RESUMO
Aquaporin-4 (AQP4) is the main water channel in brain and is enriched in perivascular astrocyte processes abutting brain microvessels. There is a rich literature on the role of AQP4 in experimental stroke. While its role in oedema formation following middle cerebral artery occlusion (MCAO) has been studied extensively, its specific impact on infarct volume remains unclear. This study investigated the effects of total and partial AQP4 deletion on infarct volume in mice subjected to distal medial cerebral artery (dMCAO) occlusion. Compared to MCAO, this model induces smaller infarcts confined to neocortex, and less oedema. We show that AQP4 deletion significantly reduced infarct volume as assessed 1 week after dMCAO, suggesting that the role of AQP4 in stroke goes beyond its effect on oedema formation and dissolution. The reduction in infarct volume was associated with increased astrocyte reactivity in the peri-infarct areas. No significant differences were observed in the number of microglia among the genotypes. These findings provide new insights in the role of AQP4 in ischaemic injury indicating that AQP4 affects both infarct volume and astrocyte reactivity in the peri-infarct zone. KEY POINTS: Aquaporin-4 (AQP4) is the main water channel in brain and is enriched in perivascular astrocyte processes abutting microvessels. A rich literature exists on the role of AQP4 in oedema formation following middle cerebral artery occlusion (MCAO). We investigated the effects of total and partial AQP4 deletion on infarct volume in mice subjected to distal medial cerebral artery occlusion (dMCAO), a model inducing smaller infarcts confined to neocortex and less oedema compared to MCAO. AQP4 deletion significantly reduced infarct volume 1 week after dMCAO, suggesting a broader role for AQP4 in stroke beyond oedema formation. The reduction in infarct volume was associated with increased astrocyte reactivity in the peri-infarct areas, while no significant differences were observed in the number of microglia among the genotypes. These findings provide new insights into the role of AQP4 in stroke, indicating that AQP4 affects both infarct volume and astrocyte reactivity in the peri-infarct zone.
Assuntos
Aquaporina 4 , Astrócitos , Animais , Aquaporina 4/genética , Aquaporina 4/metabolismo , Astrócitos/metabolismo , Astrócitos/patologia , Camundongos , Masculino , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/genética , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/fisiopatologia , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/genética , Camundongos Knockout , Edema Encefálico/patologia , Edema Encefálico/metabolismo , Edema Encefálico/genéticaRESUMO
OBJECTIVE: We attempted to record the regional cerebral blood flow (CBF) simultaneously at various regions of the cerebral cortex and the striatum during middle cerebral artery (MCA) occlusion and to evaluate neurological deficits and infarct formation. METHODS: In male C57BL/6J mice, CBF was recorded in three regions including the ipsilateral cerebral cortex and the striatum with laser Doppler flowmeters, and the origin of MCA was occluded with a monofilament suture for 15-90 min. After 48 h, neurological deficits were evaluated, and infarct was examined by triphenyltetrazolium chloride (TTC) staining. RESULTS: CBF decrease in the striatum was approximately two-thirds of the MCA-dominant region of the cortex during MCA occlusion. The characteristic CBF fluctuation because of spontaneously occurred spreading depolarization observed throughout the cortex was not found in the striatum. Ischemic foci with slight lower staining to TTC were found in the ipsilateral striatum in MCA-occluded mice for longer than 30 min (n = 54). Twenty-nine among 64 MCA-occluded mice exhibited neurological deficits even in the absence of apparent infarct with minimum staining to TTC in the cortex, and the severity of neurological deficits was not correlated with the size of the cortical infarct. CONCLUSION: Neurological deficits might be associated with the ischemic striatum rather than with cortical infarction.
Assuntos
Circulação Cerebrovascular , Corpo Estriado , Infarto da Artéria Cerebral Média , Animais , Infarto da Artéria Cerebral Média/fisiopatologia , Infarto da Artéria Cerebral Média/patologia , Camundongos , Masculino , Circulação Cerebrovascular/fisiologia , Corpo Estriado/fisiopatologia , Corpo Estriado/irrigação sanguínea , Córtex Cerebral/irrigação sanguínea , Córtex Cerebral/fisiopatologia , Camundongos Endogâmicos C57BLRESUMO
Ischemic stroke occurs due a blockage in the blood flow to the brain, leading to damage to the nervous system. The prevalent morbidities resulting from stroke include post-stroke infection, as sepsis. Additionally, oxidative stress is recognized for inducing functional deficits in peripheral organs during sepsis. Therefore, sex differences in stroke exist and we aimed to investigate the peripheral oxidative stress caused by sepsis after stroke in male and female rats. Wistar rats (male and female) were divided into sham+sham, middle cerebral artery occlusion (MCAO) + sham, sham+ cecal ligation and perforation (CLP) and MCAO+CLP groups to males and female rats. Animals were subjected to MCAO or sham and after 7 days, were subjected to sepsis by CLP or sham. After 24 h, serum, total brain, lung, liver, heart, and spleen were collected. Brain edema, myeloperoxidase (MPO) activity, nitrite/nitrate (N/N) concentration, oxidative damage to lipids and proteins, and catalase activity were evaluated. Brain edema was observed only in male rats in MCAO+CLP group compared to MCAO+sham. Regarding MPO activity, an increase was verified in male in different organs and serum in MCAO+CLP group. For N/N levels, the increase was more pronounced in females submitted to MCAO+CLP. In general, to oxidative stress, an increase was only observed in animals exposed to MCAO+CLP, or with a greater increase in this group compared to the others. The findings provided the first indication that animals exposed to MCAO exhibit a heightened vulnerability to the harmful impacts of sepsis, as evidenced by brain edema and peripheral oxidative stress, and this susceptibility is dependent of sex.
Assuntos
Edema Encefálico , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média , Estresse Oxidativo , Peroxidase , Ratos Wistar , Sepse , Animais , Feminino , Masculino , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/fisiopatologia , Infarto da Artéria Cerebral Média/sangue , Sepse/metabolismo , Sepse/fisiopatologia , Sepse/complicações , Sepse/sangue , Fatores Sexuais , Peroxidase/metabolismo , Edema Encefálico/metabolismo , Edema Encefálico/patologia , Edema Encefálico/fisiopatologia , Nitratos/sangue , Nitratos/metabolismo , Nitritos/sangue , Nitritos/metabolismo , Ratos , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/irrigação sanguínea , Catalase/metabolismoRESUMO
A 62-year-old musician-MM-developed amusia after a right middle-cerebral-artery infarction. Initially, MM showed melodic deficits while discriminating pitch-related differences in melodies, musical memory problems, and impaired sensitivity to tonal structures, but normal pitch discrimination and spectral resolution thresholds, and normal cognitive and language abilities. His rhythmic processing was intact when pitch variations were removed. After 3 months, MM showed a large improvement in his sensitivity to tonality, but persistent melodic deficits and a decline in perceiving the metric structure of rhythmic sequences. We also found visual cues aided melodic processing, which is novel and beneficial for future rehabilitation practice.
Assuntos
Infarto da Artéria Cerebral Média , Música , Humanos , Pessoa de Meia-Idade , Masculino , Infarto da Artéria Cerebral Média/complicações , Infarto da Artéria Cerebral Média/fisiopatologia , Transtornos da Percepção Auditiva/etiologia , Transtornos da Percepção Auditiva/fisiopatologiaRESUMO
BACKGROUND: Decompressive craniectomy (DC) reduces mortality without increasing the risk of very severe disability among patients with life-threatening massive cerebral infarction. However, its efficacy was demonstrated before the era of endovascular thrombectomy trials. It remains uncertain whether DC improves the prognosis of patients with malignant middle cerebral artery (MCA) infarction receiving endovascular therapy. METHODS: We pooled data from two trials (DEVT and RESCUE BT studies in China) and patients with malignant MCA infarction were included to assess outcomes and heterogeneity of DC therapy effect. Patients with herniation were dichotomized into DC and conservative groups according to their treatment strategy. The primary outcome was the rate of mortality at 90 days. Secondary outcomes included disability level at 90 days as measured by the modified Rankin Scale score (mRS) and quality-of-life score. The associations of DC with clinical outcomes were performed using multivariable logistic regression. RESULTS: Of 98 patients with herniation, 37 received DC surgery and 61 received conservative treatment. The median (interquartile range) was 70 (62-76) years and 40.8% of the patients were women. The mortality rate at 90 days was 59.5% in the DC group compared with 85.2% in the conservative group (adjusted odds ratio, 0.31 [95% confidence interval (CI), 0.10-0.94]; P=0.04). There were 21.6% of patients in the DC group and 6.6% in the conservative group who had a mRS score of 4 (moderately severe disability); and 10.8% and 4.9%, respectively, had a score of 5 (severe disability). The quality-of-life score was higher in the DC group (0.00 [0.00-0.14] vs 0.00 [0.00-0.00], P=0.004), but DC treatment was not associated with better quality-of-life score in multivariable analyses (adjusted ß Coefficient, 0.02 [95% CI, -0.08-0.11]; p=0.75). CONCLUSIONS: DC was associated with decreased mortality among patients with malignant MCA infarction who received endovascular therapy. The majority of survivors remained moderately severe disability and required improvement on quality of life. CLINICAL TRIAL REGISTRATION: The DEVT trial: http://www.chictr.org. Identifier, ChiCTR-IOR-17013568. The RESCUE BT trial: URL: http://www.chictr.org. Identifier, ChiCTR-INR-17014167.
Assuntos
Craniectomia Descompressiva , Avaliação da Deficiência , Infarto da Artéria Cerebral Média , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , China , Craniectomia Descompressiva/mortalidade , Craniectomia Descompressiva/efeitos adversos , Estado Funcional , Infarto da Artéria Cerebral Média/mortalidade , Infarto da Artéria Cerebral Média/cirurgia , Infarto da Artéria Cerebral Média/terapia , Infarto da Artéria Cerebral Média/diagnóstico , Infarto da Artéria Cerebral Média/fisiopatologia , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Recuperação de Função Fisiológica , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do TratamentoRESUMO
INTRODUCTION: Cerebral ischemia (CI) induces a profound neuroinflammatory response, but the underlying molecular mechanism remains unclear. Exosomes from adipose-derived stem cells (ADSC-exos) have been found to play a crucial role in cell communication by transferring molecules including microRNAs (miRNAs), which have been shown to modulate the inflammatory response after CI and are viable molecular targets for altering brain function. The current study aimed to explore the contribution of ADSC-exosomal miR-21-5p to the neuroinflammation after CI. METHODS: The differentially expressed miR-21-5p in CI was screened based on literature search. The target mRNAs of miR-21-5p were predicted using online databases and verified by luciferase reporter assay. Then, BV2 cells were treated with hemin to simulate the inflammatory response after CI, and its animal model was induced using the MCAO method. Ischemia was evaluated in rats using 2, 3, 5-triphenyl tetrazolium chloride (TTC) staining. ADSCs-exos were further isolated and identified by western blot analysis and transmission electron microscope. RESULTS: MiR-21-5p was significantly down-regulated in CI and alleviated neuropathic damage after CI by the PIK3R1/PI3K/AKT signaling axis. And miR-21-5p derived from ADSCs-exos alleviated neuroinflammation after CI via promoting microglial M2 polarization. CONCLUSION: We demonstrated that ADSC-exosomal miR-21-5p mitigated post-CI inflammatory response through the PIK3R1/PI3K/AKT signaling axis and could offer neuroprotection after CI through promoting polarization of M2 microglia.
Assuntos
Modelos Animais de Doenças , Exossomos , MicroRNAs , Proteínas Proto-Oncogênicas c-akt , Ratos Sprague-Dawley , Transdução de Sinais , Animais , MicroRNAs/metabolismo , MicroRNAs/genética , Exossomos/metabolismo , Exossomos/transplante , Proteínas Proto-Oncogênicas c-akt/metabolismo , Masculino , Humanos , Linhagem Celular , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/fisiopatologia , Infarto da Artéria Cerebral Média/terapia , Infarto da Artéria Cerebral Média/genética , Doenças Neuroinflamatórias/metabolismo , Microglia/metabolismo , Microglia/patologia , Camundongos , Tecido Adiposo/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Pessoa de Meia-Idade , Regulação da Expressão Gênica , Mediadores da Inflamação/metabolismo , Fosfatidilinositol 3-Quinases/metabolismoRESUMO
BACKGROUND: Notch1 signaling inhibiton with N-[N-(3,5-difluorophenacetyl)-1-alanyl]-S-phenylglycine t-butylester] (DAPT) treatment could promote brain recovery and the intervention effect is different between striatum (STR) and cortex (CTX), which might be accounted for different changes of glial activities, but the in-depth mechanism is still unknown. The purpose of this study was to identify whether DAPT could modulate microglial subtype shifts and astroglial-endfeet aquaporin-4 (AQP4) mediated waste solute drainage. METHODS: Sprague-Dawley rats (n=10) were subjected to 90min of middle cerebral artery occlusion (MCAO) and were treated with DAPT (n=5) or act as control with no treatment (n=5). Two groups of rats underwent MRI scans at 24h and 4 week, and sacrificed at 4 week after stroke for immunofluorescence (IF). RESULTS: Compared with control rats, MRI data showed structural recovery in ipsilateral STR but not CTX. And IF showed decreased pro-inflammatory M1 microglia and increased anti-inflammatory M2 microglia in striatal lesion core and peri-lesions of STR, CTX. Meanwhile, IF showed decreased AQP4 polarity in ischemic brain tissue, however, AQP4 polarity in striatal peri-lesions of DAPT treated rats was higher than that in control rats but shows no difference in cortical peri-lesions between control and treated rats. CONCLUSIONS: The present study indicated that DAPT could promote protective microglia subtype shift and striatal astrocyte mediated waste solute drainage, that the later might be the major contributor of waste solute metabolism and one of the accounts for discrepant recovery of STR and CTX.
Assuntos
Aquaporina 4 , Astrócitos , Dipeptídeos , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média , Microglia , Ratos Sprague-Dawley , Receptor Notch1 , Recuperação de Função Fisiológica , Transdução de Sinais , Animais , Aquaporina 4/metabolismo , Receptor Notch1/metabolismo , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/fisiopatologia , Masculino , Astrócitos/metabolismo , Astrócitos/efeitos dos fármacos , Astrócitos/patologia , Microglia/metabolismo , Microglia/efeitos dos fármacos , Microglia/patologia , Dipeptídeos/farmacologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/patologia , Corpo Estriado/metabolismo , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/patologia , Fatores de Tempo , Fármacos Neuroprotetores/farmacologia , AVC Isquêmico/metabolismo , AVC Isquêmico/tratamento farmacológico , AVC Isquêmico/fisiopatologia , AVC Isquêmico/patologiaRESUMO
OBJECTIVES: Ischemic stroke (IS) is a leading cause of morbidity and mortality globally. This study aimed to investigate the role of exosomes (Exo) derived from bone marrow mesenchymal stem cells (BMSCs) treated with Musk Ketone (Mus treated-Exo) in the development of IS injury. METHODS: BMSCs were pretreated with 10 µM Mus for 36 h, and Exo derived from these Mus-treated BMSCs (Mus-treated Exo) were extracted. Rats with middle cerebral artery occlusion (MCAO) were administered either 2 mg/kg of control Exo (Ctrl-Exo), 2 mg/kg of Mus treated-Exo, or 10 µM Mus. Neurological deficit and cerebral infarction in the MCAO rats were assessed utilizing neurological scores and TTC staining. Neuronal apoptosis, activation of microglia/macrophages, and inflammation were evaluated through TUNEL staining, immunofluorescence staining, and western blot analysis, respectively. RESULTS: Our findings revealed that Mus-treated Exo possessed a more pronounced neuroprotective effect on MCAO rats when compared to Ctrl-Exo and Mus treatment alone. Specifically, Mus treated-Exo effectively ameliorated neurological function, reduced the volume of cerebral infarction, and diminished hemispheric swelling in MCAO rats. Moreover, it inhibited neuronal apoptosis and activation of microglia/macrophages, promoted the expression of the anti-apoptotic protein Bcl-2 while decreasing the expression of pro-apoptotic protein Bax, Cleaved-caspase 3, and pro-inflammatory factors IL-6 and COX-2. CONCLUSIONS: The findings imply that Mus treated-Exo could confer neuroprotection in rats affected by IS, potentially by attenuating apoptosis and neuroinflammation. The underlying mechanisms, however, warrant further investigation. Mus treated-Exo shows potential as a new therapeutic strategy for IS.
Assuntos
Apoptose , Modelos Animais de Doenças , Exossomos , Infarto da Artéria Cerebral Média , AVC Isquêmico , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Ratos Sprague-Dawley , Animais , Exossomos/transplante , Exossomos/metabolismo , Apoptose/efeitos dos fármacos , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/terapia , Infarto da Artéria Cerebral Média/fisiopatologia , Infarto da Artéria Cerebral Média/metabolismo , Masculino , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/efeitos dos fármacos , AVC Isquêmico/metabolismo , AVC Isquêmico/fisiopatologia , AVC Isquêmico/terapia , AVC Isquêmico/patologia , AVC Isquêmico/tratamento farmacológico , Células Cultivadas , Microglia/efeitos dos fármacos , Microglia/patologia , Microglia/metabolismo , Recuperação de Função Fisiológica , Neurônios/efeitos dos fármacos , Neurônios/patologia , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Mediadores da Inflamação/metabolismo , Encéfalo/patologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Comportamento Animal/efeitos dos fármacos , Ativação de Macrófagos/efeitos dos fármacosRESUMO
Stroke is a leading cause of death and disability in the United States. Most strokes are ischemic, resulting in both cognitive and motor impairments. Animal models of ischemic stroke such as the distal middle cerebral artery occlusion (dMCAO) and photothrombotic stroke (PTS) procedures have become invaluable tools, with their own advantages and disadvantages. The dMCAO model is clinically relevant as it occludes the artery most affected in humans, but yields variability in the infarct location as well as the behavioral and cognitive phenotypes disrupted. The PTS model has the advantage of allowing for targeted location of infarct, but is less clinically relevant. The present study evaluates phenotype disruption over time in mice subjected to either dMCAO, PTS, or a sham surgery. Post-surgery, animals were tested over 28 days on standard motor tasks (grid walk, cylinder, tapered beam, and rotating beam), as well as a novel odor-based operant task; the 5:1 Odor Discrimination Task (ODT). Results demonstrate a significantly greater disturbance of motor control with PTS as compared with Sham and dMCAO. Disruption of the PTS group was detected up to 28 days post-stroke on the grid walk, and up to 7 days on the rotating and tapered beam tasks. PTS also led to significant short-term disruption of ODT performance (1-day post-surgery), exclusively in males, which appeared to be driven by motoric disruption of the lick response. Together, this data provides critical insights into the selection and optimization of animal models for ischemic stroke research. Notably, the PTS procedure was best suited for producing disruptions of motor behavior that can be detected with common behavioral assays and are relatively enduring, as is observed in human stroke.
Assuntos
Modelos Animais de Doenças , Infarto da Artéria Cerebral Média , Camundongos Endogâmicos C57BL , Animais , Masculino , Infarto da Artéria Cerebral Média/fisiopatologia , Infarto da Artéria Cerebral Média/complicações , Camundongos , Acidente Vascular Cerebral/fisiopatologia , Acidente Vascular Cerebral/complicações , Atividade Motora/fisiologia , AVC Trombótico , Feminino , Odorantes , Discriminação Psicológica/fisiologia , Comportamento Animal/fisiologia , AVC Isquêmico/fisiopatologiaRESUMO
The acute phase of ischemic stroke presents a critical window for therapeutic intervention, where novel approaches such as hyper-acute cerebral flow augmentation offer promising avenues for neuroprotection. In this study, we investigated the effects of two such therapies, NEH (a combination of norepinephrine and hydralazine) and Sanguinate (pegylated bovine carboxyhemoglobin), on resting-state functional connectivity, global mean signal (GMS), and blood oxygen level-dependent (BOLD) time lag in a pre-clinical canine model of stroke via permanent occlusion of the middle cerebral artery (total of n = 40 IACUC-approved mongrel canines randomly split into control/natural history and two treatment groups). Utilizing group independent component analysis (ICA), we identified and examined the integrity of sensorimotor and visual networks both pre- and post-occlusion, across treatment and control groups. Our results demonstrated that while the control group exhibited significant disruptions in these networks following stroke, the treatment groups showed remarkable preservation of network integrity. Voxel-wise functional connectivity analysis revealed less pronounced alterations in the treatment groups, suggesting maintained neural connections. Notably, the treatments stabilized GMS, with only minimal reductions observed post-occlusion compared to significant decreases in the control group. Furthermore, BOLD time-lag unity plots indicated that NEH and Sanguinate maintained consistent hemodynamic response timing, as evidenced by tighter clustering around the line of unity, suggesting a potential neuroprotective effect. These findings were underscored by robust statistical analyses, including paired T-tests and Mann-Whitney U tests, which confirmed the significance of the connectivity changes observed. The correlation of BOLD time-lag variations with neuroimaging functional biomarkers highlighted the impact of stroke and the efficacy of early therapeutic interventions. Our study supports the further study of flow augmentation therapies such as NEH and Sanguinate in stroke treatment protocols and suggests flow augmentation therapies should be further explored in an effort to improve patient outcomes.
Assuntos
Modelos Animais de Doenças , Hemodinâmica , Animais , Cães , Hemodinâmica/efeitos dos fármacos , Circulação Cerebrovascular/efeitos dos fármacos , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Imageamento por Ressonância Magnética , Masculino , Norepinefrina/farmacologia , Infarto da Artéria Cerebral Média/fisiopatologia , FemininoRESUMO
Poststroke cognitive impairment (PSCI) is a common complication of stroke, but effective treatments are currently lacking. Repetitive transcranial magnetic stimulation (rTMS) is gradually being applied to treat PSCI, but there is limited evidence of its efficacy. To determine rTMS effects on PSCI, we constructed a transient middle cerebral artery occlusion (tMCAO) rat model. Rats were then grouped by random digital table method: the sham group (nâ¯=â¯10), tMCAO group (nâ¯=â¯10) and rTMS group (nâ¯=â¯10). The shuttle box and Morris water maze (MWM) tests were conducted to detect the cognitive functions of the rats. In addition, synaptic density and synaptic ultrastructural parameters, including the active zone length, synaptic cleft width, and postsynaptic density (PSD) thickness, were quantified and analyzed using an electron microscope. What's more, synaptic associated proteins, including PSD95, SYN, and BDNF were detected by western blot. According to the shuttle box and MWM tests, rTMS improved tMCAO rats' cognitive functions, including spatial learning and memory and decision-making abilities. Electron microscopy revealed that rTMS significantly increased the synaptic density, synaptic active zone length and PSD thickness and decreased the synaptic cleft width. The western blot results showed that the expression of PSD95, SYN, and BDNF was markedly increased after rTMS stimulation. Based on these results, we propose that 20â¯Hz rTMS can significantly alleviate cognitive impairment after stroke. The underlying mechanism might be modulating the synaptic plasticity and up-regulating the expression PSD95, SYN, and BDNF in the hippocampus.
Assuntos
Isquemia Encefálica , Disfunção Cognitiva , Modelos Animais de Doenças , Hipocampo , Plasticidade Neuronal , Ratos Sprague-Dawley , Estimulação Magnética Transcraniana , Animais , Plasticidade Neuronal/fisiologia , Disfunção Cognitiva/terapia , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/fisiopatologia , Masculino , Ratos , Hipocampo/metabolismo , Isquemia Encefálica/terapia , Isquemia Encefálica/fisiopatologia , Infarto da Artéria Cerebral Média/terapia , Infarto da Artéria Cerebral Média/fisiopatologia , Infarto da Artéria Cerebral Média/complicações , Proteína 4 Homóloga a Disks-Large/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Aprendizagem em Labirinto/fisiologiaRESUMO
BACKGROUND: Neuroinflammatory responses are closely associated with poststroke prognosis severity. This study aimed to develop a predictive model, combining inflammation-derived markers and clinical indicators, for distinguishing functional outcomes in patients with subacute ischemic stroke. METHODS AND RESULTS: Based on activities of daily living assessments, ischemic stroke participants were categorized into groups with little effective (LE) recovery and obvious effective (OE) recovery. Initial biocandidates were identified by overlapping differentially expressed proteins from proteomics of clinical serum samples (5 LE, 5 OE, and 6 healthy controls) and differentially expressed genes from an RNA sequence of the ischemic cortex in middle cerebral artery occlusion mice (n=3). Multidimensional validations were conducted in ischemia-reperfusion models and a clinical cohort (15 LE, 11 OE, and 18 healthy controls). Models of robust biocandidates combined with clinical indicators were developed with machine learning in the training data set and prediction in another test data set (15 LE and 11 OE). We identified 194 differentially expressed proteins (LE versus healthy controls) and 174 differentially expressed proteins (OE versus healthy controls) in human serum, and 5121 differentially expressed genes (day 3) and 5906 differentially expressed genes (day 7) in middle cerebral artery occlusion mice cortex. Inflammation-derived biomarkers TIMP1 (tissue inhibitor metalloproteinase-1) and galactosidase-binding protein LGLAS3 (galectin-3) exhibited robust increases under ischemic injury in mice and humans. TIMP1 and LGALS3 coupled with clinical indicators (hemoglobin, low-density lipoprotein cholesterol, and uric acid) were developed into a combined model for differentiating functional outcome with high accuracy (area under the curve, 0.8). CONCLUSIONS: The combined model is a valuable tool for evaluating prognostic outcomes, and the predictive factors can facilitate development of better treatment strategies.
Assuntos
Biomarcadores , Modelos Animais de Doenças , AVC Isquêmico , Recuperação de Função Fisiológica , AVC Isquêmico/sangue , AVC Isquêmico/genética , Animais , Humanos , Masculino , Biomarcadores/sangue , Biomarcadores/metabolismo , Feminino , Pessoa de Meia-Idade , Idoso , Camundongos , Prognóstico , Infarto da Artéria Cerebral Média/sangue , Infarto da Artéria Cerebral Média/genética , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/fisiopatologia , Estudos de Casos e Controles , Camundongos Endogâmicos C57BL , Valor Preditivo dos Testes , Proteômica/métodos , Aprendizado de MáquinaRESUMO
BACKGROUND: Cardiac damage induced by ischemic stroke, such as arrhythmia, cardiac dysfunction, and even cardiac arrest, is referred to as cerebral-cardiac syndrome (CCS). Cardiac macrophages are reported to be closely associated with stroke-induced cardiac damage. However, the role of macrophage subsets in CCS is still unclear due to their heterogeneity. Sympathetic nerves play a significant role in regulating macrophages in cardiovascular disease. However, the role of macrophage subsets and sympathetic nerves in CCS is still unclear. METHODS AND RESULTS: In this study, a middle cerebral artery occlusion mouse model was used to simulate ischemic stroke. ECG and echocardiography were used to assess cardiac function. We used Cx3cr1GFPCcr2RFP mice and NLRP3-deficient mice in combination with Smart-seq2 RNA sequencing to confirm the role of macrophage subsets in CCS. We demonstrated that ischemic stroke-induced cardiac damage is characterized by severe cardiac dysfunction and robust infiltration of monocyte-derived macrophages into the heart. Subsequently, we identified that cardiac monocyte-derived macrophages displayed a proinflammatory profile. We also observed that cardiac dysfunction was rescued in ischemic stroke mice by blocking macrophage infiltration using a CCR2 antagonist and NLRP3-deficient mice. In addition, a cardiac sympathetic nerve retrograde tracer and a sympathectomy method were used to explore the relationship between sympathetic nerves and cardiac macrophages. We found that cardiac sympathetic nerves are significantly activated after ischemic stroke, which contributes to the infiltration of monocyte-derived macrophages and subsequent cardiac dysfunction. CONCLUSIONS: Our findings suggest a potential pathogenesis of CCS involving the cardiac sympathetic nerve-monocyte-derived macrophage axis.
Assuntos
Modelos Animais de Doenças , AVC Isquêmico , Macrófagos , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR , Animais , Macrófagos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/deficiência , AVC Isquêmico/fisiopatologia , AVC Isquêmico/metabolismo , AVC Isquêmico/patologia , Receptores CCR2/genética , Receptores CCR2/metabolismo , Masculino , Camundongos Knockout , Camundongos , Infarto da Artéria Cerebral Média/fisiopatologia , Infarto da Artéria Cerebral Média/patologia , Sistema Nervoso Simpático/fisiopatologia , Miocárdio/patologia , Miocárdio/metabolismo , Cardiopatias/etiologia , Cardiopatias/fisiopatologia , Cardiopatias/patologia , Receptor 1 de Quimiocina CX3C/genética , Receptor 1 de Quimiocina CX3C/metabolismo , Receptor 1 de Quimiocina CX3C/deficiênciaRESUMO
OBJECTIVE: Epilepsy develops in one third of the patients after perinatal stroke. It is still unclear which vascular syndrome of ischemic stroke carries higher risk of epilepsy. The aim of the current study was to evaluate the risk of epilepsy according to the vascular syndrome of perinatal stroke. METHODS: The study included 39 children with perinatal arterial ischemic stroke (13 with anterior or posterior trunk of the distal middle cerebral artery occlusion, 23 with proximal or distal M1 middle cerebral artery occlusion and three with lenticulostriate arteria infarction), and 44 children with presumed perinatal venous infarction. Magnetic resonance imaging obtained at the chronic stage was used to evaluate the vascular syndrome of stroke. RESULTS: The median follow-up time was 15.1 years (95% CI: 12.4-16.5 years), epilepsy developed in 19/83 (22.9%) patients. The cumulative probability to be without epilepsy at 15 years was 75.4% (95% CI: 65.8-86.4). The probability of having epilepsy was higher in the group of proximal or distal M1 artery occlusion compared to patients with periventricular venous infarction (HR 7.2, 95% CI: 2.5-26, p = .0007). Patients with periventricular venous infarction had significantly more often status epilepticus or spike-wave activation in sleep ≥85% of it compared to patients with anterior or posterior trunk of the distal middle cerebral artery occlusion (OR = 81; 95% CI: 1.3-5046, p = .029). SIGNIFICANCE: The emphasis of this study is placed on classifying the vascular syndrome of perinatal stroke and on the targeted follow-up of patients for epilepsy until young adulthood. The risk for having epilepsy after perinatal stroke is the highest in children with proximal or distal M1 middle cerebral artery occlusion. Patients with periventricular venous infarction have a more severe course of epilepsy.
Assuntos
Epilepsia , Humanos , Feminino , Masculino , Epilepsia/etiologia , Epilepsia/fisiopatologia , Adolescente , Criança , Seguimentos , Pré-Escolar , AVC Isquêmico/complicações , AVC Isquêmico/fisiopatologia , AVC Isquêmico/diagnóstico por imagem , AVC Isquêmico/etiologia , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/fisiopatologia , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/etiologia , Imageamento por Ressonância Magnética , Infarto da Artéria Cerebral Média/fisiopatologia , Infarto da Artéria Cerebral Média/diagnóstico por imagem , Infarto da Artéria Cerebral Média/complicações , Lactente , Recém-NascidoRESUMO
BACKGROUND: Electroacupuncture (EA) has been shown to facilitate brain plasticity-related functional recovery following ischemic stroke. The functional magnetic resonance imaging technique can be used to determine the range and mode of brain activation. After stroke, EA has been shown to alter brain connectivity, whereas EA's effect on brain network topology properties remains unclear. An evaluation of EA's effects on global and nodal topological properties in rats with ischemia reperfusion was conducted in this study. METHODS AND RESULTS: There were three groups of adult male Sprague-Dawley rats: sham-operated group (sham group), middle cerebral artery occlusion/reperfusion (MCAO/R) group, and MCAO/R plus EA (MCAO/R + EA) group. The differences in global and nodal topological properties, including shortest path length, global efficiency, local efficiency, small-worldness index, betweenness centrality (BC), and degree centrality (DC) were estimated. Graphical network analyses revealed that, as compared with the sham group, the MCAO/R group demonstrated a decrease in BC value in the right ventral hippocampus and increased BC in the right substantia nigra, accompanied by increased DC in the left nucleus accumbens shell (AcbSh). The BC was increased in the right hippocampus ventral and decreased in the right substantia nigra after EA intervention, and MCAO/R + EA resulted in a decreased DC in left AcbSh compared to MCAO/R. CONCLUSION: The results of this study provide a potential basis for EA to promote cognitive and motor function recovery after ischemic stroke.
Assuntos
Eletroacupuntura , Infarto da Artéria Cerebral Média , Imageamento por Ressonância Magnética , Ratos Sprague-Dawley , Traumatismo por Reperfusão , Animais , Eletroacupuntura/métodos , Masculino , Ratos , Traumatismo por Reperfusão/fisiopatologia , Traumatismo por Reperfusão/terapia , Traumatismo por Reperfusão/diagnóstico por imagem , Infarto da Artéria Cerebral Média/terapia , Infarto da Artéria Cerebral Média/fisiopatologia , Infarto da Artéria Cerebral Média/diagnóstico por imagem , Encéfalo/fisiopatologia , Encéfalo/diagnóstico por imagem , Isquemia Encefálica/terapia , Isquemia Encefálica/fisiopatologia , Isquemia Encefálica/diagnóstico por imagem , Modelos Animais de Doenças , Rede Nervosa/fisiopatologia , Rede Nervosa/diagnóstico por imagem , AVC Isquêmico/terapia , AVC Isquêmico/fisiopatologia , AVC Isquêmico/diagnóstico por imagem , Hipocampo/diagnóstico por imagem , Hipocampo/fisiopatologiaRESUMO
BACKGROUND: Experimental preeclampsia (ePE) has been shown to have worsened outcome from stroke. We investigated the effect of low-dose aspirin, known to prevent preeclampsia, on stroke hemodynamics and outcome, and the association between the vasoconstrictor and vasodilator cyclooxygenase products thromboxane A2 and prostacyclin. METHODS AND RESULTS: Middle cerebral artery occlusion was performed for 3 hours with 1 hour of reperfusion in normal pregnant rats on day 20 of gestation and compared with ePE treated with vehicle or low-dose aspirin (1.5 mg/kg per day). Multisite laser Doppler was used to measure changes in cerebral blood flow to the core middle cerebral artery and collateral vascular territories. After 30 minutes occlusion, phenylephrine was infused to increase blood pressure and assess cerebral blood flow autoregulation. Infarct and edema were measured using 2,3,5-triphenyltetrazolium chloride staining. Plasma levels of thromboxane A2, prostacyclin, and inflammatory markers in plasma and cyclooxygenase levels in cerebral arteries were measured. ePE had increased infarction compared with normal pregnant rats (P<0.05) that was reduced by aspirin (P<0.001). ePE also had intact cerebral blood flow autoregulation and reduced collateral perfusion during induced hypertension that was also prevented by aspirin. Aspirin increased prostacyclin in ePE (P<0.05) without reducing thromboxane B2, metabolite of thromboxane A2, or 8-isoprostane-prostaglandin-2α, a marker of lipid peroxidation. There were no differences in cyclooxygenase levels in cerebral arteries between groups. CONCLUSIONS: Low-dose aspirin in ePE reduced infarction that was associated with increased vasodilator prostacyclin and improved collateral perfusion during induced hypertension. The beneficial effect of aspirin on the brain and cerebral circulation is likely multifactorial and worth further study.