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1.
Tuberculosis (Edinb) ; 126: 102019, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33202351

RESUMO

Inflammation contributes to the pathophysiology and high mortality of tuberculous meningitis. The IL-1ß pathway has been implicated in immunopathology and could be a target for host-directed therapy. IL-1ß was elevated in the cerebrospinal fluid (CSF) of 225 HIV-uninfected tuberculous meningitis patients in Indonesia compared to controls, but did not predict subsequent mortality, nor did IL-6 or IL-1Ra. Furthermore, genetic loci known to regulate IL1B gene expression did not predict mortality in 443 tuberculous meningitis patients, although two of these loci did predict CSF IL-1ß concentrations. Collectively, these data argue against a role for IL-1ß targeted host-directed therapy in tuberculous meningitis.


Assuntos
Proteína Antagonista do Receptor de Interleucina 1/líquido cefalorraquidiano , Mycobacterium tuberculosis/isolamento & purificação , Tuberculose Meníngea/líquido cefalorraquidiano , Adulto , Biomarcadores/líquido cefalorraquidiano , Feminino , Seguimentos , Humanos , Indonésia/epidemiologia , Masculino , Estudos Prospectivos , Taxa de Sobrevida/tendências , Tuberculose Meníngea/microbiologia , Tuberculose Meníngea/mortalidade , Adulto Jovem
2.
Ann Clin Transl Neurol ; 6(6): 1127-1133, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31211178

RESUMO

We studied 78 participants having a parental or multiple-sibling history of Alzheimer's disease (AD) in a two-year randomized placebo-controlled trial of naproxen 220 mg b.i.d. for mitigation of early AD pathogenesis. Naproxen was detected in cerebrospinal fluid at concentrations ~100 times lower than in plasma, but produced negligible change in immune markers. The repeated lack of benefit in AD prevention trials using naproxen and related drugs may reflect limited CNS permeability, lack of expected drug effects, or both. These findings suggest reconsideration of implications from results of AD prevention trials using anti-inflammatory drugs.


Assuntos
Biomarcadores/líquido cefalorraquidiano , Naproxeno/líquido cefalorraquidiano , Naproxeno/uso terapêutico , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/tratamento farmacológico , Anti-Inflamatórios não Esteroides/uso terapêutico , Celecoxib/uso terapêutico , Citocinas/líquido cefalorraquidiano , Feminino , Humanos , Interferon alfa-2/líquido cefalorraquidiano , Proteína Antagonista do Receptor de Interleucina 1/líquido cefalorraquidiano , Masculino , Pessoa de Meia-Idade
3.
Ann Neurol ; 85(4): 526-537, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30779222

RESUMO

OBJECTIVE: We recently reported successful treatment of a child with febrile infection-related epilepsy syndrome (FIRES), a subtype of new onset refractory status epilepticus, with the recombinant interleukin-1 (IL1) receptor antagonist (IL1RA) anakinra. On this basis, we tested whether endogenous IL1RA production or function is deficient in FIRES patients. METHODS: Levels of IL1ß and IL1RA were measured in serum and cerebrospinal fluid (CSF). The inhibitory activity of endogenous IL1RA was assessed using a cell-based reporter assay. IL1RN gene variants were identified by sequencing. Expression levels for the secreted and intracellular isoforms of IL1RA were measured in patient and control cells by real-time polymerase chain reaction. RESULTS: Levels of endogenous IL1RA and IL1ß were elevated in the serum and CSF of patients with FIRES (n = 7) relative to healthy controls (n = 10). Serum from FIRES patients drove IL1R signaling activity and potentiated IL1R signaling in response to exogenous IL1ß in a cell-based reporter assay. Functional assessment of endogenous IL1RA activity in 3 FIRES patients revealed attenuated inhibition of IL1R signaling. Sequencing of IL1RN in our index patient revealed multiple variants. This was accompanied by reduced expression of intracellular but not secreted isoforms of IL1RA in the patient's peripheral blood mononuclear cells. INTERPRETATION: Our findings suggest that FIRES is associated with reduced expression of intracellular IL1RA isoforms and a functional deficiency in IL1RA inhibitory activity. These observations may provide insight into disease pathogenesis for FIRES and other inflammatory seizure disorders and may provide a valuable biomarker for therapeutic decision-making. Ann Neurol 2019;85:526-537.


Assuntos
Epilepsia Resistente a Medicamentos/metabolismo , Síndromes Epilépticas/metabolismo , Infecções/metabolismo , Proteína Antagonista do Receptor de Interleucina 1/sangue , Proteína Antagonista do Receptor de Interleucina 1/líquido cefalorraquidiano , Convulsões Febris/metabolismo , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Epilepsia Resistente a Medicamentos/diagnóstico , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Síndromes Epilépticas/diagnóstico , Síndromes Epilépticas/tratamento farmacológico , Feminino , Células HEK293 , Humanos , Infecções/diagnóstico , Infecções/tratamento farmacológico , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Masculino , Convulsões Febris/diagnóstico , Convulsões Febris/tratamento farmacológico
4.
Cell Immunol ; 327: 77-82, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29478949

RESUMO

Several parameters representing the clinical diversity of Parkinson's disease (PD), including severity, phenotypes, cognitive decline, anxiety and depression were analyzed to examine the link with interleukin-1ß (IL-1ß), the interleukin-1 receptor antagonist (IL-1RA), IL-6, IL-10, and tumor necrosis factor-α (TNFα) and also to determine the relationship between levels of these factors in serum and cerebrospinal fluid (CSF). Significantly elevated serum IL-1ß and IL-6 and reduced IL-1RA levels were found in the PD group. In CSF and serum, inflammatory factors behaved differently, with increased CSF TNFα indicating rapid PD progression, and increased IL-1ß in serum. A low level of IL-6 was associated with a longer duration of PD. Anxiety, depression, non-tremor phenotype and late-onset PD correlated with a high serum level of IL-10. The serum TNFα level was lower in PD patients with mild cognitive impairment compared to controls. Serum IL-1ß, IL-6 and IL-10 levels correlated with CSF markers.


Assuntos
Doença de Parkinson/sangue , Doença de Parkinson/líquido cefalorraquidiano , Doença de Parkinson/metabolismo , Idoso , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Feminino , Humanos , Proteína Antagonista do Receptor de Interleucina 1/análise , Proteína Antagonista do Receptor de Interleucina 1/sangue , Proteína Antagonista do Receptor de Interleucina 1/líquido cefalorraquidiano , Interleucina-10/análise , Interleucina-10/sangue , Interleucina-10/líquido cefalorraquidiano , Interleucina-1beta/análise , Interleucina-1beta/sangue , Interleucina-1beta/líquido cefalorraquidiano , Interleucina-6/análise , Interleucina-6/sangue , Interleucina-6/líquido cefalorraquidiano , Masculino , Pessoa de Meia-Idade , Fator de Necrose Tumoral alfa/análise , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/líquido cefalorraquidiano
5.
Clin Immunol ; 181: 43-50, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28578025

RESUMO

Delay in the diagnosis of multiple sclerosis (MS) stems from the lack of specific clinical and analytical markers to assist in the early diagnosis and prediction of progressive course. We propose a decision-tree model that better defines early at onset MS patients and those with the progressive form by analysing a 12-biomarkers panel in serum and CSF samples of patients with MS, other neurological diseases (OND) and healthy contols. Thus, patients at onset of neurological disease were first classified by serum IL-7 levels <141pg/ml (OR=6.51, p<0.001). Combination of IL-7 and CXCL10 indicated risk for a specific MS clinical form, where IL-7<141 and CXCL10<570pg/ml were associated with the highest risk for PP-MS (OR=22, p=0.01). Unexpectedly, both PP-MS and RR-MS patients shared significantly decreased prototypical biomarkers of inflammation and tissue regeneration in CSF than OND suggesting a defective intrinsic immune response playing a role at the beginning of the disease.


Assuntos
Esclerose Múltipla Crônica Progressiva/diagnóstico , Esclerose Múltipla Recidivante-Remitente/diagnóstico , Área Sob a Curva , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Estudos de Casos e Controles , Quimiocina CCL11 , Quimiocina CCL2 , Quimiocina CCL4 , Quimiocina CCL5 , Quimiocina CXCL10/sangue , Quimiocina CXCL10/líquido cefalorraquidiano , Quimiocina CXCL9/sangue , Quimiocina CXCL9/líquido cefalorraquidiano , Árvores de Decisões , Dipeptidil Peptidase 4/sangue , Dipeptidil Peptidase 4/líquido cefalorraquidiano , Diagnóstico Precoce , Fator de Crescimento Epidérmico , Fator 2 de Crescimento de Fibroblastos/sangue , Fator 2 de Crescimento de Fibroblastos/líquido cefalorraquidiano , Fator de Crescimento de Hepatócito , Humanos , Proteína Antagonista do Receptor de Interleucina 1/sangue , Proteína Antagonista do Receptor de Interleucina 1/líquido cefalorraquidiano , Interleucina-7/sangue , Interleucina-7/líquido cefalorraquidiano , Esclerose Múltipla Crônica Progressiva/sangue , Esclerose Múltipla Crônica Progressiva/líquido cefalorraquidiano , Esclerose Múltipla Recidivante-Remitente/sangue , Esclerose Múltipla Recidivante-Remitente/líquido cefalorraquidiano , Análise Multivariada , Doenças do Sistema Nervoso/sangue , Doenças do Sistema Nervoso/líquido cefalorraquidiano , Doenças do Sistema Nervoso/diagnóstico , Prognóstico , Medição de Risco
6.
J Infect Dis ; 213(10): 1651-60, 2016 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-26712949

RESUMO

BACKGROUND: Encephalitis is parenchymal brain inflammation, commonly due to herpes simplex virus (HSV). Key host inflammatory mediators and their relationship to blood-brain barrier (BBB) permeability, neuroimaging changes, and disease outcome are poorly understood. METHODS: We measured levels of 38 mediators in serum (n = 78) and cerebrospinal fluid (n = 37) specimens from patients with encephalitis, including 17 with disease due to HSV infection. Outcome measures were Glasgow coma and outcome scores; CSF to serum albumin ratio, reflecting BBB permeability; and, in patients with HSV infection, magnetic resonance imaging-based temporal lobe volume. RESULTS: Serum interleukin 1 receptor antagonist (IL-1RA) levels were elevated in patients with a good outcome (P= .004). Among patients infected with HSV, the ratio of CSF IL-1ß to IL-1RA was associated with a worse outcome (P= .009); a ratio of ≥0.55 pg/mL had high specificity and sensitivity for a poor outcome (100% and 83%;P= .015). Temporal lobe volume had a negative correlation with serum IL-1RA level (P= .012) and a positive correlation with serum IL-1α level (P= .0003) and CSF IL-1ß level (P= .007). A normal coma score was associated with an elevated interleukin 10 (IL-10) level in serum specimens from HSV-infected patients (P= .007) and CSF specimens from all patients (P= .016); the IL-10 level correlated inversely with BBB permeability (P= .005). CONCLUSIONS: A proinflammatory cytokine response is associated with greater clinical severity, BBB permeability, and neuroimaging damage during encephalitis. IL-1 antagonists should be investigated as adjunctive treatment in encephalitis.


Assuntos
Barreira Hematoencefálica , Permeabilidade Capilar , Encefalite por Herpes Simples/imunologia , Mediadores da Inflamação , Interleucina-1/metabolismo , Albuminas/líquido cefalorraquidiano , Estudos de Coortes , Encefalite por Herpes Simples/sangue , Encefalite por Herpes Simples/líquido cefalorraquidiano , Inglaterra , Escala de Coma de Glasgow , Humanos , Mediadores da Inflamação/sangue , Mediadores da Inflamação/líquido cefalorraquidiano , Proteína Antagonista do Receptor de Interleucina 1/sangue , Proteína Antagonista do Receptor de Interleucina 1/líquido cefalorraquidiano , Interleucina-1/sangue , Interleucina-1/líquido cefalorraquidiano , Interleucina-10/sangue , Interleucina-10/líquido cefalorraquidiano , Interleucina-1beta/sangue , Interleucina-1beta/líquido cefalorraquidiano , Imageamento por Ressonância Magnética , Neuroimagem , Estudos Prospectivos , Albumina Sérica/análise , Simplexvirus/imunologia , Lobo Temporal/patologia
7.
Neurobiol Dis ; 59: 183-93, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23938763

RESUMO

We studied whether pharmacological blockade of the IL-1ß-mediated signaling, rapidly activated in forebrain by epileptogenic injuries, affords neuroprotection in two different rat models of status epilepticus (SE). As secondary outcome, we measured treatment's effect on SE-induced epileptogenesis. IL-1ß signaling was blocked by systemic administration of two antiinflammatory drugs, namely human recombinant IL-1 receptor antagonist (anakinra), the naturally occurring and clinically used competitive IL-1 receptor type 1 antagonist, and VX-765 a specific non-peptide inhibitor of IL-1ß cleavage and release. Antiinflammatory drugs were given 60min after antiepileptic (AED) drug-controlled SE induced by pilocarpine, or 180min after unrestrained electrical SE, for 7days using a protocol yielding therapeutic drug levels in brain. This drug combination significantly decreased both IL-1ß expression in astrocytes and cell loss in rat forebrain. Neuroprotection and the antiinflammatory effect were more pronounced in the electrical SE model. Onset of epilepsy, and frequency and duration of seizures 3months after electrical SE were not significantly modified. Transcriptomic analysis in the hippocampus showed that the combined treatment did not affect the broad inflammatory response induced by SE during epileptogenesis. In particular, the treatment did not prevent the induction of the complement system and Toll-like receptors, both contributing to cell loss and seizure generation. We conclude that the IL-1ß signaling represents an important target for reducing cell loss after SE. The data highlight a new class of clinically tested agents affording neuroprotection after a delayed post-injury intervention. Earlier blockade of this rapid onset inflammatory pathway during SE, or concomitant treatment with antiinflammatory drugs targeting additional components of the broad inflammatory response to SE, or co-treatment with AEDs, is likely to be required for optimizing beneficial outcomes.


Assuntos
Epilepsia do Lobo Temporal/metabolismo , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Interleucina-1beta/metabolismo , Receptores Tipo I de Interleucina-1/metabolismo , Animais , Morte Celular/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Dipeptídeos/uso terapêutico , Modelos Animais de Doenças , Estimulação Elétrica/efeitos adversos , Epilepsia do Lobo Temporal/induzido quimicamente , Epilepsia do Lobo Temporal/patologia , Epilepsia do Lobo Temporal/prevenção & controle , Feminino , Proteína Glial Fibrilar Ácida/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Humanos , Proteína Antagonista do Receptor de Interleucina 1/sangue , Proteína Antagonista do Receptor de Interleucina 1/líquido cefalorraquidiano , Lítio/toxicidade , Masculino , Pilocarpina/toxicidade , Ratos , Ratos Sprague-Dawley , para-Aminobenzoatos/uso terapêutico
8.
Proc Natl Acad Sci U S A ; 109(31): 12728-33, 2012 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-22802629

RESUMO

During peripheral immune activation caused by an infection or an inflammatory condition, the innate immune response signals to the brain and causes an up-regulation of central nervous system (CNS) cytokine production. Central actions of proinflammatory cytokines, in particular IL-1ß, are pivotal for the induction of fever and fatigue. In the present study, the influence of peripheral chronic joint inflammatory disease in rheumatoid arthritis (RA) on CNS inflammation was investigated. Intrathecal interleukin (IL)-1ß concentrations were markedly elevated in RA patients compared with controls or with patients with multiple sclerosis. Conversely, the anti-inflammatory IL-1 receptor antagonist and IL-4 were decreased in RA cerebrospinal fluid (CSF). Tumor necrosis factor and IL-6 levels in the CSF did not differ between patients and controls. Concerning IL-1ß, CSF concentrations in RA patients were higher than in serum, indicating local production in the CNS, and there was a positive correlation between CSF IL-1ß and fatigue assessments. Next, spinal inflammation in experimental arthritis was investigated. A marked increase of IL-1ß, IL-18, and tumor necrosis factor, but not IL-6 mRNA production, in the spinal cord was observed, coinciding with increased arthritis scores in the KBxN serum transfer model. These data provide evidence that peripheral inflammation such as arthritis is associated with an immunological activation in the CNS in both humans and mice, suggesting a possible therapeutic target for centrally affecting conditions as fatigue in chronic inflammatory diseases, for which to date there are no specific treatments.


Assuntos
Artrite Reumatoide/líquido cefalorraquidiano , Sistema Nervoso Central/metabolismo , Regulação da Expressão Gênica , Interleucina-1beta/líquido cefalorraquidiano , Esclerose Múltipla/líquido cefalorraquidiano , Adulto , Animais , Modelos Animais de Doenças , Feminino , Humanos , Proteína Antagonista do Receptor de Interleucina 1/líquido cefalorraquidiano , Interleucina-18/líquido cefalorraquidiano , Interleucina-4/líquido cefalorraquidiano , Interleucina-6/líquido cefalorraquidiano , Camundongos , Camundongos Endogâmicos NOD , Pessoa de Meia-Idade , Fator de Necrose Tumoral alfa/líquido cefalorraquidiano
9.
Biol Psychiatry ; 70(7): 663-71, 2011 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-21641581

RESUMO

BACKGROUND: Schizophrenia is associated with immune system dysfunction, including aberrant cytokine levels. We performed a meta-analysis of these associations, considering effects of clinical status and antipsychotic treatment following an acute illness exacerbation. METHODS: We identified articles by searching PubMed, PsychInfo, and Institute for Scientific Information and the reference lists of identified studies. RESULTS: Forty studies met the inclusion criteria. Effect sizes were similar for studies of acutely relapsed inpatients (AR) and first-episode psychosis (FEP). Interleukin (IL)-1ß, IL-6, and transforming growth factor-ß (TGF-ß) appeared to be state markers, as they were increased in AR and FEP (p < .001 for each) and normalized with antipsychotic treatment (p < .001, p = .008, and p = .005, respectively). In contrast, IL-12, interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and soluble IL-2 receptor (sIL-2R) appeared to be trait markers, as levels remained elevated in acute exacerbations and following antipsychotic treatment. There was no difference in IL-6 levels between stable medicated outpatients and control subjects (p = .69). In the cerebrospinal fluid, IL-1ß was significantly decreased in schizophrenia versus controls (p = .01). CONCLUSIONS: Similar effect sizes in AR and FEP suggest that the association between cytokine abnormalities and acute exacerbations of schizophrenia is independent of antipsychotic medications. While some cytokines (IL-1ß, IL-6, and TGF-ß) may be state markers for acute exacerbations, others (IL-12, IFN-γ, TNF-α, and sIL-2R) may be trait markers. Although these results could provide the basis for future hypothesis testing, most studies did not control for potential confounding factors such as body mass index and smoking.


Assuntos
Antipsicóticos/farmacologia , Citocinas/sangue , Citocinas/líquido cefalorraquidiano , Esquizofrenia/sangue , Esquizofrenia/líquido cefalorraquidiano , Antipsicóticos/uso terapêutico , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Citocinas/efeitos dos fármacos , Humanos , Proteína Antagonista do Receptor de Interleucina 1/sangue , Proteína Antagonista do Receptor de Interleucina 1/líquido cefalorraquidiano , Proteína Antagonista do Receptor de Interleucina 1/efeitos dos fármacos , Receptores de Citocinas/sangue , Receptores de Citocinas/efeitos dos fármacos , Recidiva , Esquizofrenia/diagnóstico , Esquizofrenia/tratamento farmacológico
10.
J Cereb Blood Flow Metab ; 31(2): 439-47, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20628399

RESUMO

The naturally occurring antagonist of interleukin-1, IL-1RA, is highly neuroprotective experimentally, shows few adverse effects, and inhibits the systemic acute phase response to stroke. A single regime pilot study showed slow penetration into cerebrospinal fluid (CSF) at experimentally therapeutic concentrations. Twenty-five patients with subarachnoid hemorrhage (SAH) and external ventricular drains were sequentially allocated to five administration regimes, using intravenous bolus doses of 100 to 500 mg and 4 hours intravenous infusions of IL-1RA ranging from 1 to 10 mg per kg per hour. Choice of regimes and timing of plasma and CSF sampling was informed by pharmacometric analysis of pilot study data. Data were analyzed using nonlinear mixed effects modeling. Plasma and CSF concentrations of IL-1RA in all regimes were within the predicted intervals. A 500-mg bolus followed by an intravenous infusion of IL-1RA at 10 mg per kg per hour achieved experimentally therapeutic CSF concentrations of IL-1RA within 45 minutes. Experimentally, neuroprotective CSF concentrations in patients with SAH can be safely achieved within a therapeutic time window. Pharmacokinetic analysis suggests that IL-1RA transport across the blood-CSF barrier in SAH is passive. Identification of the practicality of this delivery regime allows further studies of efficacy of IL-1RA in acute cerebrovascular disease.


Assuntos
Sistema Nervoso Central/metabolismo , Proteína Antagonista do Receptor de Interleucina 1/farmacocinética , Fármacos Neuroprotetores/farmacocinética , Hemorragia Subaracnóidea/metabolismo , Adulto , Idoso , Ventrículos Cerebrais/metabolismo , Relação Dose-Resposta a Droga , Feminino , Humanos , Infusões Intravenosas , Proteína Antagonista do Receptor de Interleucina 1/administração & dosagem , Proteína Antagonista do Receptor de Interleucina 1/líquido cefalorraquidiano , Interleucina-1/metabolismo , Masculino , Pessoa de Meia-Idade , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/líquido cefalorraquidiano , Dinâmica não Linear , Projetos Piloto
11.
J Neurol Sci ; 298(1-2): 106-9, 2010 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-20807663

RESUMO

The aim of this study was to evaluate whether proconvulsive interleukin-1ß (IL-1ß) and anticonvulsive IL-1 receptor antagonist (IL-1Ra) are markers of the effectiveness of treatment in patients with West syndrome (WS). We analyzed serum and cerebrospinal fluid (CSF) levels of IL-1ß and IL-1Ra in 13 patients with WS. The serum IL-1Ra levels postimprovement (average, 384.6 pg/ml) in clinical and electroencephalographic (EEG) findings were significantly higher than the preimprovement values (average, 240.6 pg/ml). No significant difference in the preimprovement serum IL-1Ra levels was noted between the anticonvulsant (AED)-response and adrenocorticotropic hormone (ACTH)-response groups (260.0 pg/ml, n=7 vs. 218.0 pg/m, n=6) and the cryptogenic and symptomatic groups (290.1 pg/ml, n=4 vs. 218.3 pg/m, n=9), respectively; as for the preimprovement CSF levels, the AED-response group (114.5 pg/m; n=3) and ACTH-response groups (138.0 pg/m; n=6) and the cryptogenic (59.3 pg/m; n=3) and symptomatic groups (165.6 pg/m; n=6), respectively. Serum and CSF IL-1ß levels were detected only in 3 patients preimprovement. Serum IL-1Ra levels were elevated subsequent to resolution of clinical and EEG findings in WS patients. A larger study should be conducted to clarify whether an immunological processes are concerned with the pathophysiology of WS.


Assuntos
Proteína Antagonista do Receptor de Interleucina 1/sangue , Espasmos Infantis/sangue , Espasmos Infantis/tratamento farmacológico , Hormônio Adrenocorticotrópico/uso terapêutico , Anticonvulsivantes/uso terapêutico , Eletroencefalografia , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Lactente , Proteína Antagonista do Receptor de Interleucina 1/líquido cefalorraquidiano , Interleucina-1beta/sangue , Interleucina-1beta/líquido cefalorraquidiano , Masculino , Espasmos Infantis/líquido cefalorraquidiano
12.
Cytokine ; 51(2): 138-43, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20538476

RESUMO

INTRODUCTION: Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP) share histopathological features but display different disease courses; we measured the concentration of 50 inflammatory mediators in the cerebrospinal fluid (CSF) of patients with either of these diseases. PATIENTS AND METHODS: CSF samples were collected during a diagnostic lumbar puncture and stored at -30 degrees C. We analyzed the CSF of nine subjects with GBS; eight with CIDP; eight with diabetic polyneuropathy (DP) and seven with headache (controls). Fifty inflammatory mediators were simultaneously measured with a multiplex bead-based ELISA on a Suspension Array System. After Bonferroni's correction for repeated measures, non-parametric variance and post hoc test were calculated. RESULTS: Thirty-two inflammatory mediators were expressed. The median concentration of IL-6, IL-9, IL-15, IL-18, CCL4, CXCL1, LIF, MIF, PDGFbb, IFN-gamma2, IL-2ra, IL-12(p40), IL-16, SCGF-b, TRAIL, FGF, G-CSF, GM-CSF, and M-CSF was not different among groups (variance: n.s.). The median concentration of CCL2, CCL7, CCL27, CXCL9, CXCL10, CXCL12, ICAM-1, VCAM1 and VEGF was higher in CIDP and GBS compared with controls (p<0.002). The median concentration of IL-8 and IL-1ra was higher in GBS than CIDP or DP or controls, whereas stem cell factor (SCF) and hepatocyte growth factor (HGF) were higher in CIDP than GBS or DP or controls (p<0.002). DISCUSSION: Mediators of the recruitment and activation of lymphocytes and monocytes are expressed in the CSF of CIDP and GBS. IL-8 and IL-1ra are characteristic of GBS, whereas growth factors (SCF, HGF) of CIDP are possibly related to chronicity or to the survival/repair processes of neurons.


Assuntos
Síndrome de Guillain-Barré/líquido cefalorraquidiano , Mediadores da Inflamação/líquido cefalorraquidiano , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/líquido cefalorraquidiano , Adulto , Fatores de Crescimento de Células Hematopoéticas/líquido cefalorraquidiano , Fator de Crescimento de Hepatócito/líquido cefalorraquidiano , Humanos , Proteína Antagonista do Receptor de Interleucina 1/líquido cefalorraquidiano , Interleucina-8/líquido cefalorraquidiano
13.
J Neuroimmunol ; 223(1-2): 138-40, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20421138

RESUMO

Anakinra improves the central nervous system manifestations of neonatal-onset multisystem inflammatory disease, which is mediated by IL-1beta oversecretion. The cerebrospinal fluid (CSF) penetration of the IL-1 receptor antagonist anakinra was studied in rhesus monkeys after intravenous doses of 3 and 10 mg/kg. Drug exposure (area under concentration-time curve) in CSF was 0.28% of that in serum. The average CSF concentration at 3 mg/kg was 1.8 ng/mL, which is 30-fold higher than endogenous CSF levels of IL-1Ra. The CSF penetration was not dose-dependent, indicating that the CSF penetration was not saturated in the 3 to 10 mg/kg dose range.


Assuntos
Proteína Antagonista do Receptor de Interleucina 1/administração & dosagem , Proteína Antagonista do Receptor de Interleucina 1/farmacocinética , Animais , Meia-Vida , Humanos , Injeções Intravenosas , Proteína Antagonista do Receptor de Interleucina 1/sangue , Proteína Antagonista do Receptor de Interleucina 1/líquido cefalorraquidiano , Proteína Antagonista do Receptor de Interleucina 1/normas , Macaca mulatta , Masculino
14.
Neuroimmunomodulation ; 17(1): 19-22, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-19816053

RESUMO

BACKGROUND: Experimentally induced seizures are associated with increased production of inflammatory cytokines in the nervous system. Elevated cerebrospinal fluid levels of cytokine interleukin-6 (IL-6) have been found after a single generalized seizure in human patients. After prolonged seizures, levels of IL-6 have been shown to be even higher compared with single seizures. In the present study, we determined the levels of proconvulsive IL-1beta and anticonvulsive IL-1ra in cerebrospinal fluid after single tonic-clonic seizures as well as after prolonged seizures. METHODS: The levels of cytokines were measured using enzyme-linked immunosorbent assay. RESULTS: We found that after single seizures, a slight increase in anticonvulsive IL-1ra levels was found; however, after prolonged partial or recurrent tonic-clonic seizures, the levels of IL-1ra were significantly elevated, together with decreased IL-1beta levels. CONCLUSION: Our results indicate that after severe seizures, the balance between IL-1-type cytokines is changed towards a neuroprotective and anticonvulsive direction with an overproduction of IL-1ra with respect to potentially neurotoxic IL-1beta. This reaction may serve as a defense mechanism of the nervous system against excitotoxic neuronal damage.


Assuntos
Epilepsia/líquido cefalorraquidiano , Epilepsia/imunologia , Proteína Antagonista do Receptor de Interleucina 1/líquido cefalorraquidiano , Interleucina-1beta/líquido cefalorraquidiano , Convulsões/líquido cefalorraquidiano , Convulsões/imunologia , Biomarcadores/líquido cefalorraquidiano , Doença Crônica , Citoproteção/imunologia , Regulação para Baixo/imunologia , Ensaio de Imunoadsorção Enzimática , Epilepsia/fisiopatologia , Humanos , Neurotoxinas/metabolismo , Recidiva , Convulsões/fisiopatologia , Regulação para Cima/imunologia
15.
Brain Behav Immun ; 23(8): 1104-8, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19560535

RESUMO

Interleukin-1beta (IL-1beta) is involved in the regulation of sickness behaviour in response to infection and inflammation in animals. Human fatigue can be considered an element of sickness behaviour and is a prominent and often disabling phenomenon in autoimmune diseases such as primary Sjögren's syndrome (PSS). The role of the IL-1 system in the fatigue of patients with PSS was explored. A cerebrospinal fluid (CSF) analysis of IL-1beta, IL-1Ra, and IL-1sRII was performed in 54 PSS patients and 53 control subjects. Fatigue was evaluated in the patients using the Fatigue Severity Scale (FSS) and a fatigue visual analogue scale (VAS); mood was evaluated using the Beck Depression Inventory (BDI). There were higher CSF levels of IL-1Ra pg/mL in PSS patients vs. controls (median 38.4: range 15.4-81.7 vs. 33.7: 7.3-163.1, p=0.026). Fatigue VAS scores were associated with increasing CSF levels of IL-1Ra in PSS patients (R(2)=0.11, p=0.015). In a subgroup analysis of the non-depressed PSS patients (N=37; 69%), the association between VAS scores and IL-1Ra was even stronger (R(2)=0.20, p=0.006). The positive association between VAS scores and IL-1Ra remained significant in a multiple regression analysis adjusting for age and BDI scores. Increased levels of IL-1Ra in the CSF are associated with increasing fatigue in PSS patients, indicating that the activated IL-1 system is a possible biological factor associated with fatigue.


Assuntos
Fadiga/líquido cefalorraquidiano , Proteína Antagonista do Receptor de Interleucina 1/líquido cefalorraquidiano , Receptores Tipo II de Interleucina-1/metabolismo , Síndrome de Sjogren/líquido cefalorraquidiano , Adulto , Idoso , Depressão/líquido cefalorraquidiano , Fadiga/complicações , Feminino , Humanos , Comportamento de Doença , Mediadores da Inflamação/líquido cefalorraquidiano , Interleucina-1beta/líquido cefalorraquidiano , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Índice de Gravidade de Doença , Síndrome de Sjogren/complicações , Inquéritos e Questionários
16.
Epilepsy Res ; 85(2-3): 314-7, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19375283

RESUMO

We measured the levels of pro- and anti-inflammatory cytokines in the cerebrospinal fluid (CSF) of 24 patients with West syndrome to clarify whether inflammatory cytokines were involved in the pathophysiology of West syndrome. There was no significant elevation of any of the three pro-inflammatory cytokines, interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha, in patients with West syndrome as compared with those in controls. However, level of anti-inflammatory cytokine, IL-1 receptor antagonist was significantly decreased in the CSF of patients with West syndrome. Further study is needed to elucidate whether an immune system disturbance is involved in the pathophysiology of West syndrome.


Assuntos
Proteína Antagonista do Receptor de Interleucina 1/líquido cefalorraquidiano , Espasmos Infantis/líquido cefalorraquidiano , Citocinas/líquido cefalorraquidiano , Feminino , Humanos , Lactente , Interleucina-1beta/líquido cefalorraquidiano , Interleucina-6/líquido cefalorraquidiano , Masculino , Meningite Asséptica/líquido cefalorraquidiano , Fator de Necrose Tumoral alfa/líquido cefalorraquidiano
17.
J Cereb Blood Flow Metab ; 28(2): 387-94, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17684519

RESUMO

The proinflammatory cytokine interleukin (IL)-1 mediates several forms of experimentally induced acute brain injury and has been implicated in chronic neurodegenerative disorders. The IL-1 receptor antagonist, IL-1RA, protects rodents against ischaemic brain injury, but its molecular mass (17 kDa) potentially limits the brain penetration of peripherally administered IL-1RA. We therefore sought to identify whether therapeutically effective concentrations of IL-1RA in the rat were also achieved in brain of patients with subarachnoid haemorrhage (SAH), using a peripheral administration regime that had proved to be safe and reduce peripheral inflammation in patients after stroke. An intravenous bolus of IL-1RA, followed by infusion, was administered to rats after induction of focal cerebral ischaemia. The effects of IL-1RA on brain ischaemia and the concentrations achieved in cerebrospinal fluid (CSF), were determined. Interleukin-1 receptor antagonist was similarly administered to patients with SAH, and CSF was sampled via external ventricular drains. In rats, IL-1RA significantly reduced brain injury induced by focal cerebral ischaemia. The plasma IL-1RA concentrations reached 12+/-2 microg/mL by 30 mins, and CSF concentrations were maintained between 91 and 232 ng/mL between 1 and 24 h of infusion. In patients with SAH, IL-1RA reached a steady-state plasma concentration of 22+/-4 microg/mL by 15 mins, and CSF concentrations were maintained at 78 to 558 ng/mL between 1 and 24 h. Intravenous delivery of IL-1RA leads to CSF concentrations in patients comparable to those that are neuroprotective in rats, and might therefore be of therapeutic benefit.


Assuntos
Encéfalo/metabolismo , Proteína Antagonista do Receptor de Interleucina 1/farmacocinética , Fármacos Neuroprotetores/farmacocinética , Adulto , Idoso , Animais , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/metabolismo , Feminino , Humanos , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/patologia , Infusões Intravenosas , Proteína Antagonista do Receptor de Interleucina 1/sangue , Proteína Antagonista do Receptor de Interleucina 1/líquido cefalorraquidiano , Masculino , Pessoa de Meia-Idade , Artéria Cerebral Média/fisiologia , Fármacos Neuroprotetores/sangue , Fármacos Neuroprotetores/líquido cefalorraquidiano , Ratos , Ratos Sprague-Dawley , Hemorragia Subaracnóidea/metabolismo
18.
Br J Clin Pharmacol ; 65(3): 317-25, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17875190

RESUMO

UNLABELLED: What is already known about this subject? The naturally occurring interlukin-1 receptor antagonist (IL-1RA) markedly protects rodents against ischaemic, excitotoxic and traumatic brain injury, suggesting it may be of therapeutic value. When administered intravenously to patients soon after stroke, IL-1RA is safe and reduces the peripheral inflammatory response. However, IL-1RA is a large protein (17 kDa), which may limit brain penetration, thereby limiting its potential utility in brain injury. What this study adds. The purpose of these experiments was to determine the pharmacokinetics of IL-1RA in cerebrospinal fluid (CSF) of patients, to allow modelling that would aid development of therapeutic regimens. Peripherally administered IL-1RA crosses slowly into and out of the CSF of patients with subarachnoid haemorrhage and, at steady state, CSF IL-1RA concentration (range 115-886 ng ml(-1)) was similar to that found to be neuroprotective in rats (range 91-232 ng ml(-1)), although there was considerable variability among patients. However, there is a large concentration gradient of IL-1RA between plasma and CSF. These CSF:plasma data are consistent with very low permeation of IL-1RA into the CSF and elimination kinetics from it controlled by the volumetric turnover of CSF. AIM: The naturally occurring interlukin-1 receptor antagonist (IL-1RA) markedly protects rodents against ischaemic, excitotoxic and traumatic brain injury, suggesting it may be of therapeutic value. The aim was to determine the pharmacokinetics of IL-1RA in cerebrospinal fluid (CSF) of patients, to allow modelling that would aid development of therapeutic regimens. METHODS: When administered intravenously to patients soon after stroke, IL-1RA is safe and reduces the peripheral inflammatory response. However, IL-1RA is a large protein (17 kDa), which may limit brain penetration, thereby limiting its potential utility in brain injury. In seven patients with subarchnoid haemorrhage (SAH), IL-1RA was administered by intravenous bolus, then infusion for 24 h, and both blood and CSF, via external ventricular drains, were sampled during and after stopping the infusion. RESULTS: Plasma steady-state concentrations were rapidly attained and maintained throughout the infusion, whereas CSF concentrations rose slowly towards a plateau during the 24-h infusion, reaching at best only 4% of that in plasma. Plasma kinetic parameters were within the literature range. Modelling of the combined data yielded rate constants entering and leaving the CSF of 0.0019 h(-1)[relative standard error (RSE) = 19%] and 0.1 h(-1) (RSE = 19%), respectively. CONCLUSIONS: Peripherally administered IL-1RA crosses slowly into and out of the CSF of patients with SAH. However, there is a large concentration gradient of IL-1RA between plasma and CSF. These CSF:plasma data are consistent with very low permeation of IL-1RA into the CSF and elimination kinetics from it controlled by the volumetric turnover of CSF.


Assuntos
Proteína Antagonista do Receptor de Interleucina 1/farmacocinética , Modelos Biológicos , Hemorragia Subaracnóidea/sangue , Hemorragia Subaracnóidea/líquido cefalorraquidiano , Adulto , Idoso , Feminino , Humanos , Proteína Antagonista do Receptor de Interleucina 1/sangue , Proteína Antagonista do Receptor de Interleucina 1/líquido cefalorraquidiano , Masculino , Pessoa de Meia-Idade , Hemorragia Subaracnóidea/tratamento farmacológico , Fatores de Tempo
19.
Malar J ; 6: 147, 2007 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-17997848

RESUMO

BACKGROUND: Plasmodium falciparum can cause a diffuse encephalopathy known as cerebral malaria (CM), a major contributor to malaria associated mortality. Despite treatment, mortality due to CM can be as high as 30% while 10% of survivors of the disease may experience short- and long-term neurological complications. The pathogenesis of CM and other forms of severe malaria is multi-factorial and appear to involve cytokine and chemokine homeostasis, inflammation and vascular injury/repair. Identification of prognostic markers that can predict CM severity will enable development of better intervention. METHODS: Postmortem serum and cerebrospinal fluid (CSF) samples were obtained within 2-4 hours of death in Ghanaian children dying of CM, severe malarial anemia (SMA), and non-malarial (NM) causes. Serum and CSF levels of 36 different biomarkers (IL-1beta, IL-1ra, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12 (p70), IL-13, IL-15, IL-17, Eotaxin, FGF basic protein, CRP, G-CSF, GM-CSF, IFN-gamma, TNF-alpha, IP-10, MCP-1 (MCAF), MIP-1alpha, MIP-1beta, RANTES, SDF-1alpha, CXCL11 (I-TAC), Fas-ligand [Fas-L], soluble Fas [sFas], sTNF-R1 (p55), sTNF-R2 (p75), MMP-9, TGF-beta1, PDGF bb and VEGF) were measured and the results compared between the 3 groups. RESULTS: After Bonferroni adjustment for other biomarkers, IP-10 was the only serum biomarker independently associated with CM mortality when compared to SMA and NM deaths. Eight CSF biomarkers (IL-1ra, IL-8, IP-10, PDGFbb, MIP-1beta, Fas-L, sTNF-R1, and sTNF-R2) were significantly elevated in CM mortality group when compared to SMA and NM deaths. Additionally, CSF IP-10/PDGFbb median ratio was statistically significantly higher in the CM group compared to SMA and NM groups. CONCLUSION: The parasite-induced local cerebral dysregulation in the production of IP-10, 1L-8, MIP-1beta, PDGFbb, IL-1ra, Fas-L, sTNF-R1, and sTNF-R2 may be involved in CM neuropathology, and their immunoassay may have potential utility in predicting mortality in CM.


Assuntos
Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Malária Cerebral/sangue , Malária Cerebral/líquido cefalorraquidiano , Quimiocina CCL5/sangue , Quimiocina CCL5/líquido cefalorraquidiano , Quimiocina CXCL10/sangue , Quimiocina CXCL10/líquido cefalorraquidiano , Quimiocinas CC/sangue , Quimiocinas CC/líquido cefalorraquidiano , Criança , Pré-Escolar , Selectina E/sangue , Selectina E/líquido cefalorraquidiano , Ensaio de Imunoadsorção Enzimática , Proteína Ligante Fas/sangue , Proteína Ligante Fas/líquido cefalorraquidiano , Feminino , Gana , Humanos , Imunoensaio , Lactente , Proteína Antagonista do Receptor de Interleucina 1/sangue , Proteína Antagonista do Receptor de Interleucina 1/líquido cefalorraquidiano , Interleucina-8/sangue , Interleucina-8/líquido cefalorraquidiano , Malária Cerebral/mortalidade , Masculino , Prognóstico , Taxa de Sobrevida , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/líquido cefalorraquidiano
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