RESUMO
PURPOSE: The aim of this study was to assess the effects of experimentally induced photothrombotic stroke on structural and mechanical properties of rat m. flexor carpi ulnaris. METHODS: Two groups of Young-adult male Sprague-Dawley rats were measured: stroke (n = 9) and control (n = 7). Photothrombotic stroke was induced in the forelimb region of the primary sensorimotor cortex. Four weeks later, muscle-tendon unit and muscle belly length-force characteristics of the m. flexor carpi ulnaris, mechanical interaction with the neighbouring m. palmaris longus, the number of sarcomeres in series within muscle fibres, and the physiological cross-sectional area were measured. RESULTS: Stroke resulted in higher force and stiffness of the m. flexor carpi ulnaris at optimum muscle-tendon unit length, but only for the passive conditions. Stroke did not alter the length-force characteristics of m. flexor carpi ulnaris muscle belly, morphological characteristics, and the extent of mechanical interaction with m. palmaris longus muscle. CONCLUSION: The higher passive force and passive stiffness at the muscle-tendon unit level in the absence of changes in structural and mechanical characteristics of the muscle belly indicates that the experimentally induced stroke resulted in an increased stiffness of the tendon.
Assuntos
Músculo Esquelético/anatomia & histologia , Músculo Esquelético/fisiologia , Tendões/fisiologia , AVC Trombótico/patologia , Animais , Fenômenos Biomecânicos , Isquemia Encefálica , Membro Anterior/patologia , Contração Isométrica , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND AND PURPOSE: We aim to investigate whether histopathologic examination of thrombi retrieved from acute ischemic stroke patients undergoing endovascular treatment could distinguish cancer-related stroke from other etiologies. METHODS: Thrombi from patients undergoing endovascular treatment were analyzed. The etiology of stroke was divided into cardioembolism, large artery atherosclerosis, and active cancer groups. All selected thrombi were subjected to hematoxylin and eosin staining. The percentages of fibrin/platelets, red blood cells, and white blood cells within a thrombus were quantified. RESULTS: One-hundred fifty-two patients (active cancer, 19; cardioembolism, 107; large artery atherosclerosis, 26) were included. Thrombi from the active cancer group exhibited a higher fibrin/platelet composition than did those from the cardioembolism and large artery atherosclerosis groups (median, 85.7% versus 43.9% and 42.5%; P<0.001). Fibrin/platelet composition was the only independent factor (odds ratio, 1.05 [95% CI, 1.02-1.08]) in differentiating cancer-related stroke from stroke caused by cardioembolism and large artery atherosclerosis. A fibrin/platelet proportion of ≥65% accurately predicted cancer-related stroke (area under the curve, 0.84; P<0.001). CONCLUSIONS: In thrombi retrieved from patients undergoing endovascular treatment, a high fibrin/platelet composition was a probable indicator of cancer-related stroke.
Assuntos
Plaquetas/patologia , AVC Embólico/patologia , Eritrócitos/patologia , Fibrina/ultraestrutura , Leucócitos/patologia , Neoplasias/complicações , AVC Trombótico/patologia , Idoso , Idoso de 80 Anos ou mais , Plaquetas/ultraestrutura , AVC Embólico/cirurgia , Procedimentos Endovasculares , Eritrócitos/ultraestrutura , Feminino , Humanos , AVC Isquêmico/etiologia , AVC Isquêmico/patologia , AVC Isquêmico/cirurgia , Leucócitos/ultraestrutura , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Trombectomia , Trombose/etiologia , Trombose/patologia , Trombose/cirurgia , AVC Trombótico/etiologia , AVC Trombótico/cirurgiaRESUMO
BACKGROUND AND PURPOSE: The purpose was to assess quantitatively and qualitatively the composition and structure of cerebral thrombi and correlate them with the signs of intravital clot contraction (retraction), as well as with etiology, severity, duration, and outcomes of acute ischemic stroke. METHODS: We quantified high-resolution scanning electron micrographs of 41 cerebral thrombi for their detailed cellular and noncellular composition and analyzed histological images for the overall structure with the emphasis on red blood cell compression, fibrin age, and the signs of inflammation. RESULTS: Cerebral thrombi were quite compact and had extremely low porosity. The prevailing cell type was polyhedral compressed erythrocytes (polyhedrocytes) in the core, and fibrin-platelet aggregates were concentrated at the periphery; both findings are indicative of intravital contraction of the thrombi. The content of polyhedrocytes directly correlated with the stroke severity. The prevalence of fibrin bundles was typical for more severe cases, while the content of fibrin sponge prevailed in cases with a more favorable course. The overall platelet content in cerebral thrombi was surprisingly small, while the higher content of platelet aggregates was a marker of stroke severity. Fibrillar types of fibrin prevailed in atherothrombogenic thrombi. Older fibrin prevailed in thrombi from the patients who received thrombolytics, and younger fibrin dominated in cardioembolic thrombi. Alternating layers of erythrocytes and fibrin mixed with platelets were common for thrombi from the patients with more favorable outcomes. Thrombi with a higher number of leukocytes were associated with fatal cases. CONCLUSIONS: Most cerebral thrombi undergo intravital clot contraction (retraction) that may be of underestimated clinical importance. Despite the high variability of the composition and structure of cerebral thrombi, the content of certain types of blood cells and fibrin structures combined with the morphological signs of intravital contraction correlate with the clinical course and outcomes of acute ischemic stroke.
Assuntos
Plaquetas/ultraestrutura , AVC Embólico/patologia , Eritrócitos/ultraestrutura , Fibrina/ultraestrutura , Inflamação/patologia , AVC Trombótico/patologia , Idoso , Plaquetas/patologia , Forma Celular , Retração do Coágulo , AVC Embólico/fisiopatologia , AVC Embólico/terapia , Eritrócitos/patologia , Feminino , Fibrinolíticos/uso terapêutico , Humanos , AVC Isquêmico/patologia , AVC Isquêmico/fisiopatologia , AVC Isquêmico/terapia , Masculino , Microscopia Eletrônica de Varredura , Índice de Gravidade de Doença , Trombectomia , AVC Trombótico/fisiopatologia , AVC Trombótico/terapiaRESUMO
Innate immune memory is a part of the innate immune system that facilitates the elimination of pathogens. However, it may exacerbate neuropathology. In this study, we found that innate immune memory is detrimental in stroke, because it promotes the acute immune response and exacerbates ischemic infarcts. Mesenchymal stem cell therapy has been widely studied for its therapeutic potential in various diseases including stroke, but whether it diminishes innate immune memory has not been studied. Here, our study demonstrates that, after the activation of innate immune memory by lipopolysaccharide, mesenchymal stem cell therapy can diminish innate immune memory though down-regulation of H3 methylation and subsequently protect against stroke. Our results demonstrate that innate immune memory is detrimental in stroke, and we describe a novel potential therapeutic target involving the use of mesenchymal stem cells to treat stroke patients.
Assuntos
Encéfalo/efeitos dos fármacos , Imunidade Inata/efeitos dos fármacos , Memória Imunológica/efeitos dos fármacos , AVC Isquêmico/cirurgia , Lipopolissacarídeos/toxicidade , Transplante de Células-Tronco Mesenquimais , AVC Trombótico/cirurgia , Cordão Umbilical/citologia , Animais , Encéfalo/imunologia , Encéfalo/metabolismo , Encéfalo/patologia , Células Cultivadas , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Mediadores da Inflamação/metabolismo , AVC Isquêmico/imunologia , AVC Isquêmico/metabolismo , AVC Isquêmico/patologia , Lipopolissacarídeos/imunologia , Masculino , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/imunologia , Microglia/metabolismo , Microglia/patologia , AVC Trombótico/imunologia , AVC Trombótico/metabolismo , AVC Trombótico/patologiaRESUMO
We recently reported that upregulation of the constitutively active ras homolog enriched in brain [Rheb(S16H)], which induces the activation of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway, can protect adult neurons, mediated by the induction of neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), in animal models of neurodegenerative diseases. Here we show that neuronal transduction of Rheb(S16H) using adeno-associated virus serotype 1 provides neuroprotection in a mouse model of photothrombosis-induced ischemic stroke. Rheb(S16H)-expressing neurons exhibited neurotrophic effects, such as mTORC1 activation, increases in neuronal size, and BDNF production, in mouse cerebral cortex. Moreover, the upregulation of neuronal Rheb(S16H) significantly attenuated ischemic damage and behavioral impairments as compared to untreated mice, suggesting that Rheb(S16H) upregulation in cortical neurons may be a useful strategy to treat ischemic stroke.
Assuntos
Córtex Motor/metabolismo , Neurônios/metabolismo , Neuroproteção/genética , Proteína Enriquecida em Homólogo de Ras do Encéfalo/genética , AVC Trombótico/genética , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Crescimento Celular , Dependovirus , Modelos Animais de Doenças , Corantes Fluorescentes , Análise da Marcha , Técnicas de Transferência de Genes , Vetores Genéticos , AVC Isquêmico/genética , AVC Isquêmico/metabolismo , AVC Isquêmico/patologia , AVC Isquêmico/fisiopatologia , Camundongos , Córtex Motor/patologia , Mutação , Neurônios/patologia , Rosa Bengala , AVC Trombótico/metabolismo , AVC Trombótico/patologia , AVC Trombótico/fisiopatologia , Transdução GenéticaRESUMO
Emerging literature suggests that after a stroke, the peri-infarct region exhibits dynamic changes in excitability. In rodent stroke models, treatments that enhance excitability in the peri-infarct cerebral cortex promote motor recovery. This increase in cortical excitability and plasticity is opposed by increases in tonic GABAergic inhibition in the peri-infarct zone beginning three days after a stroke in a mouse model. Maintenance of a favorable excitatory-inhibitory balance promoting cerebrocortical excitability could potentially improve recovery. Brevetoxin-2 (PbTx-2) is a voltage-gated sodium channel (VGSC) gating modifier that increases intracellular sodium ([Na+]i), upregulates N-methyl-D-aspartate receptor (NMDAR) channel activity and engages downstream calcium (Ca2+) signaling pathways. In immature cerebrocortical neurons, PbTx-2 promoted neuronal structural plasticity by increasing neurite outgrowth, dendritogenesis and synaptogenesis. We hypothesized that PbTx-2 may promote excitability and structural remodeling in the peri-infarct region, leading to improved functional outcomes following a stroke. We tested this hypothesis using epicortical application of PbTx-2 after a photothrombotic stroke in mice. We show that PbTx-2 enhanced the dendritic arborization and synapse density of cortical layer V pyramidal neurons in the peri-infarct cortex. PbTx-2 also produced a robust improvement of motor recovery. These results suggest a novel pharmacologic approach to mimic activity-dependent recovery from stroke.
Assuntos
Córtex Cerebral/efeitos dos fármacos , Agonistas de Aminoácidos Excitatórios/administração & dosagem , Toxinas Marinhas/administração & dosagem , Atividade Motora/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Oxocinas/administração & dosagem , AVC Trombótico/tratamento farmacológico , Animais , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Córtex Cerebral/fisiopatologia , Modelos Animais de Doenças , Injeções , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Camundongos Transgênicos , Recuperação de Função Fisiológica , AVC Trombótico/metabolismo , AVC Trombótico/patologia , AVC Trombótico/fisiopatologiaRESUMO
Stroke is one of the leading reasons of human death. Ischemic penumbra that surrounds the stroke-induced infarction core is potentially salvageable, but molecular mechanisms of its formation are poorly known. Histone acetylation induces chromatin decondensation and stimulates gene expression. We studied the changes in the levels and localization of histone acetyltransferases HAT1 and PCAF in penumbra after photothrombotic stroke (PTS, a stroke model). In PTS, laser irradiation induces local occlusion of cerebral vessels after photosensitization by Rose Bengal. HAT1 and PCAF are poorly expressed in normal cortical neurons and astrocytes, but they are overexpressed 4-24 h after PTS. Their predominant localization in neuronal nuclei did not change after PTS, but their levels in the astrocyte nuclei significantly increased. Western blotting showed the increase of HAT1 and PCAF levels in the cytoplasmic fraction of the PTS-induced penumbra. In the nuclear fraction, PCAF level did not change, and HAT1 was overexpressed only at 24 h post-PTS. PTS-induced upregulation of HAT1 and PCAF in the penumbra was mainly associated with overexpression in the cytoplasm of neurons and especially astrocytes. HAT1 and PCAF did not co-localize with TUNEL-positive cells that indicated their nonparticipation in PTS-induced apoptosis.