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1.
J Neurosci Res ; 98(1): 121-128, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-30667078

RESUMO

Currently, there is no effective treatment for germinal matrix hemorrhage and intraventricular hemorrhage (GMH-IVH), a common and often fatal stroke subtype in premature infants. Secondary brain injury after GMH-IVH is known to involve blood clots that contribute to inflammation and neurological deficits. Furthermore, the subsequent blood clots disrupt normal cerebrospinal fluid circulation and absorption after GMH-IVH, contributing to posthemorrhagic hydrocephalus (PHH). Clinically, GMH-IVH severity is graded on a I to IV scale: Grade I is confined to the germinal matrix, grade II includes intraventricular hemorrhage, grade III includes intraventricular hemorrhage with extension into dilated ventricles, and grade IV includes intraventricular hemorrhage with extension into dilated ventricles as well as parenchymal hemorrhaging. GMH-IVH hematoma volume is the best prognostic indicator, where patients with higher grades have worsened outcomes. Various preclinical studies have shown that rapid hematoma resolution quickly ameliorates inflammation and improves neurological outcomes. Current experimental evidence identifies alternatively activated microglia as playing a pivotal role in hematoma clearance. In this review, we discuss the pathophysiology of GMH-IVH in the development of PHH, microglia/macrophage's role in the neonatal CNS, and established/potential therapeutic targets that enhance M2 microglia/macrophage phagocytosis of blood clots after GMH-IVH.


Assuntos
Encéfalo/metabolismo , Hemorragias Intracranianas/metabolismo , Macrófagos/metabolismo , Microglia/metabolismo , Encéfalo/patologia , Humanos , Hidrocefalia/etiologia , Hidrocefalia/metabolismo , Hidrocefalia/patologia , Recém-Nascido , Recém-Nascido Prematuro , Hemorragias Intracranianas/complicações , Hemorragias Intracranianas/patologia , Macrófagos/patologia , Microglia/patologia
2.
Cereb Cortex ; 29(12): 4932-4947, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-30877788

RESUMO

Preterm-born children suffer from neurological and behavioral disorders. Herein, we hypothesized that premature birth and non-maternal care of preterm newborns might disrupt neurobehavioral function, hippocampal dendritic arborization, and dendritic spine density. Additionally, we assessed whether 17ß-estradiol (E2) replacement or the TrkB receptor agonist, 7,8-dihydroxyflavone (DHF), would reverse compromised dendritic development and cognitive function in preterm newborns. These hypotheses were tested by comparing preterm (E28.5) rabbit kits cared and gavage-fed by laboratory personnel and term-kits reared and breast-fed by their mother doe at an equivalent postconceptional age. Neurobehavioral tests showed that both premature-birth and formula-feeding with non-maternal care led to increased anxiety behavior, poor social interaction, and lack of novelty preference compared with term-kits. Dendritic branching and number of total or mushroom dendritic spines were reduced in the CA1 field of preterm-kits compared with term controls. While CDC42 and Rac1/2/3 expression levels were lower, RhoA-activity was higher in preterm-kits compared with term controls. Both E2 and DHF treatment reversed prematurity-induced reduction in spine density, reduced total RhoA-GTPase levels, and enhanced cognitive function. Hence, prematurity and non-maternal care result in cognitive deficits, and reduced dendritic arbors and spines in CA1. E2 replacement or DHF treatment might reverse changes in dendritic spines and improve neurodevelopment in premature infants.


Assuntos
Cognição/fisiologia , Espinhas Dendríticas/patologia , Estradiol/farmacologia , Hipocampo/patologia , Nascimento Prematuro/fisiopatologia , Receptor trkB/agonistas , Animais , Cognição/efeitos dos fármacos , Espinhas Dendríticas/efeitos dos fármacos , Estrogênios/farmacologia , Feminino , Flavonas/farmacologia , Hipocampo/efeitos dos fármacos , Privação Materna , Gravidez , Nascimento Prematuro/patologia , Coelhos , Receptor trkB/efeitos dos fármacos
3.
Cereb Cortex ; 29(8): 3482-3495, 2019 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-30192926

RESUMO

Intraventricular hemorrhage (IVH) is a common complication of prematurity in infants born at 23-28 weeks of gestation. Survivors exhibit impaired growth of the cerebral cortex and neurodevelopmental sequeale, but the underlying mechanism(s) are obscure. Previously, we have shown that neocortical neurogenesis continues until at least 28 gestational weeks. This renders the prematurely born infants vulnerable to impaired neurogenesis. Here, we hypothesized that neurogenesis is impaired by IVH, and that signaling through GSK3ß, a critical intracellular kinase regulated by Wnt and other pathways, mediates this effect. These hypotheses were tested observationally in autopsy specimens from premature infants, and experimentally in a premature rabbit IVH model. Significantly, in premature infants with IVH, the number of neurogenic cortical progenitor cells was reduced compared with infants without IVH, indicating acutely decreased neurogenesis. This finding was corroborated in the rabbit IVH model, which further demonstrated reduction of upper layer cortical neurons after longer survival. Both the acute reduction of neurogenic progenitors, and the subsequent decrease of upper layer neurons, were rescued by treatment with AR-A014418, a specific inhibitor of GSK3ß. Together, these results indicate that IVH impairs late stages of cortical neurogenesis, and suggest that treatment with GSK3ß inhibitors may enhance neurodevelopment in premature infants with IVH.


Assuntos
Apoptose/efeitos dos fármacos , Hemorragia Cerebral Intraventricular/metabolismo , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Células-Tronco Neurais/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Tiazóis/farmacologia , Ureia/análogos & derivados , Animais , Western Blotting , Estudos de Casos e Controles , Contagem de Células , Proliferação de Células , Córtex Cerebral , Hemorragia Cerebral Intraventricular/patologia , Modelos Animais de Doenças , Células Ependimogliais/efeitos dos fármacos , Células Ependimogliais/metabolismo , Humanos , Imuno-Histoquímica , Lactente Extremamente Prematuro , Recém-Nascido , Antígeno Ki-67/metabolismo , Ventrículos Laterais , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/patologia , Fator de Transcrição PAX6/metabolismo , Fosforilação , Células Piramidais/efeitos dos fármacos , Células Piramidais/metabolismo , Células Piramidais/patologia , Coelhos , Reação em Cadeia da Polimerase em Tempo Real , Proteína do Retinoblastoma/metabolismo , Fatores de Transcrição SOXB1/metabolismo , Proteínas com Domínio T/metabolismo , Ureia/farmacologia , Substância Branca
4.
J Cereb Blood Flow Metab ; 39(1): 97-107, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-28792282

RESUMO

CD200 has been reported to be neuroprotective in neurodegenerative diseases. However, the potential protective effects of CD200 in germinal matrix hemorrhage (GMH) have not been investigated. We examined the anti-inflammatory mechanisms of CD200 after GMH. A total of 167 seven-day-old rat pups were used. The time-dependent effect of GMH on the levels of CD200 and CD200 Receptor 1 (CD200R1) was evaluated by western blot. CD200R1 was localized by immunohistochemistry. The short-term (24 h) and long-term (28 days) outcomes were evaluated after CD200 fusion protein (CD200Fc) treatment by neurobehavioral assessment. CD200 small interfering RNA (siRNA) and downstream of tyrosine kinase 1 (Dok1) siRNA were injected intracerebroventricularly. Western blot was employed to study the mechanisms of CD200 and CD200R1. GMH induced significant developmental delay and caused impairment in both cognitive and motor functions in rat pups. CD200Fc ameliorated GMH-induced damage. CD200Fc increased expression of Dok1 and decreased IL-1beta and TNF-alpha levels. CD200R1 siRNA and Dok1 siRNA abolished the beneficial effects of CD200Fc, as demonstrated by enhanced expression levels of IL-1beta and TNF-alpha. CD200Fc inhibited GMH-induced inflammation and this effect may be mediated by CD200R1/Dok1 pathway. Thus, CD200Fc may serve as a potential treatment to ameliorate brain injury for GMH patients.


Assuntos
Hemorragia Cerebral/tratamento farmacológico , Proteínas de Ligação a DNA/efeitos dos fármacos , Inflamação/patologia , Microglia/efeitos dos fármacos , Fosfoproteínas/efeitos dos fármacos , Proteínas de Ligação a RNA/efeitos dos fármacos , Receptores Imunológicos/agonistas , Animais , Animais Recém-Nascidos , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/patologia , Hemorragia Cerebral/patologia , Deficiências do Desenvolvimento/etiologia , Imunoglobulina G/uso terapêutico , Imuno-Histoquímica , Injeções Intraventriculares , Interleucina-1beta/antagonistas & inibidores , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/uso terapêutico , Ratos , Resultado do Tratamento , Fator de Necrose Tumoral alfa/antagonistas & inibidores
5.
J Neurosci ; 38(34): 7378-7391, 2018 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-30037831

RESUMO

Development of cortical interneurons continues until the end of human pregnancy. Premature birth deprives the newborns from the supply of maternal estrogen and a secure intrauterine environment. Indeed, preterm infants suffer from neurobehavioral disorders. This can result from both preterm birth and associated postnatal complications, which might disrupt recruitment and maturation of cortical interneurons. We hypothesized that interneuron subtypes, including parvalbumin-positive (PV+), somatostatin-positive (SST+), calretinin-positive (CalR+), and neuropeptide Y-positive (NPY+) interneurons, were recruited in the upper and lower cortical layers in a distinct manner with advancing gestational age. In addition, preterm birth would disrupt the heterogeneity of cortical interneurons, which might be reversed by estrogen treatment. These hypotheses were tested by analyzing autopsy samples from premature infants and evaluating the effect of estrogen supplementation in prematurely delivered rabbits. The PV+ and CalR+ neurons were abundant, whereas SST+ and NPY+ neurons were few in cortical layers of preterm human infants. Premature birth of infants reduced the density of PV+ or GAD67+ neurons and increased SST+ interneurons in the upper cortical layers. Importantly, 17 ß-estradiol treatment in preterm rabbits increased the number of PV+ neurons in the upper cortical layers relative to controls at postnatal day 14 (P14) and P21 and transiently reduced SST population at P14. Moreover, protein and mRNA levels of Arx, a key regulator of cortical interneuron maturation and migration, were higher in estrogen-treated rabbits relative to controls. Therefore, deficits in PV+ and excess of SST+ neurons in premature newborns are ameliorated by estrogen replacement, which can be attributed to elevated Arx levels. Estrogen replacement might enhance neurodevelopmental outcomes in extremely preterm infants.SIGNIFICANCE STATEMENT Premature birth often leads to neurodevelopmental delays and behavioral disorders, which may be ascribed to disturbances in the development and maturation of cortical interneurons. Here, we show that preterm birth in humans is associated with reduced population of parvalbumin-positive (PV+) neurons and an excess of somatostatin-expressing interneurons in the cerebral cortex. More importantly, 17 ß-estradiol treatment increased the number of PV+ neurons in preterm-born rabbits, which appears to be mediated by an elevation in the expression of Arx transcription factor. Hence the present study highlights prematurity-induced reduction in PV+ neurons in human infants and reversal in their population by estrogen replacement in preterm rabbits. Because preterm birth drops plasma estrogen level 100-fold, estrogen replacement in extremely preterm infants might improve their developmental outcome and minimize neurobehavioral disorders.


Assuntos
Córtex Cerebral/patologia , Estradiol/farmacologia , Doenças do Prematuro/patologia , Interneurônios/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Calbindina 2/análise , Contagem de Células , Feminino , Idade Gestacional , Glutamato Descarboxilase/análise , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Interneurônios/química , Interneurônios/classificação , Interneurônios/fisiologia , Masculino , Proteínas do Tecido Nervoso/análise , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética , Neuropeptídeo Y/análise , Parvalbuminas/análise , Coelhos , Somatostatina/análise , Fatores de Transcrição/biossíntese , Fatores de Transcrição/genética
6.
J Neurochem ; 140(5): 776-786, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28054340

RESUMO

Fingolimod, a sphingosine-1-phosphate receptor (S1PR) agonist, is clinically available to treat multiple sclerosis and is showing promise in treating stroke. We investigated if fingolimod provides long-term protection from experimental neonatal germinal matrix hemorrhage (GMH), aiming to support a potential mechanism of acute fingolimod-induced protection. GMH was induced in P7 rats by infusion of collagenase (0.3 U) into the right ganglionic eminence. Animals killed at 4 weeks post-GMH received low- or high-dose fingolimod (0.25 or 1.0 mg/kg) or vehicle, and underwent neurocognitive testing before histopathological evaluation. Subsequently, a cohort of animals killed at 72 h post-GMH received 1.0 mg/kg fingolimod; the specific S1PR1 agonist, SEW2871; or fingolimod co-administered with the S1PR1/3/4 inhibitor, VPC23019, or the Rac1 inhibitor, EHT1864. All drugs were injected intraperitoneally 1, 24, and 48 h post-surgery. At 72 h post-GMH, brain water content, extravasated Evans blue dye, and hemoglobin were measured as well as the expression levels of phospho-Akt, Akt, GTP-Rac1, Total-Rac1, ZO1, occludin, and claudin-3 determined. Fingolimod significantly improved long-term neurocognitive performance and ameliorated brain tissue loss. At 72 h post-GMH, fingolimod reduced brain water content and Evans blue dye extravasation as well as reversed GMH-induced loss of tight junctional proteins. S1PR1 agonism showed similar protection, whereas S1PR or Rac1 inhibition abolished the protective effect of fingolimod. Fingolimod treatment improved functional and morphological outcomes after GMH, in part, by tempering acute post-hemorrhagic blood-brain barrier disruption via the activation of the S1PR1/Akt/Rac1 pathway.


Assuntos
Cloridrato de Fingolimode/farmacologia , Hemorragias Intracranianas/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Proteínas rac1 de Ligação ao GTP/metabolismo , Animais , Água Corporal/metabolismo , Encéfalo/patologia , Química Encefálica/efeitos dos fármacos , Edema Encefálico/tratamento farmacológico , Edema Encefálico/etiologia , Cognição/efeitos dos fármacos , Feminino , Hemorragias Intracranianas/metabolismo , Hemorragias Intracranianas/psicologia , Contagem de Leucócitos , Masculino , Oxidiazóis/farmacologia , Fosfosserina/análogos & derivados , Fosfosserina/farmacologia , Gravidez , Pironas/farmacologia , Quinolinas/farmacologia , Ratos , Ratos Sprague-Dawley , Tiofenos/farmacologia , Proteínas de Junções Íntimas/metabolismo , Proteínas rac1 de Ligação ao GTP/antagonistas & inibidores
7.
Acta Neurochir Suppl ; 121: 63-7, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26463924

RESUMO

Germinal matrix hemorrhage (GMH) is the most common and devastating neurological injury of premature infants, and current treatment approaches are ineffective. Remote ischemic postconditioning (RIPC) is a method by which brief limb ischemic stimuli protect the injured brain. We hypothesized that RIPC can improve outcomes following GMH in rats. Neonatal rats (P7) were subjected to either stereotactic ganglionic eminence collagenase infusion or sham surgery. Groups were as follows: sham (n = 0), GMH non-RIPC (n = 10), GMH + 1 week RIPC (n = 10), GMH + 2 weeks RIPC (n = 10). Neurobehavior analysis at the fourth week consisted of Morris water maze (MWM) and rotarod (RR). This was followed by euthanasia for histopathology on day 28. Both 1- and 2-week RIPC showed significant improvement in FF and RR motor testing compared with untreated animals (i.e., GMH without RIPC). RIPC treatment also improved cognition (MWM) and attenuated neuropathological ventricular enlargement (hydrocephalus) in juvenile animals following GMH. RIPC is a safe and noninvasive approach that improved sensorimotor and neuropathological outcomes following GMH in rats. Further studies are needed to evaluate for mechanisms of neuroprotection.


Assuntos
Hemorragia Cerebral/terapia , Pós-Condicionamento Isquêmico/métodos , Animais , Animais Recém-Nascidos , Comportamento Animal , Encéfalo/fisiopatologia , Hemorragia Cerebral/induzido quimicamente , Hemorragia Cerebral/fisiopatologia , Modelos Animais de Doenças , Extremidades , Aprendizagem em Labirinto , Colagenase Microbiana/toxicidade , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Teste de Desempenho do Rota-Rod
8.
Acta Neurochir Suppl ; 121: 237-41, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26463955

RESUMO

Hemorrhagic transformation occurs in as many as 48 % of stroke patients and is a major contributor to post-insult morbidity and mortality. Experimental models of hemorrhagic transformation are utilized for understanding the mechanisms behind its development, as well as for investigating potential therapeutics for prevention and reduction of bleeding. Thoroughly studying animal models of hemorrhagic transformation is critically important for testing novel treatments. Thus far, no study has examined the progression of brain swelling and hemorrhagic transformation after transient middle cerebral artery occlusion (MCAO). Herein, we investigate the development of infarction, brain swelling, and hemorrhagic transformation following MCAO in hyperglycemic rats. Twenty-five Sprague-Dawley rats were subjected to either 1.5 h of MCAO or sham surgery 15 min after induction of hyperglycemia. Animals were sacrificed at 0.25, 1, 3, or 24 h after reperfusion for measurement of infarct volume, brain swelling, and hemoglobin volume. Within 15 min of reperfusion, the infarct volume was significantly larger than in sham animals and did not increase in size over the 24 h. However, both brain swelling and hemorrhagic transformation, which began immediately after reperfusion, increase over 24 h after reperfusion.


Assuntos
Glicemia/metabolismo , Edema Encefálico/metabolismo , Hemorragia Cerebral/metabolismo , Hiperglicemia/metabolismo , Infarto da Artéria Cerebral Média/metabolismo , Animais , Edema Encefálico/etiologia , Hemorragia Cerebral/etiologia , Modelos Animais de Doenças , Glucose/farmacologia , Hiperglicemia/induzido quimicamente , Infarto da Artéria Cerebral Média/complicações , Masculino , Ratos , Ratos Sprague-Dawley , Fatores de Risco , Edulcorantes/farmacologia , Fatores de Tempo
9.
Neurobiol Dis ; 82: 349-358, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26176793

RESUMO

BACKGROUND AND PURPOSE: Edema formation, inflammation and increased blood-brain barrier permeability contribute to poor outcomes after intracerebral hemorrhage (ICH). This study examined the therapeutic effect of dimethyl fumarate (DMF), a fumaric acid ester that activates nuclear factor erythroid-2 related factor 2 (Nrf2) and Nrf2 heterodimerization effector protein musculo-aponeurotic fibrosarcoma-G (MAFG) in a murine ICH model. METHODS: Male CD-1 mice (n=176) were subjected to intrastriatal infusion of bacterial collagenase (n=126), autologous blood (n=18) or sham surgery (n=32). Four (4) animals not subjected to ICH (naive) were also included in the study. After ICH, animals either received vehicle, dimethyl fumarate (10 mg or 100 mg/kg) or casein kinase 2 inhibitor (E)-3-(2,3,4,5-tetrabromophenyl)acrylic acid (TBCA). Thirty-two mice also received scrambled siRNA or MAFG siRNA 24h before ICH. Brain water content and neurological function were evaluated. RESULTS: Dimethyl fumarate reduced Evans blue dye extravasation, decreased brain water content, and improved neurological deficits at 24 and 72 h after ICH. Casein kinase 2 inhibitor TBCA and MAFG siRNA prevented the effect of dimethyl fumarate on brain edema and neurological function. After ICH, ICAM-1 levels increased and casein kinase 2 levels decreased. Dimethyl fumarate reduced ICAM-1 but enhanced casein kinase 2 levels. Again, casein kinase 2 inhibitor TBCA and MAFG siRNA abolished the effect of dimethyl fumarate on ICAM-1 and casein kinase 2. Dimethyl fumarate preserved pNrf2 and MAFG expression in the nuclear lysate after ICH and the effect of dimethyl fumarate was abolished by casein kinase 2 inhibitor TBCA and MAFG siRNA. Dimethyl fumarate reduced microglia activation in peri-hematoma areas after ICH. The protective effect of dimethyl fumarate on brain edema and neurological function was also observed in a blood injection mouse model. CONCLUSION: Dimethyl fumarate ameliorated inflammation, reduced blood-brain barrier permeability, and improved neurological outcomes by casein kinase 2 and Nrf2 signaling pathways after experimental ICH in mice.


Assuntos
Caseína Quinase II/metabolismo , Hemorragia Cerebral/tratamento farmacológico , Fumarato de Dimetilo/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Fármacos Neuroprotetores/farmacologia , Acrilatos/farmacologia , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/enzimologia , Edema Encefálico/tratamento farmacológico , Edema Encefálico/enzimologia , Caseína Quinase II/antagonistas & inibidores , Hemorragia Cerebral/enzimologia , Colagenases , Modelos Animais de Doenças , Molécula 1 de Adesão Intercelular/metabolismo , Fator de Transcrição MafG/genética , Fator de Transcrição MafG/metabolismo , Masculino , Camundongos , Microglia/efeitos dos fármacos , Microglia/enzimologia , Neuroimunomodulação/efeitos dos fármacos , Neuroimunomodulação/fisiologia , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo
10.
J Neuroimmune Pharmacol ; 10(4): 576-86, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25946986

RESUMO

Cerebral hemorrhages account for 15-20 % of stroke sub-types and have very poor prognoses. The mortality rate for cerebral hemorrhage patients is between 40 and 50 %, of which at least half of the deaths occur within the first 2 days, and 75 % of survivors are incapable of living independently after 1 year. Current emergency interventions involve lowering blood pressure and reducing intracranial pressure by controlled ventilations or, in the worst case scenarios, surgical intervention. Some hemostatic and coagulatherapeutic interventions are being investigated, although a few that were promising in experimental studies have failed in clinical trials. No significant immunomodulatory intervention, however, exists for clinical management of cerebral hemorrhage. The inflammatory response following cerebral hemorrhage is particularly harmful in the acute stage because blood-brain barrier disruption is amplified and surrounding tissue is destroyed by secreted proteases and reactive oxygen species from infiltrated leukocytes. In this review, we discuss both the destructive and regenerative roles the immune response play following cerebral hemorrhage and focus on microglia, macrophages, and T-lymphocytes as the primary agents directing the response. Microglia, macrophages, and T-lymphocytes each have sub-types that significantly influence the over-arching immune response towards either a pro-inflammatory, destructive, or an anti-inflammatory, regenerative, state. Both pre-clinical and clinical studies of cerebral hemorrhages that selectively target these immune cells are reviewed and we suggest immunomodulatory therapies that reduce inflammation, while augmenting neural repair, will improve overall cerebral hemorrhage outcomes.


Assuntos
Hemorragia Cerebral/imunologia , Inflamação/imunologia , Macrófagos/imunologia , Microglia/imunologia , Linfócitos T/imunologia , Humanos
11.
Exp Neurol ; 263: 141-9, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25448005

RESUMO

Granulocyte-colony stimulating factor (G-CSF), a growth factor, has known neuroprotective effects in a variety of experimental brain injury models. Herein we show that G-CSF administration attenuates neuronal apoptosis after neonatal hypoxia-ischemia (HI) via glycogen synthase kinase-3ß (GSK-3ß) inhibition. Ten day old Sprague-Dawley rat pups (n=157) were subjected to unilateral carotid artery ligation followed by 2.5h of hypoxia or sham surgery. HI animals received control siRNA, GSK-3ß siRNA (4 µL/pup), G-CSF (50 µg/kg), G-CSF combined with 0.1 or 0.4 nM G-CSF receptor (G-CSFR) siRNA, phosphatidylinositol 3-kinase (PI3K) inhibitor Wortmannin (86 ng/pup), or DMSO (vehicle for Wortmannin). Pups were euthanized 48 h post-HI to quantify brain infarct volume. G-CSFR, activated Akt (p-Akt), activated GSK-3ß (p-GSK-3ß), Cleaved Caspase-3 (CC3), Bcl-2, and Bax were quantified using Western blot analysis and the localizations of each was visualized via immunofluorescence staining. Neuronal cell death was determined using terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL). Our results showed p-GSK-3ß increased after HI until its peak at 48 h post-ictus, and both GSK-3ß siRNA and G-CSF administration reduced p-GSK-3ß expression, as well as infarct volume. p-GSK-3ß and CC3 were generally co-localized in neurons. Furthermore, G-CSF increased p-Akt expression and the Bcl-2/Bax ratio and also decreased p-GSK-3ß and CC3 expression levels in the ipsilateral hemisphere, which were all reversed by G-CSFR siRNA, Wortmannin, and GSK-3ß siRNA. In conclusion, G-CSF attenuated caspase activation and reduced brain injury by inhibiting GSK-3ß activity after experimental HI in rat pups. This neuroprotective effect was abolished by both G-CSFR siRNA and Wortmannin.


Assuntos
Apoptose/efeitos dos fármacos , Quinase 3 da Glicogênio Sintase/metabolismo , Fator Estimulador de Colônias de Granulócitos/farmacologia , Hipóxia-Isquemia Encefálica/metabolismo , Fármacos Neuroprotetores/farmacologia , Animais , Animais Recém-Nascidos , Apoptose/fisiologia , Western Blotting , Modelos Animais de Doenças , Imunofluorescência , Glicogênio Sintase Quinase 3 beta , Hipóxia-Isquemia Encefálica/patologia , Marcação In Situ das Extremidades Cortadas , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , RNA Interferente Pequeno , Ratos , Ratos Sprague-Dawley , Transfecção
12.
PLoS One ; 9(2): e89042, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24533168

RESUMO

INTRODUCTION: Neurogenic pulmonary edema (NPE) is an acute and serious complication after subarachnoid hemorrhage (SAH) with high mortality. The present study aimed to test the therapeutic potential of brilliant blue G (BBG), a selective P2X purinoceptor 7 (P2X7R) antagonist, on NPE in a rat SAH model. METHODS: SAH was induced by endovascular perforation. 86 Sprague-Dawley rats were randomly divided into sham, vehicle-, or BBG-treatment groups. Mortality, body weight, SAH grading, neurological deficits, NPE clinical symptoms, and pulmonary index were measured at 24 hours following SAH. Western blot, gelatin zymography, lung histopathology, and immunofluorescence staining were performed in the left lung lobe to explore the underlying mechanisms at 24 hours post-surgery. RESULTS: The incidence of clinical symptoms was correlated with pulmonary index. P2X7R and the marker of alveolar type I epithelial cells (the mucin-type glycoprotein T1-α) immunoreactivities were generally co-localized. BBG administration decreased mature interleukin-1ß, myeloperoxidase, and matrix metallopeptidase-9 activation, but increased tight junction proteins, such as ZO-1 and occludin, which ameliorated pulmonary edema via anti-inflammation and improved neurological deficits. CONCLUSION: P2X7R inhibition prevented NPE after SAH by attenuating inflammation. Thus, BBG is a potential therapeutic application for NPE after SAH and warrants further research.


Assuntos
Edema Pulmonar/complicações , Edema Pulmonar/metabolismo , Receptores Purinérgicos P2X7/metabolismo , Hemorragia Subaracnóidea/complicações , Animais , Peso Corporal/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/fisiopatologia , Exame Neurológico , Edema Pulmonar/patologia , Edema Pulmonar/fisiopatologia , Antagonistas do Receptor Purinérgico P2X/farmacologia , Antagonistas do Receptor Purinérgico P2X/uso terapêutico , Ratos , Ratos Sprague-Dawley , Corantes de Rosanilina/farmacologia , Corantes de Rosanilina/uso terapêutico
13.
Stroke ; 44(12): 3587-90, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24149004

RESUMO

BACKGROUND AND PURPOSE: This study investigated whether isoflurane ameliorates neurological sequelae after germinal matrix hemorrhage (GMH) through activation of the cytoprotective sphingosine kinase/sphingosine-1-phosphate receptor/Akt pathway. METHODS: GMH was induced in P7 rat pups by intraparenchymal infusion of bacterial collagenase (0.3 U) into the right hemispheric germinal matrix. GMH animals received 2% isoflurane either once 1 hour after surgery or every 12 hours for 3 days. Isoflurane treatment was then combined with sphingosine-1-phosphate receptor-1/2 antagonist VPC23019 or sphingosine kinase 1/2 antagonist N,N-dimethylsphingosine. RESULTS: Brain protein expression of sphingosine kinase-1 and phosphorylated Akt were significantly increased after isoflurane post-treatment, and cleaved caspase-3 was decreased at 24 hours after surgery, which was reversed by the antagonists. Isoflurane significantly reduced posthemorrhagic ventricular dilation and improved motor, but not cognitive, functions in GMH animals 3 weeks after surgery; no improvements were observed after VPC23019 administration. CONCLUSIONS: Isoflurane post-treatment improved the neurological sequelae after GMH possibly by activation of the sphingosine kinase/Akt pathway.


Assuntos
Encéfalo/efeitos dos fármacos , Hemorragias Intracranianas/tratamento farmacológico , Isoflurano/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Animais , Animais Recém-Nascidos , Encéfalo/metabolismo , Modelos Animais de Doenças , Hemorragias Intracranianas/induzido quimicamente , Hemorragias Intracranianas/metabolismo , Isoflurano/farmacologia , Fármacos Neuroprotetores/farmacologia , Fosforilação/efeitos dos fármacos , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Receptores de Lisoesfingolipídeo/metabolismo , Recuperação de Função Fisiológica/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Esfingosina/análogos & derivados , Esfingosina/farmacologia , Esfingosina/uso terapêutico
14.
BMC Neurol ; 13: 40, 2013 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-23642050

RESUMO

BACKGROUND: Malignant myoepithelioma is a relatively rare malignant tumor occurring most frequently in the salivary glands. A few isolated cases have been described in other locations, including soft tissue, bone, lung, bronchus, oral cavity, nasopharynx, larynx, and maxillary sinus. Malignant myoepithelioma, however, is uncommonly involved within the cavernous sinus. To the best of our knowledge, this is the first report of malignant myoepithelioma arising from within the cavernous sinus. CASE PRESENTATION: Herein, we report a case of a 48-year-old woman who presented a 1-month history of diplopia and blepharoptosis as well as radiological evidence of a rapidly developing cavernous sinus tumor. The patient underwent a trans-sphenoidal biopsy and a histological diagnosis indicated a malignant myoepithelioma. After diagnosis, the tumor grew rapidly and her clinical condition deteriorated progressively. Therefore, a pterional craniotomy with partial tumor removal was performed. The patient's clinical state was worsened, and she died two months after the initial operation. Because the malignant myoepithelioma could not be traced to an organ of origin, other than the cavernous sinus, this case was diagnosed as a primary intracranial malignant myoepithelioma. CONCLUSION: The purpose of presenting this case report is to raise awareness among clinicians to consider malignant myoepithelioma as a differential diagnosis when a cavernous sinus mass is identified. Furthermore, an ideal management strategy for malignant myoepithelioma is not known and the prognosis seems to be unfavorable; therefore, more cases are needed to enhance our knowledge of the diagnosis, treatment, and prognosis of this rare intracranial lesion.


Assuntos
Seio Cavernoso/patologia , Neoplasias do Seio Maxilar/diagnóstico , Mioepitelioma/diagnóstico , Actinas/metabolismo , Biópsia , Feminino , Proteína Glial Fibrilar Ácida/metabolismo , Humanos , Imageamento por Ressonância Magnética , Neoplasias do Seio Maxilar/cirurgia , Pessoa de Meia-Idade , Mioepitelioma/cirurgia , Proteínas S100/metabolismo , Vimentina/metabolismo
15.
Stroke ; 44(6): 1743-7, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23613493

RESUMO

BACKGROUND AND PURPOSE: Blood-brain barrier disruption and consequent vasogenic edema formation codetermine the clinical course of intracerebral hemorrhage (ICH). This study examined the effect of PHA-543613, a novel α7 nicotinic acetylcholine receptor agonist, on blood-brain barrier preservation after ICH. METHODS: Male CD-1 mice, subjected to intrastriatal blood infusion, received PHA-543613 alone or in combination with α7 nicotinic acetylcholine receptor antagonist methyllycaconitine or phosphatidylinositol 3-kinase inhibitor wortmannin. RESULTS: PHA-543613 alone, but not in combination with methyllycaconitine or wortmannin, inhibited glycogen synthase kinase-3ß, thus, stabilizing ß-catenin and tight junction proteins, which was paralleled by improved blood-brain barrier stability and ameliorated neurofunctional deficits in ICH animals. CONCLUSIONS: PHA-543613 preserved blood-brain barrier integrity after ICH, possibly through phosphatidylinositol 3-kinase-Akt-induced inhibition of glycogen synthase kinase-3ß and ß-catenin stabilization.


Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Hemorragia Cerebral/fisiopatologia , Quinuclidinas/farmacologia , Receptores Nicotínicos/fisiologia , Transdução de Sinais/efeitos dos fármacos , Aconitina/análogos & derivados , Aconitina/farmacologia , Androstadienos/farmacologia , Animais , Barreira Hematoencefálica/fisiologia , Hemorragia Cerebral/metabolismo , Claudina-3/metabolismo , Modelos Animais de Doenças , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Quinase 3 da Glicogênio Sintase/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta , Masculino , Camundongos , Camundongos Endogâmicos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/fisiologia , Wortmanina , beta Catenina/metabolismo
16.
Mol Neurobiol ; 47(3): 903-13, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23275173

RESUMO

Repulsive guidance molecule-a (RGMa) is associated with axon growth inhibition in different central nervous system (CNS) injuries, but its signaling pathways remain unclear. We examined the involvement of collapsin response mediator protein-2 (CRMP-2), a common downstream target of Rho-kinase and GSK-3ß, in vitro by culturing neonatal rat primary cortical neurons with RGMa protein, Rho-kinase inhibitor (Y-27632), and GSK-3ß inhibitor. We examined CRMP-2 in vivo by suppressing RGMa expression using recombinant adenovirus (rAd-shRGMa) in a rat MCAO/reperfusion model. RGMa induced neurite retraction and CRMP-2 phosphorylation in vitro, which were reversed by either Rho-kinase or GSK-3ß inhibitors. After MCAO/reperfusion in rats, pCRMP-2 protein was greatly increased in the ischemic cortex, axons were damaged severely, Neurofilament-200 (NF-200) expression was significantly decreased, and neurological deficits were significant, which were all improved by down-regulating RGMa. We concluded RGMa inhibits axon growth by phosphorylating CRMP-2 via both Rho-kinase and GSK-3ß signaling pathways.


Assuntos
Axônios/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Proteínas do Tecido Nervoso/farmacologia , Animais , Axônios/efeitos dos fármacos , Isquemia Encefálica/complicações , Isquemia Encefálica/patologia , Isquemia Encefálica/fisiopatologia , Córtex Cerebral/patologia , Proteínas Ligadas por GPI/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Infarto da Artéria Cerebral Média/complicações , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/fisiopatologia , Peptídeos e Proteínas de Sinalização Intercelular/genética , Masculino , Proteínas de Membrana/genética , Camundongos , Regeneração Nervosa/efeitos dos fármacos , Proteínas do Tecido Nervoso/genética , Neuritos/efeitos dos fármacos , Neuritos/metabolismo , Proteínas de Neurofilamentos/metabolismo , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica/efeitos dos fármacos , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/fisiopatologia , Quinases Associadas a rho/antagonistas & inibidores , Quinases Associadas a rho/metabolismo
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