1α luciferase reporter assays and Hif-1α-knockdown experiments. At 21% O2, cell proliferation was decreased and process arborization of OPCs was reduced. Expression of MBP, CNP, Olig1, Sox9 and Sox10 was lower at 21% O2, while Nrf2, SOD2, nitrotyrosine were increased. Apoptosis was unchanged. Luciferease reporter assay in OLN93 cells indicated increased Hif-1α activity at 5% O2. In OLN93 cells at 5% O2, Hif-1α knockdown decreased the expression of MBP and CNP, similar to that observed at 21% O2. These data indicate that culturing OPCs at 21% O2 negatively affects development and maturation. Both enhanced oxidative stress and reduced expression of Hif-1α-regulated genes contribute to these hyperoxia-induced changes.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Oxigênio/farmacologia , 2',3'-Nucleotídeo Cíclico 3'-Fosfodiesterase/genética , 2',3'-Nucleotídeo Cíclico 3'-Fosfodiesterase/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Proteína Básica da Mielina/genética , Proteína Básica da Mielina/metabolismo , Oligodendroglia/citologia , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Ratos , Fatores de Transcrição SOX9/genética , Fatores de Transcrição SOX9/metabolismo , Tirosina/análogos & derivados , Tirosina/metabolismo , Regulação para Cima/efeitos dos fármacos
12.
Int J Mol Sci ; 18(1)2017 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-28106777

RESUMO

Sequelae of prematurity triggered by oxidative stress and free radical-mediated tissue damage have coined the term "oxygen radical disease of prematurity". Caffeine, a potent free radical scavenger and adenosine receptor antagonist, reduces rates of brain damage in preterm infants. In the present study, we investigated the effects of caffeine on oxidative stress markers, anti-oxidative response, inflammation, redox-sensitive transcription factors, apoptosis, and extracellular matrix following the induction of hyperoxia in neonatal rats. The brain of a rat pups at postnatal Day 6 (P6) corresponds to that of a human fetal brain at 28-32 weeks gestation and the neonatal rat is an ideal model in which to investigate effects of oxidative stress and neuroprotection of caffeine on the developing brain. Six-day-old Wistar rats were pre-treated with caffeine and exposed to 80% oxygen for 24 and 48 h. Caffeine reduced oxidative stress marker (heme oxygenase-1, lipid peroxidation, hydrogen peroxide, and glutamate-cysteine ligase catalytic subunit (GCLC)), promoted anti-oxidative response (superoxide dismutase, peroxiredoxin 1, and sulfiredoxin 1), down-regulated pro-inflammatory cytokines, modulated redox-sensitive transcription factor expression (Nrf2/Keap1, and NFκB), reduced pro-apoptotic effectors (poly (ADP-ribose) polymerase-1 (PARP-1), apoptosis inducing factor (AIF), and caspase-3), and diminished extracellular matrix degeneration (matrix metalloproteinases (MMP) 2, and inhibitor of metalloproteinase (TIMP) 1/2). Our study affirms that caffeine is a pleiotropic neuroprotective drug in the developing brain due to its anti-oxidant, anti-inflammatory, and anti-apoptotic properties.


Assuntos
Lesões Encefálicas/tratamento farmacológico , Cafeína/uso terapêutico , Hiperóxia/complicações , Hiperóxia/tratamento farmacológico , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Animais , Animais Recém-Nascidos , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Lesões Encefálicas/patologia , Cafeína/administração & dosagem , Cafeína/farmacologia , Citocinas/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/patologia , Metaloproteinases da Matriz/metabolismo , NF-kappa B/metabolismo , Fármacos Neuroprotetores/farmacologia , Óxido Nítrico Sintase Tipo II/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Oxirredutases atuantes sobre Doadores de Grupo Enxofre/metabolismo , Peroxirredoxinas/metabolismo , Plasminogênio/metabolismo , Ratos Wistar , Ativador de Plasminogênio Tecidual/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
13.
Oxid Med Cell Longev ; 2016: 9247493, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27493706

RESUMO

Cerebral white and grey matter injury is the leading cause of an adverse neurodevelopmental outcome in prematurely born infants. High oxygen concentrations have been shown to contribute to the pathogenesis of neonatal brain damage. Here, we focused on motor-cognitive outcome up to the adolescent and adult age in an experimental model of preterm brain injury. In search of the putative mechanisms of action we evaluated oligodendrocyte degeneration, myelination, and modulation of synaptic plasticity-related molecules. A single dose of erythropoietin (20,000 IU/kg) at the onset of hyperoxia (24 hours, 80% oxygen) in 6-day-old Wistar rats improved long-lasting neurocognitive development up to the adolescent and adult stage. Analysis of white matter structures revealed a reduction of acute oligodendrocyte degeneration. However, erythropoietin did not influence hypomyelination occurring a few days after injury or long-term microstructural white matter abnormalities detected in adult animals. Erythropoietin administration reverted hyperoxia-induced reduction of neuronal plasticity-related mRNA expression up to four months after injury. Thus, our findings highlight the importance of erythropoietin as a neuroregenerative treatment option in neonatal brain injury, leading to improved memory function in adolescent and adult rats which may be linked to increased neuronal network connectivity.


Assuntos
Eritropoetina/farmacologia , Hiperóxia , Plasticidade Neuronal/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Animais , Animais Recém-Nascidos , Comportamento Animal/efeitos dos fármacos , Lesões Encefálicas/etiologia , Lesões Encefálicas/metabolismo , Lesões Encefálicas/patologia , Sobrevivência Celular/efeitos dos fármacos , Cognição/efeitos dos fármacos , Imagem de Tensor de Difusão , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Imuno-Histoquímica , Microscopia Confocal , Mitocôndrias/metabolismo , Proteína Básica da Mielina/metabolismo , Neuregulina-1/genética , Neuregulina-1/metabolismo , Neuropilina-1/genética , Neuropilina-1/metabolismo , Oligodendroglia/citologia , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/metabolismo , Ratos , Ratos Wistar , Sinaptofisina/genética , Sinaptofisina/metabolismo , Substância Branca/efeitos dos fármacos , Substância Branca/metabolismo
14.
Brain Behav ; 6(3): e00435, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27099799

RESUMO

INTRODUCTION: The birth of most mammals features a dramatic increase in oxygen while placenta-derived hormones such as ß-estradiol and progesterone plummet. In experimental newborn animals, transiently elevated oxygen concentrations cause death of neurons, astrocytes, and oligodendrocyte precursors. High oxygen has been associated with cerebral palsy in human preterm infants while progesterone is being used to prevent preterm delivery and investigated as a neuroprotective agent. METHODS: In this study, we investigated the effects of hyperoxia (80% O2 for 24, 48, and 72 h) on cultured C8-D1A astrocytes in the presence or absence of progesterone at concentrations ranging from 10(-9) to 10(-5) mol/L. RESULTS: Hyperoxia measured by methytetrazolium assay (MTT) reduced cell viability, increased release of lactate dehydrogenase (LDH), reduced carboxyfluorescein diacetate succinimidyl ester (CFSE)-assessed cell proliferation, and downregulated Cylin D2 expression. Progesterone did not affect any of these hyperoxia-mediated indicators of cell death or malfunctioning. Real-time PCR analysis showed that hyperoxia caused downregulation of the progesterone receptors PR-AB und PR-B. CONCLUSIONS: Our experiments showed that there was no protective effect of progesterone on hyperoxia-inducted cell damage on mouse C8-D1A astrocytes. Down regulation of the progesterone receptors might be linked to the lack of protective effects.


Assuntos
Hiperóxia/complicações , Hiperóxia/tratamento farmacológico , Progesterona/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Astrócitos/efeitos dos fármacos , Técnicas de Cultura de Células/métodos , Proliferação de Células , Camundongos , Fármacos Neuroprotetores/farmacologia , Oligodendroglia/efeitos dos fármacos , Oxigênio/efeitos adversos , Oxigênio/fisiologia , Reação em Cadeia da Polimerase em Tempo Real , Receptores de Progesterona/metabolismo
15.
Glia ; 63(10): 1825-39, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25964099

RESUMO

According to recent research, brain injury after premature birth often includes impaired growth of the cerebellum. However, causes of cerebellar injury in this population are poorly understood. In this study, we analyzed whether postnatal hyperoxia perturbs white matter development of the cerebellum, and whether cerebellar glial damage can be prevented by minocycline. We used a hyperoxia model in neonatal rats providing 24 h exposure to fourfold increased oxygen concentration (80% O2) from P6 to P7, followed by recovery in room air until P9, P11, P15, P30. Injections with minocycline were performed at the beginning and 12 h into hyperoxia exposure. Hyperoxia induced oxidative stress in the cerebellum at P7 as evidenced by increased nitrotyrosine concentrations. Numbers of proliferating, NG2+Ki67+ oligodendroglial precursor cells were decreased at P7 after hyperoxia and at P11 following recovery in room air. Numbers of mature, CC1+ oligodendrocytes were diminished in recovering hyperoxia rats, and myelin basic protein expression was still decreased at P30. Electron microscopy analysis of myelinated fibers at P30 revealed thinner myelin sheath after hyperoxia. Long-term injury of the cerebellum by neonatal hyperoxia was confirmed by reduced volumes in MRI measurements at P30. In response to 80% O2, expression of platelet-derived growth factor (PDGF)-A was largely reduced in cerebellar tissue and also in cultured cerebellar astrocytes. Treatment with minocycline during hyperoxia prevented oxidative stress, attenuated oligodendroglial injury, and improved astroglial PDGF-A levels. In conclusion, early hyperoxia causes white matter damage in the cerebellum with astroglial dysfunction being involved, and both can be prevented by treatment with minocycline. Neonatal exposure to hyperoxia causes hypomyelination of the cerebellum. Reduced astroglial growth factor production but not microglial inflammation seems to contribute to oligodendroglial damage, and minocycline rescues oligodendroglia development in the cerebellum after hyperoxia.


Assuntos
Cerebelo/patologia , Hiperóxia/patologia , Hiperóxia/prevenção & controle , Minociclina/uso terapêutico , Oligodendroglia/patologia , Fatores Etários , Animais , Animais Recém-Nascidos , Apoptose/efeitos dos fármacos , Comunicação Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Cerebelo/efeitos dos fármacos , Cerebelo/crescimento & desenvolvimento , Citocinas/metabolismo , Modelos Animais de Doenças , Embrião de Mamíferos , Proteínas do Tecido Nervoso/metabolismo , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/ultraestrutura , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Células-Tronco/efeitos dos fármacos
16.
Oxid Med Cell Longev ; 2015: 530371, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25653737

RESUMO

Dexmedetomidine is a highly selective agonist of α2-receptors with sedative, anxiolytic, analgesic, and anesthetic properties. Neuroprotective effects of dexmedetomidine have been reported in various brain injury models. In the present study, we investigated the effects of dexmedetomidine on neurodegeneration, oxidative stress markers, and inflammation following the induction of hyperoxia in neonatal rats. Six-day-old Wistar rats received different concentrations of dexmedetomidine (1, 5, or 10 µg/kg bodyweight) and were exposed to 80% oxygen for 24 h. Sex-matched littermates kept in room air and injected with normal saline or dexmedetomidine served as controls. Dexmedetomidine pretreatment significantly reduced hyperoxia-induced neurodegeneration in different brain regions of the neonatal rat. In addition, dexmedetomidine restored the reduced/oxidized glutathione ratio and attenuated the levels of malondialdehyde, a marker of lipid peroxidation, after exposure to high oxygen concentration. Moreover, administration of dexmedetomidine induced downregulation of IL-1ß on mRNA and protein level in the developing rat brain. Dexmedetomidine provides protections against toxic oxygen induced neonatal brain injury which is likely associated with oxidative stress signaling and inflammatory cytokines. Our results suggest that dexmedetomidine may have a therapeutic potential since oxygen administration to neonates is sometimes inevitable.


Assuntos
Apoptose/efeitos dos fármacos , Dexmedetomidina/farmacologia , Fármacos Neuroprotetores/farmacologia , Animais , Animais Recém-Nascidos , Lesões Encefálicas/tratamento farmacológico , Lesões Encefálicas/metabolismo , Lesões Encefálicas/patologia , Dexmedetomidina/uso terapêutico , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Glutationa/metabolismo , Hiperóxia , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Malondialdeído/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Ratos , Ratos Wistar
17.
Int J Mol Sci ; 15(3): 3784-98, 2014 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-24595240

RESUMO

Exposure to N-methyl-d-aspartate (NMDA) receptor antagonists has been demonstrated to induce neurodegeneration in newborn rats. However, in clinical practice the use of NMDA receptor antagonists as anesthetics and sedatives cannot always be avoided. The present study investigated the effect of the indirect cholinergic agonist physostigmine on neurotrophin expression and the extracellular matrix during NMDA receptor antagonist induced injury to the immature rat brain. The aim was to investigate matrix metalloproteinase (MMP)-2 activity, as well as expression of tissue inhibitor of metalloproteinase (TIMP)-2 and brain-derived neurotrophic factor (BDNF) after co-administration of the non-competitive NMDA receptor antagonist MK801 (dizocilpine) and the acetylcholinesterase (AChE) inhibitor physostigmine. The AChE inhibitor physostigmine ameliorated the MK801-induced reduction of BDNF mRNA and protein levels, reduced MK801-triggered MMP-2 activity and prevented decreased TIMP-2 mRNA expression. Our results indicate that AChE inhibition may prevent newborn rats from MK801-mediated brain damage by enhancing neurotrophin-associated signaling pathways and by modulating the extracellular matrix.


Assuntos
Encéfalo/efeitos dos fármacos , Inibidores da Colinesterase/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Acetilcolinesterase/metabolismo , Animais , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Maleato de Dizocilpina/farmacologia , Expressão Gênica/efeitos dos fármacos , Immunoblotting , Metaloproteinase 2 da Matriz/metabolismo , Fisostigmina/farmacologia , Ratos Wistar , Receptores de N-Metil-D-Aspartato/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Inibidor Tecidual de Metaloproteinase-2/genética , Inibidor Tecidual de Metaloproteinase-2/metabolismo
18.
Exp Neurol ; 254: 153-65, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24491957

RESUMO

Poor neurological outcome in preterm infants is associated with periventricular white matter damage and hypomyelination, often caused by perinatal inflammation, hypoxia-ischemia, and hyperoxia. Minocycline has been demonstrated in animal models to protect the immature brain against inflammation and hypoxia-ischemia by microglial inhibition. Here we studied the effect of minocycline on white matter damage caused by hyperoxia. To mimic the 3- to 4-fold increase of oxygen tension caused by preterm birth, we have used the hyperoxia model in neonatal rats providing 24h exposure to 4-fold increased oxygen concentration (80% instead of 21% O2) from P6 to P7. We analyzed whether minocycline prevents activation of microglia and damage of oligodendroglial precursor cell development, and whether acute treatment of hyperoxia-exposed rats with minocycline improves long term white matter integrity. Minocycline administration during exposure to hyperoxia resulted in decreased apoptotic cell death and in improved proliferation and maturation of oligodendroglial precursor cells (OPC). Minocycline blocked changes in microglial morphology and IL-1ß release induced by hyperoxia. In primary microglial cell cultures, minocycline inhibited cytokine release while in mono-cultures of OPCs, it improved survival and proliferation. Long term impairment of white matter diffusivity in MRI/DTI in P30 and P60 animals after neonatal hyperoxia was attenuated by minocycline. Minocycline protects white matter development against oxygen toxicity through direct protection of oligodendroglia and by microglial inhibition. This study moreover demonstrates long term benefits of minocycline on white matter integrity.


Assuntos
Hiperóxia/tratamento farmacológico , Leucoencefalopatias/prevenção & controle , Microglia/efeitos dos fármacos , Minociclina/farmacologia , Fibras Nervosas Mielinizadas/efeitos dos fármacos , Oligodendroglia/efeitos dos fármacos , Fatores Etários , Animais , Animais Recém-Nascidos , Antibacterianos/farmacologia , Imagem de Tensor de Difusão , Modelos Animais de Doenças , Feminino , Humanos , Hiperóxia/patologia , Recém-Nascido , Leucoencefalopatias/patologia , Masculino , Microglia/citologia , Fármacos Neuroprotetores/farmacologia , Oligodendroglia/citologia , Gravidez , Cultura Primária de Células , Ratos , Ratos Wistar
19.
Free Radic Biol Med ; 67: 221-34, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24129198

RESUMO

Caffeine administered to preterm infants has been shown to reduce rates of cerebral palsy and cognitive delay, compared to placebo. We investigated the neuroprotective potential of caffeine for the developing brain in a neonatal rat model featuring transient systemic hyperoxia. Using 6-day-old rat pups, we found that after 24 and 48h of 80% oxygen exposure, apoptotic (TUNEL(+)) cell numbers increased in the cortex, hippocampus, and central gray matter, but not in the hippocampus or dentate gyrus. In the dentate gyrus, high oxygen exposure led to a decrease in the number of proliferating (Ki67(+)) cells and the number of Ki67(+) cells double staining for nestin (immature neurons), doublecortin (progenitors), and NeuN (mature neurons). Absolute numbers of nestin(+), doublecortin(+), and NeuN(+) cells also decreased after hyperoxia. This was mirrored in a decline of transcription factors expressed in immature neurons (Pax6, Sox2), progenitors (Tbr2), and mature neurons (Prox1, Tbr1). Administration of a single dose of caffeine (10mg/kg) before high oxygen exposure almost completely prevented these effects. Our findings suggest that caffeine exerts protection for neonatal neurons exposed to high oxygen, possibly via its antioxidant capacity.


Assuntos
Cafeína/farmacologia , Córtex Cerebral/efeitos dos fármacos , Giro Denteado/efeitos dos fármacos , Substância Cinzenta/efeitos dos fármacos , Hiperóxia/prevenção & controle , Neurônios/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Antígenos Nucleares/genética , Antígenos Nucleares/metabolismo , Biomarcadores/metabolismo , Proliferação de Células , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Giro Denteado/metabolismo , Giro Denteado/patologia , Proteínas do Olho/genética , Proteínas do Olho/metabolismo , Expressão Gênica , Substância Cinzenta/metabolismo , Substância Cinzenta/patologia , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Hiperóxia/metabolismo , Hiperóxia/patologia , Antígeno Ki-67/genética , Antígeno Ki-67/metabolismo , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Nestina/genética , Nestina/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Neuropeptídeos/genética , Neuropeptídeos/metabolismo , Fator de Transcrição PAX6 , Fatores de Transcrição Box Pareados/genética , Fatores de Transcrição Box Pareados/metabolismo , Ratos , Ratos Wistar , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Fatores de Transcrição SOXB1/genética , Fatores de Transcrição SOXB1/metabolismo , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
20.
Dev Neurosci ; 35(2-3): 255-64, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23445753

RESUMO

The cholinergic anti-inflammatory pathway is a neural mechanism that suppresses the innate inflammatory response and controls inflammation employing acetylcholine as the key endogenous mediator. In this study, we investigated the effects of the cholinergic agonists, physostigmine and donepezil, on neurodegeneration, inflammation and oxidative stress during oxygen toxicity in the developing rat brain. The aim of this study was to investigate the level of neurodegeneration, expression of proinflammatory cytokines, glutathione and lipid peroxidation after hyperoxia and treatment with the acetylcholinesterase (AChE) inhibitors, physostigmine and donepezil in the brain of neonatal rats. Six-day-old Wistar rats were exposed to 80% oxygen for 12-24 h and received 100 µg/kg physostigmine or 200 µg/kg donepezil intraperitoneally. Sex-matched littermates kept in room air and injected with normal saline, physostigmine or donepezil served as controls. Treatment with both inhibitors significantly reduced hyperoxia-triggered activity of AChE, neural cell death and the upregulation of the proinflammatory cytokines IL-1ß and TNF-α in the immature rat brain on the mRNA and protein level. In parallel, hyperoxia-induced oxidative stress was reduced by concomitant physostigmine and donepezil administration, as shown by an increased reduced/oxidized glutathione ratio and attenuated malondialdehyde levels, as a sign of lipid peroxidation. Our results suggest that a single treatment with AChE inhibitors at the beginning of hyperoxia attenuated the detrimental effects of oxygen toxicity in the developing brain and may pave the way for AChE inhibitors, which are currently used for the treatment of Alzheimer's disease, as potential candidates for adjunctive neuroprotective therapies to the immature brain.


Assuntos
Encéfalo/efeitos dos fármacos , Inibidores da Colinesterase/farmacologia , Hiperóxia/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Western Blotting , Encéfalo/crescimento & desenvolvimento , Encéfalo/patologia , Modelos Animais de Doenças , Donepezila , Feminino , Hiperóxia/patologia , Imuno-Histoquímica , Indanos/farmacologia , Masculino , Degeneração Neural/patologia , Degeneração Neural/prevenção & controle , Oxigênio/toxicidade , Fisostigmina/farmacologia , Piperidinas/farmacologia , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real
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