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1.
Zh Nevrol Psikhiatr Im S S Korsakova ; 119(8. Vyp. 2): 39-45, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31825361

RESUMO

INTRODUCTION: At the present time, there is an increased interest in the search for biological predictors of the course and outcome of ischemic stroke (IS). Numerous studies have shown the relationship between neuroinflammation (in the brain) and systemic inflammatory response (in the blood). AIM: To study the relationship of inflammatory and autoimmune markers in blood serum of patients with acute ischemic stroke (on the 1st day) with the dynamics of the severity of neurological deficit (on the 1st and 10th day) and to assess the predictive ability of these indicators. MATERIAL AND METHODS: Twenty-two patients in the acute period of IS (mean age 60±15.5 years) were examined. The severity of neurological deficit was assessed by ESS and NIHSS. The enzymatic activity of leukocyte elastase (LE), α1-proteinase inhibitor (α1-PI), level of autoantibodies to S-100B and MBP in serum was determined. The control group consisted of 33 healthy subjects. Blood samples were carried out on the 1st day of the post-stroke period, the clinical examination was performed on the 1st and 10th day of observation. RESULTS: Depending on the dynamics of neurological symptoms by the 10th day of observation, two subgroups of patients were identified. The1st subgroup was characterized by the normalization of neurological deficit (n=10). In the 2nd group, the negative dynamics of neurological deficit/lack of any positive changes was observed (n=12). Both subgroups demonstrated the increase in the LE and α1-PI activity as compared to the control (p=0.0019, p=0.00079; p=0.038, p=0.00041, respectively). The highest LE activity was detected in the 1st subgroup (p=0.035). The high level of autoantibodies to MBP was also observed in the 1st subgroup as compared to the control and the 2nd group (p=0.047, p=0.03, respectively). The 2nd subgroup was characterized by a higher functional activity of acute phase protein α1-PI (p=0.04). Using regression analysis, a model for predicting the course of the early post-stroke period depending on the determined immunological parameters was developed. CONCLUSION: The results suggest that the studied inflammatory and autoimmune markers may be possible predictors of the course of the early post-stroke period.


Assuntos
Biomarcadores , Isquemia Encefálica , Inflamação , Acidente Vascular Cerebral , Adulto , Idoso , Doenças Autoimunes , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/imunologia , Humanos , Elastase de Leucócito/metabolismo , Pessoa de Meia-Idade , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/imunologia , alfa 1-Antitripsina
2.
Immunopharmacol Immunotoxicol ; 41(5): 558-564, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31542978

RESUMO

Background: The phenomenon of ischemic stroke receives maximal attention nowadays. Many studies are designed to discover new therapies for reducing debilitating consequences of this disorder. Development of stroke-related tissue damage is due to the combination of blood flow occlusion and reperfusion phase. Inflammatory pathways participate in excess oxidative stress formation after reperfusion. Modafinil is a well-known medication prescribed for sleep disorders. Recently, several studies have focused on finding new indications for modafinil treatment. Anti-inflammatory effects of modafinil through disrupting NF-κB signaling pathway is reported previously. Downregulation of inflammatory cytokines and further oxidative damage have also been mentioned in various experiments. So far, no specific experiment had been conducted to assess the anti-inflammatory effects of modafinil on ischemic stroke. Material and methods: We evaluated outcomes of acutely administered modafinil on post-stroke behaviors and histopathological features (including apoptotic caspase-3 expressing neurons) through bilateral common carotid artery occlusion in rats. Alterations in concentrations of TNFɑ and IL-1ß were assessed, together with malon di-aldehyde (MDA) to represent oxidation level. Western blotting was used to reveal the involvement of NF-κB downregulation. Considering possible alterations in blood flow and neuronal metabolism, we also assessed the effects of modafinil on cerebral glucose metabolism through PET scan. Results and discussion: Modafinil exhibited promising effects on remission of behavioral deficits and the number of degenerated neurons in ischemic hippocampus CA1 region. IL-1ß and MDA levels were downregulated in treated animals. However, no significant alteration was observed in PET results and TNFɑ between treated and non-treated ischemic brains. Decreased protein levels of NF-κB was also measured in modafinil treated animals. Conclusion: Our findings demonstrate a promising therapeutic effect of modafinil for animal models of stroke.


Assuntos
Anti-Inflamatórios/uso terapêutico , Isquemia Encefálica/complicações , Modafinila/uso terapêutico , NF-kappa B/metabolismo , Acidente Vascular Cerebral/prevenção & controle , Animais , Comportamento Animal/efeitos dos fármacos , Isquemia Encefálica/diagnóstico por imagem , Isquemia Encefálica/imunologia , Modelos Animais de Doenças , Regulação para Baixo , Masculino , NF-kappa B/genética , Tomografia por Emissão de Pósitrons , Ratos Wistar , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/imunologia
3.
Int J Mol Sci ; 20(15)2019 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-31382688

RESUMO

We recently reported that neonatal ischemia induces microglia/macrophage activation three days post-ischemia. We also found that female mice sustained smaller infarcts than males three months post-ischemia. The objective of our current study was to examine whether differential acute neuroinflammatory response and infiltrated immune cells occurs between male and females after three days post-ischemia. Permanent middle cerebral artery occlusion was induced in male and female postnatal 9-day-old (P9) mice, and mice were sacrificed three days after ischemia. Brains were analyzed for mRNA transcription after microglia magnetic cell sorting to evaluate M1 and M2 markers. FACS analysis was performed to assess myeloid infiltration and microglial expression of CX3 chemokine receptor 1 (CX3CR1). Inflammatory cytokine expression and microglia/macrophage activation were analyzed via in situ hybridization combined with immunofluorescence techniques. Lesion volume and cell death were measured. An increase in microglia/macrophages occurred in male versus female mice. The cells exhibited amoeboid morphology, and TNFα and ptgs2 (Cox-2) genes were more expressed in males. More myeloid cell infiltration was found in male versus female brains. However, we did not observe sex-dependent differences in the injured volume or cell death density. Our data show that sex differences in the acute microglial and immune responses to neonatal ischemia are likely both gene- and region-specific.


Assuntos
Isquemia Encefálica/imunologia , Imunidade Inata/genética , Inflamação/imunologia , Acidente Vascular Cerebral/imunologia , Animais , Animais Recém-Nascidos/imunologia , Encéfalo/imunologia , Encéfalo/patologia , Isquemia Encefálica/genética , Isquemia Encefálica/patologia , Modelos Animais de Doenças , Feminino , Infarto da Artéria Cerebral Média , Inflamação/genética , Inflamação/patologia , Ativação de Macrófagos/genética , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Caracteres Sexuais , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/patologia
4.
J Neuroinflammation ; 16(1): 142, 2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31291966

RESUMO

Stroke, the third leading cause of death and disability worldwide, is undergoing a change in perspective with the emergence of new ideas on neurodegeneration. The concept that stroke is a disorder solely of blood vessels has been expanded to include the effects of a detrimental interaction between glia, neurons, vascular cells, and matrix components, which is collectively referred to as the neurovascular unit. Following the acute stroke, the majority of which are ischemic, there is secondary neuroinflammation that both promotes further injury, resulting in cell death, but conversely plays a beneficial role, by promoting recovery. The proinflammatory signals from immune mediators rapidly activate resident cells and influence infiltration of a wide range of inflammatory cells (neutrophils, monocytes/macrophages, different subtypes of T cells, and other inflammatory cells) into the ischemic region exacerbating brain damage. In this review, we discuss how neuroinflammation has both beneficial as well as detrimental roles and recent therapeutic strategies to combat pathological responses. Here, we also focus on time-dependent entry of immune cells to the ischemic area and the impact of other pathological mediators, including oxidative stress, excitotoxicity, matrix metalloproteinases (MMPs), high-mobility group box 1 (HMGB1), arachidonic acid metabolites, mitogen-activated protein kinase (MAPK), and post-translational modifications that could potentially perpetuate ischemic brain damage after the acute injury. Understanding the time-dependent role of inflammatory factors could help in developing new diagnostic, prognostic, and therapeutic neuroprotective strategies for post-stroke inflammation.


Assuntos
Inflamação/patologia , Acidente Vascular Cerebral/patologia , Animais , Humanos , Inflamação/imunologia , Acidente Vascular Cerebral/imunologia
5.
Nat Rev Neurol ; 15(8): 473-481, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31263257

RESUMO

Ischaemic stroke elicits a strong neuroinflammatory response, but the functional relevance and therapeutic potential of neuroinflammation has only recently become apparent. In acute experimental stroke, T cells contribute to ischaemia-reperfusion injury after recanalization in an antigen-independent manner. Surprisingly, the detrimental T cell effects are platelet-dependent. Glycoprotein (GP)Ib-mediated and GPVI-mediated platelet activation, but not GPIIb-IIIa-mediated platelet aggregation, is an important checkpoint that orchestrates thrombotic and pro-inflammatory pathways, and downstream activation of coagulation factor XII is a driving force of ischaemia-reperfusion injury in acute stroke. The evidence therefore suggests that T cells interact with platelets and facilitate further infarct development through a complex process that we refer to as thrombo-inflammation. Results of clinical trials of agents that target lymphocytes support this concept. However, in the majority of patients with ischaemic stroke, recanalization cannot be achieved and the contribution of T cells in the setting of the resultant permanent ischaemia and subacute stroke is less clear and more complex. In some settings, T cells still seem to aggravate neuronal damage late after the ischaemic insult, but stroke triggers systemic immunodepression, therefore further anti-inflammatory treatments would need to be used carefully in this context. Targeting stroke-related neuroinflammation could become an effective adjunct therapy to improve outcomes after ischaemic stroke, but this approach will require caution regarding the timing and avoidance of adverse effects.


Assuntos
Plaquetas/imunologia , Isquemia Encefálica/imunologia , Isquemia Encefálica/terapia , Encefalite/imunologia , Trombose Intracraniana/imunologia , Acidente Vascular Cerebral/imunologia , Acidente Vascular Cerebral/terapia , Linfócitos T/imunologia , Animais , Isquemia Encefálica/complicações , Encefalite/complicações , Humanos , Trombose Intracraniana/complicações , Microbiota/imunologia , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/imunologia , Traumatismo por Reperfusão/terapia , Acidente Vascular Cerebral/complicações
6.
BMC Neurol ; 19(1): 148, 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31269910

RESUMO

BACKGROUND: Almost 40% of stroke patients have a poor outcome at 3 months after the index event. Predictors for stroke outcome in the early acute phase may help to tailor stroke treatment. Infection and inflammation are considered to influence stroke outcome. METHODS: In a prospective multicenter study in Germany and Spain, including 486 patients with acute ischemic stroke, we used multivariable regression analysis to investigate the association of poor outcome with monocytic HLA-DR (mHLA-DR) expression, interleukin 6 (IL-6), interleukin 10 (IL-10), tumor necrosis factor alpha (TNF-alpha) and lipopolysaccharide-binding protein (LBP) as markers for immunodepression, inflammation and infection. Outcome was assessed at 3 months after stroke via a structured telephone interview using the modified Rankin Scale (mRS). Poor outcome was defined as a mRS score of 3 or higher which included death. Furthermore, a time-to-event analysis for death within 3 months was performed. RESULTS: Three-month outcome data was available for 391 patients. Female sex, older age, diabetes mellitus, atrial fibrillation, stroke-associated pneumonia (SAP) and higher National Institute of Health Stroke Scale (NIHSS) score as well as lower mHLA-DR levels, higher IL-6 and LBP-levels at day 1 were associated with poor outcome at 3 months in bivariate analysis. Furthermore, multivariable analysis revealed that lower mHLA-DR expression was associated with poor outcome. Female sex, older age, atrial fibrillation, SAP, higher NIHSS score, lower mHLA-DR expression and higher IL-6 levels were associated with shorter survival time in bivariate analysis. In multivariable analysis, SAP and higher IL-6 levels on day 1 were associated with shorter survival time. CONCLUSIONS: SAP, lower mHLA-DR-expression and higher IL-6 levels on day one are associated with poor outcome and shorter survival time at 3 months after stroke onset. TRIAL REGISTRATION: www.clinicaltrials.gov, NCT01079728 , March 3, 2010.


Assuntos
Isquemia Encefálica/imunologia , Antígenos HLA-DR/sangue , Interleucina-6/sangue , Pneumonia/etiologia , Acidente Vascular Cerebral/imunologia , Proteínas da Fase Aguda , Idoso , Idoso de 80 Anos ou mais , Fibrilação Atrial/complicações , Biomarcadores/sangue , Isquemia Encefálica/sangue , Isquemia Encefálica/complicações , Isquemia Encefálica/mortalidade , Proteínas de Transporte/sangue , Diabetes Mellitus , Feminino , Alemanha , Humanos , Tolerância Imunológica , Inflamação/complicações , Interleucina-10/sangue , Masculino , Glicoproteínas de Membrana/sangue , Pessoa de Meia-Idade , Pneumonia/mortalidade , Estudos Prospectivos , Espanha , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/mortalidade , Fatores de Tempo , Fator de Necrose Tumoral alfa/sangue
7.
Stroke ; 50(7): 1869-1878, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31177975

RESUMO

Background and Purpose- Cerebral ischemic stroke elicits profound responses of CD4+ T cells, which in turn significantly affect the ischemic brain injury. ACC1 (acetyl coenzyme A carboxylase 1) is a key enzyme that has been recently found to propagate CD4+ T cell-associated inflammation by mediating de novo fatty acid synthesis; however, its role in the context of ischemic stroke remains unknown. Methods- Focal cerebral ischemia was induced by transient middle cerebral artery occlusion for 60 minutes in mice. Seahorse XF glycolysis assay and targeted lipidomic profiling were used to detect metabolic changes in CD4+ T cell after stroke. CD4 cre mice were crossed with ACC1 fl/fl mice to generate the CD4+ T-cell-specific deletion of ACC1 (CD4 creACC1 fl/fl mice) mice. Pretreatment with calorie restriction (CR; with 30% reduction of food for 4 weeks before middle cerebral artery occlusion) or post-treatment with ACC1 inhibitor, soraphen A were both used to test the effect of ACC1 modulation on poststroke neuroinflammation. Results- Cerebral ischemic stroke increased glycolysis and fatty acid synthesis in peripheral CD4+ T cells, in which the expression of ACC1 was also upregulated. CR downregulated the expression of ACC1 in CD4+ T cells after stroke. Both CD4 creACC1 fl/fl mice and CR-pretreated mice exhibited significantly reduced ischemic brain injury and preserved the balance of peripheral regulatory T cells/T helper 17 (Th17) cells. Furthermore, conditional knockout of ACC1 in CD4+ T cells attenuated the protection exerted by CR both on ischemic brain injury and peripheral balance of regulatory T cells/Th17 cells. Pharmacological inhibition of ACC1 after middle cerebral artery occlusion attenuates neuroinflammation, preserves regulatory T cells/Th17 balance, and improves neurological outcomes after ischemic stroke. Conclusions- ACC1 is a novel immune metabolic modulation target to balance the regulatory T cells and Th17 cells and blunt neuroinflammation after stroke. Inhibition of ACC1 can be a previously unrecognized mechanism that underlies CR-afforded neuroprotection against cerebral ischemic stroke.


Assuntos
Acetil-CoA Carboxilase/genética , Isquemia Encefálica/tratamento farmacológico , Fatores Imunológicos/farmacologia , Acidente Vascular Cerebral/tratamento farmacológico , Acetil-CoA Carboxilase/antagonistas & inibidores , Acetil-CoA Carboxilase/imunologia , Animais , Isquemia Encefálica/imunologia , Linfócitos T CD4-Positivos/imunologia , Restrição Calórica , Ácidos Graxos/biossíntese , Infarto da Artéria Cerebral Média/patologia , Inflamação/etiologia , Inflamação/prevenção & controle , Macrolídeos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Acidente Vascular Cerebral/imunologia , Células Th17/imunologia
8.
J Neuroinflammation ; 16(1): 121, 2019 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-31174550

RESUMO

The NLRP3 (nucleotide-binding oligomerization domain-like receptor [NLR] family pyrin domain-containing 3) inflammasome is a member of the NLR family of innate immune cell sensors. These are crucial regulators of cytokine secretions, which promote ischemic cell death and insulin resistance. This review summarizes recent progress regarding the NLRP3 inflammasome as a potential treatment for ischemic stroke in patients with diabetes, two complicated diseases that often occur together. Stroke worsens glucose metabolism abnormalities, and the outcomes after stroke are more serious for diabetic patients compared with those without diabetes. Inflammation contributes to organ injury after ischemic stroke and diabetes. Recent research has focused on inhibiting the activation of inflammasomes and thus reducing the maturation of proinflammatory cytokines such as interleukin (IL)-1ß and IL-18. Studies suggest that inhibition of NLRP3 prevents or alleviates both ischemic stroke and diabetes. Targeting against the assembly and activity of the NLRP3 inflammasome is a potential and novel therapy for inflammasome-associated diseases, including ischemic stroke concomitant with diabetes.


Assuntos
Isquemia Encefálica/metabolismo , Complicações do Diabetes/metabolismo , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Acidente Vascular Cerebral/metabolismo , Animais , Isquemia Encefálica/complicações , Isquemia Encefálica/imunologia , Complicações do Diabetes/imunologia , Diabetes Mellitus/imunologia , Diabetes Mellitus/metabolismo , Humanos , Inflamassomos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/imunologia
9.
Neurol Sci ; 40(9): 1877-1885, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31069585

RESUMO

BACKGROUND: The immune response to acute ischemic stroke (AIS) is implicated in diagnosis, prognosis, and intervention; however, the temporal dynamics of leukocytes following AIS are poorly understood. The purpose of this study was to characterize peripheral leukocyte dynamics following AIS among individuals with poor and favorable outcomes. METHODS: A retrospective chart review was conducted among patients with a diagnosis of AIS who were treated at a comprehensive stroke center across a 3-year timeframe. Groups were defined according to stroke outcomes. Patients with poor outcomes were distinguished from those with favorable outcomes by discharge National Institute of Health Stroke Score, infarct size, and Modified Rankin Scale. Leukocyte counts were compared among controls and AIS outcome groups. RESULTS: The neutrophil-lymphocyte ratio (NLR) calculated at 48-72 h post-AIS was identified as the strongest predictor of outcome. NLR was significantly higher in the poor outcome group (8.68 ± 0.93) compared with both the favorable outcome (4.5 ± 0.51, p = 0.009) and control group (4.33 ± 0.66, p < 0.001). Patients with a 48-72 h NLR ≥ 4.58 were 5.58 times more likely to have a poor outcome than AIS patients with an NLR < 4.58. CONCLUSIONS: The results of this study improve the understanding of the immune response in AIS. Low neutrophil count relative to high lymphocyte count at 48-72 h post-AIS should be considered a predictor of a favorable stroke outcome. Conversely, high neutrophil count relative to low lymphocyte count at 48-72 h post-AIS should be considered a predictor of a poor stroke outcome.


Assuntos
Isquemia Encefálica/sangue , Linfócitos , Neutrófilos , Acidente Vascular Cerebral/sangue , Idoso , Idoso de 80 Anos ou mais , Infarto Encefálico/patologia , Isquemia Encefálica/imunologia , Isquemia Encefálica/patologia , Isquemia Encefálica/fisiopatologia , Feminino , Humanos , Contagem de Leucócitos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Índice de Gravidade de Doença , Acidente Vascular Cerebral/imunologia , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/fisiopatologia
10.
Cells ; 8(5)2019 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-31083342

RESUMO

Mast cells (MCs) are densely granulated perivascular resident cells of hematopoietic origin. Through the release of preformed mediators stored in their granules and newly synthesized molecules, they are able to initiate, modulate, and prolong the immune response upon activation. Their presence in the central nervous system (CNS) has been documented for more than a century. Over the years, MCs have been associated with various neuroinflammatory conditions of CNS, including stroke. They can exacerbate CNS damage in models of ischemic and hemorrhagic stroke by amplifying the inflammatory responses and promoting brain-blood barrier disruption, brain edema, extravasation, and hemorrhage. Here, we review the role of these peculiar cells in the pathophysiology of stroke, in both immature and adult brain. Further, we discuss the role of MCs as potential targets for the treatment of stroke and the compounds potentially active as MCs modulators.


Assuntos
Barreira Hematoencefálica/imunologia , Edema Encefálico/imunologia , Isquemia Encefálica/imunologia , Encefalite/imunologia , Mastócitos/imunologia , Acidente Vascular Cerebral/imunologia , Animais , Células Cultivadas , Modelos Animais de Doenças , Humanos , Mastócitos/citologia , Camundongos , Ratos
11.
J Neuroinflammation ; 16(1): 112, 2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31138227

RESUMO

BACKGROUND: Ischemic stroke provokes a neuroinflammatory response and simultaneously promotes release of epinephrine and norepinephrine by the sympathetic nervous system. This increased sympathetic outflow can act on ß2-adrenergic receptors expressed by immune cells such as brain-resident microglia and monocyte-derived macrophages (MDMs), but the effect on post-stroke neuroinflammation is unknown. Thus, we investigated how changes in ß2-adrenergic signaling after stroke onset influence the microglia/MDM stroke response, and the specific importance of microglia/MDM ß2-adrenergic receptors to post-stroke neuroinflammation. METHODS: To investigate the effects of ß2-adrenergic receptor manipulation on post-stroke neuroinflammation, we administered the ß2-adrenergic receptor agonist clenbuterol to mice 3 h after the onset of photothrombotic stroke. We immunostained to quantify microglia/MDM numbers and proliferation and to assess morphology and activation 3 days later. We assessed stroke outcomes by measuring infarct volume and functional motor recovery and analyzed gene expression levels of neuroinflammatory molecules. Finally, we evaluated changes in cytokine expression and microglia/MDM response in brains of mice with selective knockout of the ß2-adrenergic receptor from microglia and monocyte-lineage cells. RESULTS: We report that clenbuterol treatment after stroke onset causes enlarged microglia/MDMs and impairs their proliferation, resulting in reduced numbers of these cells in the peri-infarct cortex by 1.7-fold at 3 days after stroke. These changes in microglia/MDMs were associated with increased infarct volume in clenbuterol-treated animals. In mice that had the ß2-adrenergic receptor specifically knocked out of microglia/MDMs, there was no change in morphology or numbers of these cells after stroke. However, knockdown of ß2-adrenergic receptors in microglia and MDMs resulted in increased expression of TNFα and IL-10 in peri-infarct tissue, while stimulation of ß2-adrenergic receptors with clenbuterol had the opposite effect, suppressing TNFα and IL-10 expression. CONCLUSIONS: We identified ß2-adrenergic receptor signaling as an important regulator of the neuroimmune response after ischemic stroke. Increased ß2-adrenergic signaling after stroke onset generally suppressed the microglia/MDM response, reducing upregulation of both pro- and anti-inflammatory cytokines, and increasing stroke size. In contrast, diminished ß2-adrenergic signaling in microglia/MDMs augmented both pro- and anti-inflammatory cytokine expression after stroke. The ß2-adrenergic receptor may therefore present a therapeutic target for improving the post-stroke neuroinflammatory and repair process.


Assuntos
Agonistas Adrenérgicos beta/farmacologia , Isquemia Encefálica/imunologia , Mediadores da Inflamação/imunologia , Receptores Adrenérgicos beta 2/imunologia , Transdução de Sinais/fisiologia , Acidente Vascular Cerebral/imunologia , Animais , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptores Adrenérgicos beta 2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologia
12.
Bull Exp Biol Med ; 166(6): 714-718, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31020580

RESUMO

Specific features of neurological deficit and changes in the cellular composition of tracheal lymphoid structures during the immediate stage (day 1) of hemorrhagic stroke were studied in rats with various behavioral parameters. Modeling of hemorrhage in the left caudate nucleus of the brain was followed by the development of motor disturbances in the forelimb use asymmetry test and corner rotation paradigm. These animals preferred to use the left forelimb (ipsilateral to the side of hemorrhage) to lean on the cylinder wall. The frequency of using the right forelimb or both forelimbs was reduced under these conditions. The number of left-sided rotations increased, while the percentage of right-sided rotations decreased. The observed changes were accompanied by immune dysfunction. It was manifested in the depletion of lymphoid aggregates of the tracheal wall in lymphocytes and plasma cells. The severity of abnormal neurological symptoms and disturbances in immune homeostasis during the immediate stage of hemorrhagic stroke was greater in behaviorally passive rats than in active specimens.


Assuntos
Núcleo Caudado/fisiopatologia , Hemorragia Cerebral/fisiopatologia , Tecido Linfoide/fisiopatologia , Acidente Vascular Cerebral/fisiopatologia , Traqueia/fisiopatologia , Animais , Comportamento Animal , Núcleo Caudado/imunologia , Núcleo Caudado/patologia , Hemorragia Cerebral/imunologia , Hemorragia Cerebral/patologia , Modelos Animais de Doenças , Lateralidade Funcional , Imunidade Inata , Contagem de Linfócitos , Linfócitos/imunologia , Linfócitos/patologia , Tecido Linfoide/imunologia , Tecido Linfoide/patologia , Masculino , Atividade Motora , Ratos , Ratos Wistar , Acidente Vascular Cerebral/imunologia , Acidente Vascular Cerebral/patologia , Traqueia/imunologia , Traqueia/patologia
13.
Front Med ; 13(4): 420-426, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30929189

RESUMO

This article presents a synopsis of the current data on the mechanisms of blood-brain barrier (BBB) alteration and autoimmune response in acute ischemic stroke. Most researchers confirm the relationship between the severity of immunobiochemical changes and clinical outcome of acute ischemic stroke. Ischemic stroke is accompanied by aseptic inflammation, which alters the brain tissue and exposes the co-stimulatory molecules of the immune system and the neuronal antigens. To date, BBB is not considered the border between the immune system and central nervous system, and the local immune subsystems are found within and behind the BBB. BBB disruption contributes to the leakage of brain autoantigens and induction of secondary autoimmune response to neuronal antigens and long-term inflammation. Glymphatic system function is altered and jeopardized both in hemorrhagic and ischemic stroke types. The receptors of innate immunity (toll-like receptor-2 and toll-like receptor-4) are also involved in acute ischemia-reperfusion injury. Immune response is related to the key processes of blood clotting and fibrinolysis. At the same time, the stroke-induced immune activation may promote reparation phenomena in the brain. Subsequent research on the reduction of the acute ischemic brain injury through the target regulation of the immune response is promising.


Assuntos
Autoimunidade , Barreira Hematoencefálica/imunologia , Isquemia Encefálica/imunologia , Acidente Vascular Cerebral/imunologia , Animais , Autoantígenos/imunologia , Humanos , Imunidade Inata , Inflamação , Camundongos
14.
J Neuroinflammation ; 16(1): 88, 2019 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-30995924

RESUMO

INTRODUCTION: In humans, a major component of natural killer (NK) and T cell target recognition depends on the surveillance of human leukocyte antigen (HLA) class I molecules by killer immunoglobulin-like receptors (KIRs). AIMS: To implement the knowledge about the immunological genetic background of acute ischemic stroke susceptibility in relation to the frequency of the KIR genes and HLA alleles. METHODS: Subjects with acute ischemic stroke and subjects without stroke were genotyped for the presence of KIR genes and of the three major KIR ligand groups, HLA-C1, HLA-C2, and HLA-Bw4, both HLA-B and HLA-A loci. RESULTS: Between November 2013 and February 2016, consecutive patients with acute ischemic stroke were recruited. As healthy controls, we enrolled subjects without acute ischemic stroke. Subjects with acute ischemic stroke in comparison with controls showed a higher frequency of 2DL3, 2DL5B, 2DS2, and 2DS4 KIR genes and a lower frequency of HLA-B-Bw4I alleles. Subjects without acute ischemic stroke showed a higher frequency of interaction between KIR 2DS2 and HLAC2. We also observed a higher frequency of 2DL3 and 2 DL4 KIR genes in subjects with atherosclerotic (LAAS) subtype. Multiple logistic regression analysis showed a protective effect towards stroke of HLA-B-Bw4I and interaction between KIR 2DL2 and HLAC1 and 2DS2-HLAC2 and a detrimental effect of 2DL2-HLA-C1_A interactions. CONCLUSION: Our findings of a higher frequency of activating KIR genes seem to be consistent with findings previously reported patients with coronary syndrome. This higher frequency of "proinflammatory" genes in subjects with ischemic stroke could also explain the immunoinflammatory activation of the acute phase of stroke.


Assuntos
Antígenos de Histocompatibilidade Classe I/genética , Receptores KIR/genética , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/imunologia , Idoso , Estudos Transversais , Feminino , Predisposição Genética para Doença/genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade
15.
Neurology ; 92(20): e2375-e2384, 2019 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-31004072

RESUMO

OBJECTIVE: We studied circulating interleukin (IL)-6, IL-8, and IL-10 concentrations and incident ischemic stroke risk in a biracial cohort, and determined if these cytokines mediated the racial disparity in stroke incidence affecting the black population. METHODS: The Reasons for Geographic and Racial Differences in Stroke study enrolled 30,237 black and white men and women age ≥45 in 2003-2007. We measured baseline IL-6, IL-8, and IL-10 in a case-cohort study of 557 participants with incident stroke over 5.4 years and 951 participants in a cohort sample. RESULTS: IL-6, but not IL-8 or IL-10, was higher in cases compared to the cohort sample (mean 4.5 vs 3.7 ng/mL; p < 0.001). Only IL-6 was associated with stroke risk factors. Adjusting for age, sex, and race, the hazard ratio (HR; 95% confidence interval) for incident stroke for the highest vs lowest quartile of IL-6 was 2.4 (1.6-3.4). HRs for the highest vs lowest quartiles of IL-8 and IL-10 were 1.5 (1.0-2.1) and 1.4 (1.0-1.9), respectively. After additional adjustment for stroke risk factors, only higher IL-6 remained associated with stroke risk (HR 2.0; 1.2-3.1). Associations did not differ by race. Mediation analyses showed that IL-6 mediated the black-white disparity in stroke risk, but mediation was via IL-6 associations with stroke risk factors. CONCLUSIONS: In this biracial population-based sample, IL-6 was strongly associated with risk of incident stroke and mediated the racial disparity in stroke via inflammatory effects of risk factors. Further study on the clinical utility of IL-6 measurement in stroke risk assessment would be helpful.


Assuntos
Isquemia Encefálica/imunologia , Interleucina-10/imunologia , Interleucina-6/imunologia , Interleucina-8/imunologia , Acidente Vascular Cerebral/imunologia , Afro-Americanos/estatística & dados numéricos , Idoso , Isquemia Encefálica/etnologia , Estudos de Casos e Controles , Citocinas/imunologia , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Acidente Vascular Cerebral/etnologia
16.
Proc Natl Acad Sci U S A ; 116(12): 5558-5563, 2019 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-30819895

RESUMO

CD3+CD4-CD8- T cells (double-negative T cells; DNTs) have diverse functions in peripheral immune-related diseases by regulating immunological and inflammatory homeostasis. However, the functions of DNTs in the central nervous system remain unknown. Here, we found that the levels of DNTs were dramatically increased in both the brain and peripheral blood of stroke patients and in a mouse model in a time-dependent manner. The infiltrating DNTs enhanced cerebral immune and inflammatory responses and exacerbated ischemic brain injury by modulating the FasL/PTPN2/TNF-α signaling pathway. Blockade of this pathway limited DNT-mediated neuroinflammation and improved the outcomes of stroke. Our results identified a critical function of DNTs in the ischemic brain, suggesting that this unique population serves as an attractive target for the treatment of ischemic stroke.


Assuntos
Isquemia Encefálica/imunologia , Complexo CD3/imunologia , Acidente Vascular Cerebral/imunologia , Subpopulações de Linfócitos T/imunologia , Idoso de 80 Anos ou mais , Animais , Encéfalo/imunologia , Antígenos CD4/imunologia , Antígenos CD8/imunologia , Modelos Animais de Doenças , Feminino , Humanos , Inflamação/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/imunologia , Fator de Necrose Tumoral alfa/metabolismo
17.
Brain ; 142(4): 978-991, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30860258

RESUMO

Stroke is a leading cause of cognitive impairment and dementia, but the mechanisms that underlie post-stroke cognitive decline are not well understood. Stroke produces profound local and systemic immune responses that engage all major innate and adaptive immune compartments. However, whether the systemic immune response to stroke contributes to long-term disability remains ill-defined. We used a single-cell mass cytometry approach to comprehensively and functionally characterize the systemic immune response to stroke in longitudinal blood samples from 24 patients over the course of 1 year and correlated the immune response with changes in cognitive functioning between 90 and 365 days post-stroke. Using elastic net regularized regression modelling, we identified key elements of a robust and prolonged systemic immune response to ischaemic stroke that occurs in three phases: an acute phase (Day 2) characterized by increased signal transducer and activator of transcription 3 (STAT3) signalling responses in innate immune cell types, an intermediate phase (Day 5) characterized by increased cAMP response element-binding protein (CREB) signalling responses in adaptive immune cell types, and a late phase (Day 90) by persistent elevation of neutrophils, and immunoglobulin M+ (IgM+) B cells. By Day 365 there was no detectable difference between these samples and those from an age- and gender-matched patient cohort without stroke. When regressed against the change in the Montreal Cognitive Assessment scores between Days 90 and 365 after stroke, the acute inflammatory phase Elastic Net model correlated with post-stroke cognitive trajectories (r = -0.692, Bonferroni-corrected P = 0.039). The results demonstrate the utility of a deep immune profiling approach with mass cytometry for the identification of clinically relevant immune correlates of long-term cognitive trajectories.


Assuntos
Cognição/fisiologia , Acidente Vascular Cerebral/imunologia , Acidente Vascular Cerebral/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Isquemia Encefálica/complicações , Proteína de Ligação a CREB/metabolismo , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/imunologia , Disfunção Cognitiva/complicações , Disfunção Cognitiva/imunologia , Estudos de Coortes , Feminino , Humanos , Imunoglobulina M , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Neutrófilos , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Acidente Vascular Cerebral/complicações , Sobreviventes
18.
Pak J Pharm Sci ; 32(1(Special)): 413-419, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30852478

RESUMO

This paper aims to observe and analyze the safety and clinical efficacy of Fingolimod combined with alteplase intravenous thrombolysis in the treatment of acute ischemic stroke. 90 patients with acute ischemic stroke were randomly divided into two groups. 45 patients in the control group were given alteplase intravenous thrombolysis for injection. 45 cases in the trial group were treated with Fingolimod combined with alteplase. There was no significant difference in NIHSS score, mRS score and BI index between the two groups 14 days after treatment, but 90 days after treatment, NIHSS score and mRS score of the experimental group were significantly lower than that of the control group, and BI index was significantly higher (P<0.05). 24 hours after oral administration of Fingolimod (0.5 mg), the circulating blood CD4 + T, CD8 + T, CD19 + B and CD56 + natural killer cells of the patients in the combined treatment group decreased steadily to varying degrees. The results confirm the pharmacological effect of Fingolimod: it changes lymphocyte migration, promotes lymphocyte to enter lymphoid tissue, prevents lymphocyte from leaving lymphoid tissue to enter the peripheral circulation, and thus prevents these immune cells from infiltrating the central nervous system. The results showed that Fingolimod combined with alteplase intravenous thrombolysis is safe for patients with acute ischemic stroke. .


Assuntos
Fibrinolíticos/uso terapêutico , Cloridrato de Fingolimode/uso terapêutico , Reabilitação do Acidente Vascular Cerebral/enfermagem , Acidente Vascular Cerebral/tratamento farmacológico , Terapia Trombolítica/métodos , Ativador de Plasminogênio Tecidual/uso terapêutico , Administração Oral , Esquema de Medicação , Quimioterapia Combinada , Feminino , Fibrinolíticos/administração & dosagem , Cloridrato de Fingolimode/administração & dosagem , Cloridrato de Fingolimode/efeitos adversos , Humanos , Infusões Intravenosas , Linfócitos/citologia , Linfócitos/imunologia , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/imunologia , Ativador de Plasminogênio Tecidual/administração & dosagem , Ativador de Plasminogênio Tecidual/efeitos adversos , Resultado do Tratamento
19.
Neuroreport ; 30(6): 428-433, 2019 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-30829959

RESUMO

Ischemic stroke is a common life-threatening disease. Epidemiological studies have shown that chronic periodontitis is closely related to ischemic stroke. However, it remains unknown whether periodontitis plays a direct role in the injury of cerebral ischemia. To explore the role of chronic periodontitis in the development process of ischemic stroke, we combined two mouse models: experimental periodontitis induced by a periodontal injection of lipopolysaccharide and ischemic stroke induced by the photothrombotic method. Alveolar bone loss and inflammatory infiltration of the periodontal tissue were found in the mice with experimental periodontitis. Periodontitis significantly increased the infarction volume, and numbers of activated microglia and astrocytes. Furthermore, an increased expression of nod-like receptor protein 3 inflammasome and interleukin-1ß was detected in the peri-infarct region. We drew a conclusion that chronic periodontitis exacerbated ischemic stroke by increasing the activation of microglia/astrocytes and the expression of nod-like receptor protein 3 inflammasome and interleukin-1ß. This suggested that chronic periodontitis played a role in ischemic brain injury directly through exacerbating the inflammation of the damaged brain.


Assuntos
Infarto Cerebral/patologia , Inflamação/patologia , Periodontite/patologia , Animais , Infarto Cerebral/imunologia , Inflamação/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Periodontite/complicações , Periodontite/imunologia , Acidente Vascular Cerebral/imunologia , Acidente Vascular Cerebral/patologia
20.
J Immunol ; 202(6): 1704-1714, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30710045

RESUMO

Glycine is a simple nonessential amino acid known to have neuroprotective properties. Treatment with glycine results in reduced infarct volume of the brain, neurologic function scores, and neuronal and microglial death in ischemic stroke injury. Neuroinflammation has been considered a major contributor to cerebral ischemia-induced brain damage. However, the role of glycine in neuroinflammation following ischemic stroke is unclear. The present study aimed to determine whether neuroinflammation is involved in the neuroprotective effects of glycine in cerebral ischemia injury. Ischemic stroke promotes M1 microglial polarization. Interestingly, we found that the injection of glycine in rats after injury can inhibit ischemia-induced inflammation and promote M2 microglial polarization in vivo (Sprague-Dawley rats) and in vitro (cortical microglia and BV-2 cells). We show that glycine suppresses Hif-1α by inhibiting the upregulation of NF-κB p65 after ischemia-reperfusion injury, resulting in the inhibition of proinflammatory activity. The activation of AKT mediates the inhibition of NF-κB p65/Hif-1α signaling by glycine. Moreover, we confirm that glycine-regulated AKT activation is mediated by the inhibition of PTEN in a PTEN depletion cell line, U251 cells. Glycine modulates microglial polarization after ischemic stroke, which indirectly inhibits ischemia-induced neuronal death and functional recovery. Taken together, our findings provide a new understanding of glycine in neuroprotection by inhibiting M1 microglial polarization and promoting anti-inflammation by suppressing NF-κB p65/Hif-1α signaling.


Assuntos
Encéfalo/efeitos dos fármacos , Glicina/farmacologia , Microglia/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Acidente Vascular Cerebral/imunologia , Animais , Encéfalo/imunologia , Encéfalo/patologia , Isquemia Encefálica/imunologia , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Feminino , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologia , Fator de Transcrição RelA/metabolismo
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