RESUMO
INTRODUCTION: The prognostic value of leptomeningeal collateral circulation in thrombectomy-treated patients remains unclear. We evaluated the construct validity of assessing leptomeningeal collateral circulation using a new regional perfusion CT source image-based approach, the Perfusion Acquisition for THrombectomy Scale (PATHS). We also compared the prognostic value of PATHS with a further 6 scales based on various techniques: CT-angiography, perfusion CT, and digital subtraction angiography. Additionally, we studied the relationship between the scores for the different scales. PATIENTS AND METHODS: We performed a retrospective study of consecutive patients with stroke and M1/terminal carotid occlusion treated with thrombectomy in our center. Leptomeningeal collateral circulation was prospectively evaluated using 7 scales: Tan and Miteff (CT Angiography); Calleja, Cao, American Society of Intervention and Therapeutic Neuroradiology/Society of Interventional Radiology, and PATHS (perfusion); and Christoforidis (Digital Subtraction Angiography). Correlations were studied using the Spearman method. RESULTS: The study population comprised 108 patients. All scales predicted the modified Rankin Scale at 3 months (P ≤ .02) and all but 1 (Christoforidis) correlated with 24-hour brain infarct volume (P ≤ .02). These correlations were higher with PATHS (rhoâ¯=â¯-0.47, P < .001 for 3-month modified Rankin Scale; rhoâ¯=â¯-0.35, P < .001 for follow-up infarct volume). The multivariate analysis showed PATHS to be an independent predictor of modified Rankin Scale at 3 months less than equal to 2. A crosscorrelation analysis revealed a better correlation between scales that used the same techniques. CONCLUSIONS: PATHS can be used to assess leptomeningeal collateral circulation. PATHS had better prognostic value than other scales; therefore, it might be considered for assessment of leptomeningeal collateral circulation in candidates for thrombectomy. The moderate correlation between scales suggests that scores are not interchangeable.
Assuntos
Circulação Cerebrovascular , Circulação Colateral , Infarto da Artéria Cerebral Média/terapia , Artéria Cerebral Média/diagnóstico por imagem , Tomografia Computadorizada Multidetectores , Imagem de Perfusão/métodos , Trombectomia , Idoso , Angiografia Cerebral , Angiografia por Tomografia Computadorizada , Avaliação da Deficiência , Feminino , Humanos , Infarto da Artéria Cerebral Média/diagnóstico por imagem , Infarto da Artéria Cerebral Média/mortalidade , Infarto da Artéria Cerebral Média/fisiopatologia , Masculino , Pessoa de Meia-Idade , Artéria Cerebral Média/fisiopatologia , Variações Dependentes do Observador , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Estudos Retrospectivos , Fatores de Risco , Trombectomia/efeitos adversos , Trombectomia/mortalidade , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Perimesencephalic subarachnoid hemorrhage (p-SAH) is linked to a benign prognosis compared with aneurysmal SAH. However, the outcome in nonperimesencephalic angiographically negative SAH (np-SAH) is not well established. We reviewed our experience and evaluated the clinical and prognostic differences between patients with p-SAH and np-SAH. METHODS: Retrospective observational study based on data collected prospectively from all patients admitted to our hospital with SAH during the past 11 years. After selecting patients with normal angiography, we categorized them as either p-SAH or np-SAH according to the Rinkel criteria. Demographic, clinical, radiologic, and prognostic features were recorded. RESULTS: We collected a total of 41 (12.53%) angiographically negative SAH: 17 p-SAH (41.46%) and 24 np-SAH (58%-53%). The np-SAH group included the 6 patients with Glasgow Coma Scale (GCS) less than 15 (P = .083), and all 5 patients with Hunt & Hess (H&H) scores more than II (P = .045), being the GCS = 15 and H&H less than II in the rest of np-SAH and in all of the p-SAH patients. The average hospital stay in days was longer in the np-SAH group (24 ± 7.08) than in the p-SAH group (17 ± 5.11; P = .55). Hydrocephalus requiring external ventricular drainage (EVD) was only recorded in the np-SAH group (29.16%, P = .029). On discharge, all patients had H&H grade less than II and modified Rankin Scale measured 3 months later was less than 2 in both groups. CONCLUSIONS: Our results agree with other studies showing a low complication rate for SAH patients with a normal angiography, especially in the p-SAH group. The prognosis appears to be less favorable in terms of a more frequent need for EVD, so a more cautious approach is recommended in this subgroup.
Assuntos
Angiografia por Ressonância Magnética , Acidente Vascular Cerebral/complicações , Hemorragia Subaracnóidea/diagnóstico , Hemorragia Subaracnóidea/etiologia , Adulto , Idoso , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Índice de Gravidade de Doença , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND AND PURPOSE: Neutrophils have been traditionally recognized as major mediators of a deleterious inflammatory response in acute ischemic stroke, but their potential as a therapeutic target remains unexplored. Recent evidence indicates that neutrophils may acquire different phenotypes and contribute to resolution of inflammation through the release of anti-inflammatory mediators. Thus, similar to M2 macrophages, neutrophils have been proposed to shift toward an N2 phenotype, a polarization that is peroxisome proliferator-activated receptor-γ dependent in macrophages. We hypothesize that peroxisome proliferator-activated receptor-γ activation with rosiglitazone induces changes in neutrophilic mobilization and phenotype that might influence stroke outcome. METHODS: Brain sections and cell suspensions were prepared from mice exposed to permanent distal middle cerebral artery occlusion. Double immunostaining with stereological counting of brain sections and flow-cytometry analysis of brain cell suspensions were performed. RESULTS: Rosiglitazone accelerated neutrophil infiltration to the ischemic core, concomitantly to neuroprotection. Some neutrophils (≈31%) expressed M2 markers, namely Ym1 and CD206 (mannose receptor). After treatment with the peroxisome proliferator-activated receptor-γ agonist rosiglitazone, most neutrophils (≈77%) acquired an N2 phenotype. Interestingly, rosiglitazone increased neutrophil engulfment by microglia/macrophages, a clearance that preferentially affected the N2 subset. CONCLUSIONS: We present the first evidence of neutrophil reprogramming toward an N2 phenotype in brain inflammation, which can be modulated by activation of the peroxisome proliferator-activated receptor-γ nuclear receptor. We also show that N2 polarization is associated with an increased neutrophil clearance, thus suggesting that this switch is a crucial event for resolution of inflammation that may participate in neuroprotection.
Assuntos
Encéfalo/efeitos dos fármacos , Encefalite/metabolismo , Infarto da Artéria Cerebral Média/metabolismo , Neutrófilos/efeitos dos fármacos , PPAR gama/agonistas , Acidente Vascular Cerebral/metabolismo , Tiazolidinedionas/farmacologia , Encéfalo/metabolismo , Encefalite/tratamento farmacológico , Infarto da Artéria Cerebral Média/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Neutrófilos/metabolismo , Rosiglitazona , Acidente Vascular Cerebral/tratamento farmacológico , Tiazolidinedionas/uso terapêuticoRESUMO
PURPOSE: To investigate if glutamate levels also increase in carotid angioplasty and stent placement (CAS) procedures, since high plasma glutamate levels are associated with ischemic infarction and transient ischemic attacks, but the length of ischemia needed to elicit such elevation has not been assessed. MATERIALS AND METHODS: All patients or their relatives signed informed consent. By using high-performance liquid chromatography, plasma glutamate concentrations were determined in 74 patients treated with CAS. Blood samples were obtained with arterial and peripheral venous catheterization before and after the procedure, and venous blood samples were obtained 24, 48, and 72 hours after CAS. Glutamate concentrations were also analyzed in two different control groups: 16 patients without carotid stenosis before and after diagnostic cerebral angiography and 20 patients treated with coronary angioplasty and stent placement. The χ(2) test, t test, and analysis of variance were used to compare glutamate concentrations among the groups. RESULTS: Baseline glutamate concentrations were similar between patients who underwent CAS and both control groups. In CAS patients, glutamate concentrations in venous blood increased immediately after the procedure (354.1 µmol/L ± 132.8) and returned to baseline levels at 24 hours (129.5 µmol/L ± 56.8) (P < .0001). Glutamate concentrations remained unchanged over time in both control groups. CONCLUSION: A rapid increase in plasma glutamate levels occurs after CAS procedures, unrelated to stroke.
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Angioplastia , Isquemia Encefálica/sangue , Estenose das Carótidas/cirurgia , Ácido Glutâmico/sangue , Stents , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Biomarcadores/sangue , Isquemia Encefálica/diagnóstico por imagem , Estenose das Carótidas/diagnóstico por imagem , Estudos de Casos e Controles , Angiografia Cerebral , Distribuição de Qui-Quadrado , Cromatografia Líquida de Alta Pressão , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Estatísticas não Paramétricas , Ultrassonografia Doppler TranscranianaRESUMO
BACKGROUND AND PURPOSE: Ischemic stroke continues to be one of the main causes of death worldwide. Inflammation accounts for a large part of damage in this pathology. The cannabinoid type 2 receptor (CB2R) has been proposed to have neuroprotective properties in neurological diseases. Therefore, our aim was to determine the effects of the activation of CB2R on infarct outcome and on ischemia-induced brain expression of classic and alternative markers of macrophage/microglial activation. METHODS: Swiss wild-type and CB2R knockout male mice were subjected to a permanent middle cerebral artery occlusion. Mice were treated with either a CB2R agonist (JWH-133), with or without a CB2R antagonist (SR144528) or vehicle. Infarct outcome was determined by measuring infarct volume and neurological outcome. An additional group of animals was used to assess mRNA and protein expression of CB2R, interleukin (IL)-1ß, IL-6, tumor necrosis factor α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory peptide (MIP) -1α, RANTES, inducible nitric oxide synthase (iNOS), cyclooxygenase-2, IL-4, IL-10, transforming growth factor ß (TGF-ß), arginase I, and Ym1. RESULTS: Administration of JWH-133 significantly improved infarct outcome, as shown by a reduction in brain infarction and neurological impairment. This effect was reversed by the CB2R antagonist and was absent in CB2R knockout mice. Concomitantly, administration of JWH-133 led to a lower intensity of Iba1+ microglia/macrophages and a decrease in middle cerebral artery occlusion-induced gene expression of both classic (IL-6, TNF-α, MCP-1, MIP-1α, RANTES, and iNOS) and alternative mediators/markers (IL-10, TGF-ß, and Ym1) of microglial/macrophage activation after permanent middle cerebral artery occlusion. CONCLUSIONS: The inhibitory effect of CB2R on the activation of different subpopulations of microglia/macrophages may account for the protective effect of the selective CB2R agonist JWH-133 after stroke.
Assuntos
Encéfalo/metabolismo , Infarto da Artéria Cerebral Média/metabolismo , Macrófagos/metabolismo , Microglia/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Canfanos/farmacologia , Canabinoides/farmacologia , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Regulação para Baixo/efeitos dos fármacos , Infarto da Artéria Cerebral Média/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Masculino , Camundongos , Camundongos Knockout , Microglia/efeitos dos fármacos , Microglia/patologia , Óxido Nítrico Sintase Tipo II/metabolismo , Pirazóis/farmacologia , Receptor CB2 de Canabinoide/genéticaRESUMO
A role of iron as a target to prevent stroke-induced neurodegeneration has been recently revisited due to new evidence showing that ferroptosis inhibitors are protective in experimental ischemic stroke and might be therapeutic in other neurodegenerative brain pathologies. Ferroptosis is a new form of programmed cell death attributed to an overwhelming lipidic peroxidation due to excessive free iron and reactive oxygen species (ROS). This study aims to evaluate the safety and tolerability and to explore the therapeutic efficacy of the iron chelator and antioxidant deferoxamine mesylate (DFO) in ischemic stroke patients. Administration of placebo or a single DFO bolus followed by a 72 h continuous infusion of three escalating doses was initiated during the tPA infusion, and the impact on blood transferrin iron was determined. Primary endpoint was safety and tolerability, and secondary endpoint was good clinical outcome (clinicalTrials.gov NCT00777140). DFO was found safe as adverse effects were not different between placebo and DFO arms. DFO (40-60 mg/Kg/day) reduced the iron saturation of blood transferrin. A trend to efficacy was observed in patients with moderate-severe ischemic stroke (NIHSS > 7) treated with DFO 40-60 mg/Kg/day. A good outcome was observed at day 90 in 31% of placebo vs. 50-58% of the 40-60 mg/Kg/day DFO-treated patients.
RESUMO
Peroxisome proliferator-activated receptors gamma (PPARgamma) are nuclear receptors with essential roles as transcriptional regulators of glucose and lipid homeostasis. PPARgamma are also potent anti-inflammatory receptors, a property that contributes to the neuroprotective effects of PPARgamma agonists in experimental stroke. The mechanism of these beneficial actions, however, is not fully elucidated. Therefore, we have explored further the actions of the PPARgamma agonist rosiglitazone in experimental stroke induced by permanent middle cerebral artery occlusion (MCAO) in rodents. Rosiglitazone induced brain 5-lipoxygenase (5-LO) expression in ischemic rat brain, concomitantly with neuroprotection. Rosiglitazone also increased cerebral lipoxin A(4) (LXA(4)) levels and inhibited MCAO-induced production of leukotriene B4 (LTB(4)). Furthermore, pharmacological inhibition and/or genetic deletion of 5-LO inhibited rosiglitazone-induced neuroprotection and downregulation of inflammatory gene expression, LXA(4) synthesis and PPARgamma transcriptional activity in rodents. Finally, LXA(4) caused neuroprotection, which was partly inhibited by the PPARgamma antagonist T0070907, and increased PPARgamma transcriptional activity in isolated nuclei, showing for the first time that LXA(4) has PPARgamma agonistic actions. Altogether, our data illustrate that some effects of rosiglitazone are attributable to de novo synthesis of 5-LO, able to induce a switch from the synthesis of proinflammatory LTB(4) to the synthesis of the proresolving LXA(4). Our study suggests novel lines of study such as the interest of lipoxin-like anti-inflammatory drugs or the use of these molecules as prognostic and/or diagnostic markers for pathologies in which inflammation is involved, such as stroke.
Assuntos
Araquidonato 5-Lipoxigenase/fisiologia , Lipoxinas/biossíntese , Fármacos Neuroprotetores/farmacologia , PPAR gama/agonistas , Acidente Vascular Cerebral/metabolismo , Tiazolidinedionas/farmacologia , Animais , Araquidonato 5-Lipoxigenase/biossíntese , Araquidonato 5-Lipoxigenase/genética , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Infarto Encefálico/etiologia , Infarto Encefálico/metabolismo , Infarto Encefálico/patologia , Infarto da Artéria Cerebral Média/complicações , Leucotrieno B4/biossíntese , Camundongos , PPAR gama/fisiologia , Ratos , Rosiglitazona , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/patologiaRESUMO
BACKGROUND: The liver X receptors (LXRs) belong to the nuclear receptor superfamily and act as transcriptional regulators of cholesterol metabolism in several tissues. Recent work also has identified LXRs as potent antiinflammatory molecules in macrophages and other immune cells. Combined changes in lipid and inflammatory profiles are likely mediating the protective role of LXRs in models of chronic injury like atherosclerosis. These beneficial actions, however, have not been illustrated in other models of acute injury such as stroke in which inflammation is an important pathophysiological feature. METHODS AND RESULTS: We have studied LXR expression and function in the course of experimental stroke caused by permanent middle cerebral artery occlusion in rats and mice. Here, we show that administration of the synthetic LXR agonists GW3965 or TO901317 after the ischemic occlusion improves stroke outcome as shown by decreased infarct volume area and better neurological scores in rats. Neuroprotection observed with LXR agonists correlated with decreased expression of proinflammatory genes in the brain and with reduced nuclear factor-kappaB transcriptional activity. Loss of function studies using LXRalpha,beta(-/-) mice demonstrated that the effect of LXR agonists is receptor specific. Interestingly, infarcted brain area and inflammatory signaling were significantly extended in LXRalpha,beta(-/-) mice compared with control animals, indicating that endogenous LXR signaling mediates neuroprotection in this setting. CONCLUSIONS: This work highlights the transcriptional action of LXR as a protective pathway in brain injury and the potential use of LXR agonists as therapeutic agents in stroke.
Assuntos
Isquemia Encefálica/patologia , Encéfalo/patologia , Proteínas de Ligação a DNA/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Receptores Citoplasmáticos e Nucleares/metabolismo , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/prevenção & controle , Animais , Benzoatos/farmacologia , Benzoatos/uso terapêutico , Benzilaminas/farmacologia , Benzilaminas/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Isquemia Encefálica/metabolismo , Isquemia Encefálica/prevenção & controle , Proteínas de Ligação a DNA/agonistas , Inflamação/patologia , Inflamação/prevenção & controle , Receptores X do Fígado , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Fármacos Neuroprotetores/farmacologia , Receptores Nucleares Órfãos , Ratos , Ratos Endogâmicos F344 , Receptores Citoplasmáticos e Nucleares/agonistas , Acidente Vascular Cerebral/metabolismoRESUMO
BACKGROUND AND PURPOSE: Increased body iron stores have been related to greater oxidative stress and brain injury in clinical and experimental cerebral ischemia and reperfusion. We aimed to investigate the biological signatures of excitotoxicity, inflammation and blood brain barrier disruption potentially associated with high serum ferritin levels-related damage in acute stroke patients treated with i.v. t-PA. METHODS: Serum levels of ferritin (as index of increased cellular iron stores), glutamate, interleukin-6, matrix metalloproteinase-9 and cellular fibronectin were determined in 134 patients treated with i.v. t-PA within 3 hours from stroke onset in blood samples obtained before t-PA treatment, at 24 and 72 hours. RESULTS: Serum ferritin levels before t-PA infusion correlated to glutamate (r = 0.59, p < 0.001) and interleukin-6 (r = 0.55, p < 0.001) levels at baseline, and with glutamate (r = 0.57, p < 0.001), interleukin-6 (r = 0.49, p < 0.001), metalloproteinase-9 (r = 0.23, p = 0.007) and cellular fibronectin (r = 0.27, p = 0.002) levels measured at 24 hours and glutamate (r = 0.415, p < 0.001), interleukin-6 (r = 0.359, p < 0.001) and metalloproteinase-9 (r = 0.261, p = 0.004) at 72 hours. The association between ferritin and glutamate levels remained after adjustment for confounding factors in generalized linear models. CONCLUSIONS: Brain damage associated with increased iron stores in acute ischemic stroke patients treated with iv. tPA may be mediated by mechanisms linked to excitotoxic damage. The role of inflammation, blood brain barrier disruption and oxidative stress in this condition needs further research.
Assuntos
Lesões Encefálicas/sangue , Isquemia Encefálica/sangue , Isquemia Encefálica/tratamento farmacológico , Ferritinas/sangue , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/tratamento farmacológico , Terapia Trombolítica , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Lesões Encefálicas/etiologia , Isquemia Encefálica/complicações , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Acidente Vascular Cerebral/complicações , Ativador de Plasminogênio Tecidual/uso terapêuticoRESUMO
BACKGROUND AND PURPOSE: Plasma levels of cellular fibronectin (c-Fn) > or =3.6 microg/mL and of matrix metalloproteinase-9 (MMP-9) > or =140 ng/mL have been associated with parenchymal hematoma (PH) after treatment with tissue-type plasminogen activator (t-PA) in patients with acute ischemic stroke. In this prospective study, we sought to validate the predictive capacity of the preestablished cutoff values of these biomarkers for PH in a larger series of patients. METHODS: We studied 134 patients treated with t-PA within 3 hours from symptom onset according to the SITS-MOST criteria (median time to infusion, 152 minutes; median National Institutes of Health Stroke Scale score, 14) in 4 university hospitals. Hemorrhagic transformation was classified according to the European-Australasian Acute Stroke Study II definitions on computed tomography scans performed 24 to 36 hours after treatment. Relevant hemorrhagic transformation was defined as hemorrhagic infarction type 2 or any PH. Serum c-Fn and MMP-9 levels were determined by an ELISA om blood samples obtained before treatment. RESULTS: Cranial computed tomography showed hemorrhagic transformation in 27 patients (20%), hemorrhagic infarction in 15 (type 2 in 8 patients), and PH in 12 patients (symptomatic in 4). Serum c-Fn and MMP-9 concentrations at baseline were significantly higher in patients with relevant hemorrhagic transformation and PH than in those without (all P<0.001). The sensitivity, specificity, and positive and negative predictive values for PH by c-Fn levels > or =3.6 microg/mL were 100%, 60%, 20%, and 100%, respectively, whereas corresponding values were 92%, 74%, 26%, and 99% for MMP-9 levels > or =140 ng/mL. When both biomarkers were at levels above the cutoff points, specificity increased to 87% and the positive predictive value increased to 41%. CONCLUSIONS: This prospective study confirmed the high sensitivity and negative predictive value, with retained good specificity, of c-Fn and MMP-9 for the prediction of PH in patients treated with t-PA. Development of faster analytic methods will prove the applicability of these biomarkers in routine clinical practice.
Assuntos
Isquemia Encefálica/sangue , Fibronectinas/sangue , Hematoma Epidural Craniano/sangue , Metaloproteinase 9 da Matriz/sangue , Acidente Vascular Cerebral/sangue , Terapia Trombolítica , Idoso , Biomarcadores/sangue , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/epidemiologia , Feminino , Hematoma Epidural Craniano/tratamento farmacológico , Hematoma Epidural Craniano/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/epidemiologia , Terapia Trombolítica/efeitos adversosRESUMO
BACKGROUND AND PURPOSE: Iron overload has been associated with greater oxidative stress and brain injury in experimental cerebral ischemia and reperfusion. This study investigates whether high serum ferritin levels, as an index of increased cellular iron stores, are associated with poor outcome, hemorrhagic transformation, and brain edema after treatment with tissue plasminogen activator in patients with acute ischemic stroke. METHODS: A total of 134 consecutive patients treated with intravenous tissue plasminogen activator were prospectively studied in four centers. Serum ferritin levels were determined at baseline, 24 and 72 hours after treatment. Cranial computed tomography was performed on admission and at 24 to 36 hours after tissue plasminogen activator infusion. Stroke severity and outcome were evaluated by using the National Institute of Health Stroke Scale and the modified Rankin Scale. RESULTS: Computed tomography showed hemorrhagic transformation in 27 patients (hemorrhagic infarction in 15 and parenchymal hematoma in 12; symptomatic in four) and brain swelling with midline shift in 15. Poor outcome (modified Rankin Scale >2) at 90 days was observed in 54.5% of patients. Ferritin levels at baseline were higher in patients with poor outcome at 90 days (median [quartiles], 165 [98,307] versus 17 [12,37] ng/mL; P<0.001) and in those who developed parenchymal hematoma (P=0.006), symptomatic hemorrhagic transformation (P=0.008), and severe brain edema (P<0.001). Serum ferritin levels higher than 79 ng/mL before tissue plasminogen activator treatment were independently associated with poor outcome (OR, 117 [95% CI, 25 to 557]). CONCLUSIONS: Increased body iron stores are associated with poor outcome, symptomatic hemorrhagic transformation, and severe edema in patients treated with tissue plasminogen activator after ischemic stroke. These findings suggest that iron overload may offset the beneficial effect of thrombolytic therapies.
Assuntos
Hemorragia Cerebral/sangue , Hemorragia Cerebral/induzido quimicamente , Ferro/sangue , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/tratamento farmacológico , Ativador de Plasminogênio Tecidual/efeitos adversos , Idoso , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Edema Encefálico/sangue , Edema Encefálico/induzido quimicamente , Edema Encefálico/fisiopatologia , Causalidade , Artérias Cerebrais/efeitos dos fármacos , Artérias Cerebrais/metabolismo , Artérias Cerebrais/patologia , Hemorragia Cerebral/fisiopatologia , Feminino , Ferritinas/sangue , Fibrinolíticos/efeitos adversos , Humanos , Injeções Intravenosas , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Medição de Risco , Acidente Vascular Cerebral/fisiopatologia , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
Excessive levels of extracellular glutamate in the nervous system are excitotoxic and lead to neuronal death. Glutamate transport, mainly by glutamate transporter GLT1/EAAT2, is the only mechanism for maintaining extracellular glutamate concentrations below excitotoxic levels in the central nervous system. We recently showed that neuroprotection after experimental ischemic preconditioning (IPC) involves, at least partly, the upregulation of the GLT1/EAAT2 glutamate transporter in astrocytes, but the mechanisms were unknown. Thus, we decided to explore whether activation of the nuclear receptor peroxisome proliferator-activated receptor (PPAR) gamma, known for its antidiabetic and antiinflammatory properties, is involved in glutamate transport. First, we found that the PPARgamma antagonist T0070907 inhibits both IPC-induced tolerance and reduction of glutamate release after lethal oxygen-glucose deprivation (OGD) (70.1%+/-3.4% versus 97.7%+/-5.2% of OGD-induced lactate dehydrogenase (LDH) release and 61.8%+/-5.9% versus 85.9%+/-7.9% of OGD-induced glutamate release in IPC and IPC+T0070907 1 mumol/L, respectively, n=6 to 12, P<0.05), as well as IPC-induced astrocytic GLT-1 overexpression. IPC also caused an increase in nuclear PPARgamma transcriptional activity in neurons and astrocytes (122.1%+/-8.1% and 158.6%+/-22.6% of control PPARgamma transcriptional activity, n=6, P<0.05). Second, the PPARgamma agonist rosiglitazone increased both GLT-1/EAAT2 mRNA and protein expression and [(3)H]glutamate uptake, and reduced OGD-induced cell death and glutamate release (76.3%+/-7.9% and 65.5%+/-15.1% of OGD-induced LDH and glutamate release in rosiglitazone 1 mumol/l, respectively, n=6 to 12, P<0.05). Finally, we have identified six putative PPAR response elements (PPREs) in the GLT1/EAAT2 promoter and, consistently, rosiglitazone increased fourfold GLT1/EAAT2 promoter activity. All these data show that the GLT1/EAAT2 glutamate transporter is a target gene of PPARgamma leading to neuroprotection by increasing glutamate uptake.
Assuntos
Encéfalo/metabolismo , Transportador 2 de Aminoácido Excitatório/genética , Transportador 2 de Aminoácido Excitatório/metabolismo , Precondicionamento Isquêmico , PPAR gama/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Astrócitos/patologia , Benzamidas/farmacologia , Western Blotting , Encéfalo/irrigação sanguínea , Encéfalo/efeitos dos fármacos , Células Cultivadas , Cromatografia Líquida de Alta Pressão , Técnicas de Cocultura , Expressão Gênica , Ácido Glutâmico/análise , Ácido Glutâmico/metabolismo , Hipoglicemiantes/farmacologia , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Masculino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Regiões Promotoras Genéticas , Piridinas/farmacologia , RNA Mensageiro/análise , RNA Mensageiro/efeitos dos fármacos , Ratos , Ratos Endogâmicos F344 , Ratos Wistar , Elementos de Resposta , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Rosiglitazona , Tiazolidinedionas/farmacologiaRESUMO
Some agonists of the peroxisome proliferator-activated receptor gamma (PPARgamma) belonging to the thiazolidinedione (TZD) family, as well as the cyclopentenone prostaglandin 15-dPGJ2, have been shown to cause neuroprotection in animal models of stroke. We have tested whether the TZD-unrelated PPARgamma agonist L-796,449 is neuroprotective after permanent middle cerebral artery occlusion (MCAO) in the rat brain. Our results show that L-796,449 decreases MCAO-induced infarct size and improves neurologic scores. This protection is concomitant to inhibition of MCAO-induced brain expression of inducible NO synthase (iNOS) and the matrix metalloproteinase MMP-9 and to upregulation of the cytoprotective stress protein heme oxygenase-1 (HO-1). Analysis of the NF-kappaB p65 monomer and the NF-kappaB inhibitor IkappaBalpha protein levels as well as gel mobility shift assays indicate that L-796,449 inhibits NF-kappaB signaling, and that it may be recruiting both PPARgamma-dependent and independent pathways. In summary, our results provide new insights for stroke treatment.
Assuntos
Benzofuranos/uso terapêutico , Isquemia Encefálica/tratamento farmacológico , Inflamação/prevenção & controle , Fármacos Neuroprotetores/uso terapêutico , PPAR gama/agonistas , Fenilacetatos/uso terapêutico , Animais , Western Blotting , Caspase 3 , Caspases/metabolismo , Ciclo-Oxigenase 2 , Modelos Animais de Doenças , Ensaio de Desvio de Mobilidade Eletroforética , Heme Oxigenase (Desciclizante)/biossíntese , Heme Oxigenase (Desciclizante)/efeitos dos fármacos , Heme Oxigenase-1 , Proteínas I-kappa B/efeitos dos fármacos , Proteínas I-kappa B/metabolismo , Masculino , Metaloproteinase 9 da Matriz/biossíntese , Metaloproteinase 9 da Matriz/efeitos dos fármacos , NF-kappa B/efeitos dos fármacos , NF-kappa B/metabolismo , Óxido Nítrico Sintase/biossíntese , Óxido Nítrico Sintase/efeitos dos fármacos , Óxido Nítrico Sintase Tipo II , PPAR gama/metabolismo , Prostaglandina-Endoperóxido Sintases/biossíntese , Prostaglandina-Endoperóxido Sintases/efeitos dos fármacos , RatosRESUMO
PPARγ-achieved neuroprotection in experimental stroke has been explained by the inhibition of inflammatory genes, an action in which 5-LO, Alox5, is involved. In addition, PPARγ is known to promote the expression of CD36, a scavenger receptor that binds lipoproteins and mediates bacterial recognition and also phagocytosis. As phagocytic clearance of neutrophils is a requisite for resolution of the inflammatory response, PPARγ-induced CD36 expression might help to limit inflammatory tissue injury in stroke, an effect in which 5-LO might also be involved. Homogenates, sections, and cellular suspensions were prepared from brains of WT and Alox5(-/-) mice exposed to distal pMCAO. BMMs were obtained from Lys-M Cre(+) PPARγ(f/f) and Lys-M Cre(-) PPARγ(f/f) mice. Stereological counting of double-immunofluorescence-labeled brain sections and FACS analysis of cell suspensions was performed. In vivo and in vitro phagocytosis of neutrophils by microglia/macrophages was analyzed. PPARγ activation with RSG induced CD36 expression in resident microglia. This process was mediated by the 5-LO gene, which is induced in neurons by PPARγ activation and at least by one of its products--LXA4--which induced CD36 independently of PPARγ. Moreover, CD36 expression helped resolution of inflammation through phagocytosis, concomitantly to neuroprotection. Based on these findings, in addition to a direct modulation by PPARγ, we propose in brain a paracrine model by which products generated by neuronal 5-LO, such as LXA4, increase the microglial expression of CD36 and promote tissue repair in pathologies with an inflammatory component, such as stroke.
Assuntos
Araquidonato 5-Lipoxigenase/fisiologia , Antígenos CD36/fisiologia , Hipoglicemiantes/farmacologia , Inflamação/imunologia , Neutrófilos/imunologia , PPAR gama/fisiologia , Tiazolidinedionas/farmacologia , Animais , Isquemia Encefálica/imunologia , Antígenos CD36/análise , Células Cultivadas , Lipoxinas/biossíntese , Camundongos , Camundongos Endogâmicos C57BL , PPAR gama/agonistas , Fagocitose , Ratos , Rosiglitazona , Regulação para CimaRESUMO
Primary cardiac tumors constitute an infrequent heart pathology with a generally good prognosis. We present the case of a 45-year-old woman without a relevant medical history and with recurrent transient ischemic attacks of unknown origin. After follow-up with neurologic examination and repeated echocardiograms, an elongated mobile mass image was seen in the left atrial appendage. Surgical treatment consisted of resecting the mass by left atrial appendage excision through left atriotomy, closing with running suture. Anatomopathologic examination revealed findings compatible with a hamartomatous-like malformation. Discharged 5 days after surgery, the patient has no symptoms and does not require any drugs 1 year later.
Assuntos
Apêndice Atrial/patologia , Hamartoma/cirurgia , Cardiopatias/cirurgia , Ataque Isquêmico Transitório/etiologia , Apêndice Atrial/cirurgia , Procedimentos Cirúrgicos Cardíacos/métodos , Ecocardiografia Doppler , Feminino , Seguimentos , Hamartoma/complicações , Hamartoma/diagnóstico por imagem , Átrios do Coração , Cardiopatias/complicações , Cardiopatias/diagnóstico por imagem , Humanos , Ataque Isquêmico Transitório/fisiopatologia , Pessoa de Meia-Idade , Medição de Risco , Resultado do TratamentoRESUMO
TITLE: Demencia rapidamente progresiva con criterios de enfermedad de Creutzfeldt-Jakob: un caso de linfoma intravascular cerebral.