RESUMO
Although thiopurine is a crucial drug for treating acute lymphoblastic leukemia, individual variations in intolerance are observed due to gene polymorphisms. A 3-year-old boy with B-cell precursor acute lymphoblastic leukemia who was administered thiopurine developed mucositis, sepsis, and hemophagocytic lymphohistiocytosis due to prolonged hematologic toxicity, chronic disseminated candidiasis, and infective endocarditis that triggered multiple brain infarctions. The patient was found to harbor 3 gene polymorphisms associated with thiopurine intolerance including homozygous NUDT15 R139C, heterozygous ITPA C94A, and homozygous MTHFR C677T and heterozygous RFC1 G80A. Thus, the combined effect of intolerance via multiple gene polymorphisms should be considered in case of unexpected adverse reactions.
Assuntos
Hipersensibilidade a Drogas/patologia , Homozigoto , Mercaptopurina/efeitos adversos , Polimorfismo Genético , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Pirofosfatases/genética , Antimetabólitos Antineoplásicos , Infarto Encefálico/induzido quimicamente , Infarto Encefálico/genética , Infarto Encefálico/patologia , Pré-Escolar , Hipersensibilidade a Drogas/etiologia , Humanos , Infecções/induzido quimicamente , Infecções/genética , Infecções/patologia , Linfo-Histiocitose Hemofagocítica/induzido quimicamente , Linfo-Histiocitose Hemofagocítica/genética , Linfo-Histiocitose Hemofagocítica/patologia , Masculino , Mucosite/induzido quimicamente , Mucosite/genética , Mucosite/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Prognóstico , Sepse/induzido quimicamente , Sepse/genética , Sepse/patologiaRESUMO
Mitochondria-related cell death pathways play a major role in ischemic brain injury. Thus, mitochondrial "protective" molecules could be considered for new therapeutic regimens. We recently reported that acute administration of docosahexaenoic acid (DHA) triglyceride lipid emulsion, immediately after hypoxic-ischemic (HI) insult, markedly attenuated brain infarct size. This was associated with an early change of DHA-derived specialized pro-resolving mediator (SPM) profiles. Specifically, DHA treatment induced a 50% increase of neuroprotectin D1 (NPD1) levels in ischemic brain. Based on these findings, we questioned if direct administration of NPD1 after HI injury also affords neuroprotection, and if so, by what mechanisms. Using HI insult to mimic ischemic stroke in neonatal mice, we observed that acute intraperitoneal injection of NPD1 immediately after HI injury prevented the expansion of the ischemic core by ~40% and improved coordination and motor abilities compared to the control group. At 7 days after HI injury, NPD1 treatment decreased ipsilateral hemisphere atrophy and preserved motor functions in wire-holding and bridge-crossing tests compared to control littermates. Brain mitochondria, isolated at 4 h after reperfusion from mice treated with NPD1, showed an increase in the capacity to buffer calcium after HI injury, as result of the preservation of mitochondrial membranes. Further, NPD1 induced a reduction of mitochondrial BAX translocation and oligomerization, attenuated cytochrome C release and decreased AIF nuclear translocation. To confirm whether NPD1 acts as BAX inhibitor, we evaluated NPD1 action co-administrated with a pro-apoptotic agent, staurosporine, using mouse embryonic fibroblasts as in vitro model of apoptosis. NPD1 exposure markedly decreased mitochondria-mediated apoptosis, blocking BAX translocation from cytosol to mitochondria and subsequently reducing caspase-3 activation. Our findings provide novel evidence that the neuroprotective action of NPD1 is elicited rapidly in the first few hours after ischemic injury and is associated with both preserved mitochondrial membrane structure and reduced BAX mitochondrial translocation and activation.
Assuntos
Apoptose/efeitos dos fármacos , Isquemia Encefálica/prevenção & controle , Ácidos Docosa-Hexaenoicos/farmacologia , Mitocôndrias/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Animais , Animais Recém-Nascidos , Atrofia , Encéfalo/patologia , Infarto Encefálico/induzido quimicamente , Infarto Encefálico/tratamento farmacológico , Ácidos Docosa-Hexaenoicos/uso terapêutico , AVC Isquêmico/induzido quimicamente , AVC Isquêmico/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/uso terapêutico , Desempenho Psicomotor/efeitos dos fármacos , Traumatismo por Reperfusão/tratamento farmacológico , Proteína X Associada a bcl-2/antagonistas & inibidores , Proteína X Associada a bcl-2/metabolismoRESUMO
Stroke is the leading cause of long-term, severe disability worldwide. Immediately after the stroke, endogenous inflammatory processes are upregulated, leading to the local neuroinflammation and the potentiation of brain tissue destruction. The innate immune response is triggered as early as 24 h post-brain ischemia, followed by adaptive immunity activation. Together these immune cells produce many inflammatory mediators, i.e., cytokines, growth factors, and chemokines. Our study examines the immune response components in the early stage of deep brain lacunar infarct in the rat brain, highly relevant to the clinical scenario. The lesion was induced by stereotactic injection of ouabain into the adult rat striatum. Ouabain is a Na/K ATPase pump inhibitor that causes excitotoxicity and brings metabolic and structural changes in the cells leading to focal brain injury. We have shown a surge of neurodegenerative changes in the peri-infarct area in the first days after brain injury. Immunohistochemical analysis revealed early microglial activation and the gradual infiltration of immune cells with a significant increase of CD4+ and CD8+ T lymphocytes in the ipsilateral hemisphere. In our studies, we identified the higher level of pro-inflammatory cytokines, i.e., interleukin-1α, interleukin-1ß, tumor necrosis factor-α, and interferon-γ, but a lower level of anti-inflammatory cytokines, i.e., interleukin-10 and transforming growth factor-ß2 in the injured brain than in normal rats. Concomitantly focal brain injury showed a significant increase in the level of chemokines, i.e., monocyte chemoattractant protein-1 and CC motif chemokine ligand 5 compared to control. Our findings provide new insights into an early inflammatory reaction in our model of the deep-brain lacunar infarct. The results of this study may highlight future stroke immunotherapies for targeting the acute immune response accompanied by the insult.
Assuntos
Infarto Encefálico/complicações , Encefalite/etiologia , Acidente Vascular Cerebral Lacunar/complicações , Animais , Infarto Encefálico/induzido quimicamente , Infarto Encefálico/patologia , Relação CD4-CD8 , Quimiocinas/metabolismo , Citocinas/metabolismo , Encefalite/patologia , Inibidores Enzimáticos , Masculino , Microglia/patologia , Neurogênese , Ouabaína , Ratos , Ratos Wistar , ATPase Trocadora de Sódio-Potássio/antagonistas & inibidores , Acidente Vascular Cerebral Lacunar/induzido quimicamente , Acidente Vascular Cerebral Lacunar/patologiaRESUMO
Kratom is a psychoactive herb that has stimulant properties at low doses and has opioid-like properties at higher doses. It has been used for centuries in southeast Asia as a stimulant but has gained increasing popularity as a substitute for opioids in western countries as it is easily available. As most cases of kratom use involve other drugs too, the Food and Drug Administration (FDA) has stopped short of restricting kratom due to difficulty in assessing the adverse effects of kratom alone. We present the case of a young healthy 35-year-old man who suffered a cardiac arrest due to kratom use with no other coingestants. He was subsequently intubated and found to have systolic dysfunction and small brain infarcts. Fortunately, he made a successful recovery and was discharged after a stay at thebehavioural health centre. Our case highlights the potential adverse effects of kratom and the need to regulate its use.
Assuntos
Infarto Encefálico/induzido quimicamente , Parada Cardíaca/induzido quimicamente , Mitragyna/intoxicação , Psicotrópicos/efeitos adversos , Adulto , Infarto Encefálico/terapia , Diagnóstico Diferencial , Parada Cardíaca/terapia , Humanos , Hipotermia Induzida , Masculino , Síndrome de Abstinência a SubstânciasRESUMO
Background and Purpose- We developed a rat model of silent brain infarcts based on microsphere infusion and investigated their impact on perfusion and tissue damage. Second, we studied the extent and mechanisms of perfusion recovery. Methods- At day 0, 15 µm fluorescent microspheres were injected into the right common carotid artery of F344 rats. At days 1, 7, or 28, the brain was removed, cut in 100-µm cryosections, and processed for immunofluorescent staining and analysis. Results- Injection of microspheres caused mild and transient damage to the treated hemisphere, with a decrease in perfused capillary volume at day 1, as compared with the untreated hemisphere. At day 1 but not at days 7 and 28, we observed IgG staining outside of the vessels, indicating vessel leakage. All microspheres were located inside the lumen of the vessels at day 1, whereas the vast majority (≈80%) of the microspheres were extravascular at day 7, and 100% at day 28. This was accompanied by restoration of perfused capillary volume. Conclusions- Microspheres cause mild and transient damage, and effective extravasation mechanisms exist in the brain to clear microsized emboli from the vessels.
Assuntos
Infarto Encefálico , Microesferas , Animais , Infarto Encefálico/induzido quimicamente , Infarto Encefálico/metabolismo , Infarto Encefálico/patologia , Modelos Animais de Doenças , Masculino , Ratos , Ratos Endogâmicos F344RESUMO
OBJECTIVES: To report a case of reversible cerebral vasoconstriction syndrome (RCVS) possibly precipitated by tocilizumab. BACKGROUND: Immunosuppressant drugs are a rare cause of reversible cerebral vasoconstriction, a syndrome characterized by segmental vasospasm. However, although it is considered a reversible process that resolves within 3 months, the cerebral vasoconstriction over time may lead to severe complications such as strokes. RESULTS: We describe a 53-year-old woman who presented with a reversible vasoconstriction syndrome possibly associated with tocilizumab, an inhibitor of IL-6 receptor used in inflammatory diseases such as rheumatoid arthritis. The patient developed a cerebellar infarction as the major complication of the vasoconstriction syndrome. CONCLUSION: Tocilizumab could be a trigger of RCVS. It is important to bear in mind the role of tocilizumab as a possible precipitating factor in order to remove it and reduce complications such as strokes. It is, to our knowledge, the first reversible vasoconstriction syndrome possibly precipitated by tocilizumab published to date.
Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Artrite/tratamento farmacológico , Infarto Encefálico/induzido quimicamente , Encéfalo/diagnóstico por imagem , Imunossupressores/efeitos adversos , Vasoespasmo Intracraniano/induzido quimicamente , Anticorpos Monoclonais Humanizados/uso terapêutico , Infarto Encefálico/diagnóstico por imagem , Feminino , Humanos , Imunossupressores/uso terapêutico , Espectroscopia de Ressonância Magnética , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios X , Vasoespasmo Intracraniano/diagnóstico por imagemAssuntos
Infarto Encefálico/induzido quimicamente , Bupropiona/intoxicação , Overdose de Drogas/complicações , Hipocampo/diagnóstico por imagem , Síndrome da Serotonina/induzido quimicamente , Cloridrato de Vilazodona/intoxicação , Adolescente , Infarto Encefálico/diagnóstico por imagem , Overdose de Drogas/diagnóstico por imagem , Febre/induzido quimicamente , Febre/diagnóstico por imagem , Alucinações/induzido quimicamente , Alucinações/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Masculino , Testes Neuropsicológicos , Síndrome da Serotonina/diagnóstico por imagem , Tremor/induzido quimicamente , Tremor/diagnóstico por imagemRESUMO
PURPOSE: To describe the consistency in the frequency of 5 health outcomes across the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) and Tenth Revision, Clinical Modification (ICD-10-CM) eras in the US. METHODS: We examined the incidence of 3 acute conditions (acute myocardial infarction [AMI], angioedema, ischemic stroke) and the prevalence of 2 chronic conditions (diabetes, hypertension) during the final 5 years of the ICD-9-CM era (January 2010-September 2015) and the first 15 months of the ICD-10-CM era (October 2015-December 2016) in 13 electronic health care databases in the Sentinel System. For each health outcome reviewed during the ICD-10-CM era, we evaluated 4 definitions, including published algorithms derived from other countries, as well as simple-forward, simple-backward, and forward-backward mapping using the General Equivalence Mappings. For acute conditions, we also compared the incidence between April to December 2014 and April to December 2016. RESULTS: The analyses included data from approximately 172 million health plan members. While the incidence or prevalence of AMI and hypertension performed similarly across the 2 eras, the other 3 outcomes did not demonstrate consistent trends for some or all the ICD-10-CM definitions assessed. CONCLUSIONS: When using data from both the ICD-9-CM and ICD-10-CM eras, or when using results from ICD-10-CM data to compare to results from ICD-9-CM data, researchers should test multiple ICD-10-CM outcome definitions as part of sensitivity analysis. Ongoing assessment of the impact of ICD-10-CM transition on identification of health outcomes in US electronic health care databases should occur as more data accrue.
Assuntos
Sistemas de Notificação de Reações Adversas a Medicamentos/estatística & dados numéricos , Codificação Clínica/classificação , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Avaliação de Resultados em Cuidados de Saúde/métodos , Doença Aguda/epidemiologia , Angioedema/induzido quimicamente , Angioedema/diagnóstico , Angioedema/epidemiologia , Infarto Encefálico/induzido quimicamente , Infarto Encefálico/diagnóstico , Infarto Encefálico/epidemiologia , Doença Crônica/epidemiologia , Codificação Clínica/estatística & dados numéricos , Diabetes Mellitus/induzido quimicamente , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Humanos , Hipertensão/induzido quimicamente , Hipertensão/diagnóstico , Hipertensão/epidemiologia , Incidência , Classificação Internacional de Doenças , Infarto do Miocárdio/induzido quimicamente , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/epidemiologia , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Prevalência , Acidente Vascular Cerebral/induzido quimicamente , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/epidemiologia , Estados Unidos/epidemiologiaRESUMO
We report a case of atypical cerebellar infarction following accidental inhalation of toluene mixed paint. An unconscious 57-year-old housewife with hypertension arrived at our emergency department by ambulance. She had been rescued from a basement (30â¯m3) 12â¯h after exposure to paint containing toluene (34%). On arrival, she was comatose (E1V1M1) with a mild fever (37.4⯰C). Physical examination showed chemical burns on her buttocks and rales on the left lung. Initial arterial blood gas with 15â¯L/min of oxygen showed a pH of 7.142, PCO2 of 47.3â¯mmHg, and PaO2 of 204.7â¯mmHg. She received endotracheal intubation and mechanical ventilation. Laboratory tests showed elevated white blood cells (26.86â¯×â¯109/L), C-reactive protein (0.18â¯mg/dL), glucose (238â¯mg/Dl), and CPK (1389â¯U/L). At 5.5â¯h after arrival, she became responsive to verbal commands. On day 3, after removal of the endotracheal tube, she began to complain of an occipital headache without neurologic abnormalities. Brain magnetic resonance angiography (MRA) performed on day 6 showed a tiny acute infarction on the right cerebellar hemisphere. We serially measured urinary hippuric acid concentrations (reference range, ≤2.5â¯g/g creatinine) from 74â¯h (3.88) after hospital arrival to 218â¯h (0.5). She was discharged on day 14. Herein we presented a near fatal toluene intoxication (>45,000â¯mg/m3 estimated based on the basement volume and quantity of paint used) with atypical cerebellar infarction, compared with prior findings of bilateral involvement or reversibility.
Assuntos
Poluentes Atmosféricos/efeitos adversos , Infarto Encefálico/induzido quimicamente , Doenças Cerebelares/induzido quimicamente , Exposição por Inalação/efeitos adversos , Pintura/efeitos adversos , Solventes/efeitos adversos , Tolueno/efeitos adversos , Acidentes , Infarto Encefálico/fisiopatologia , Infarto Encefálico/terapia , Doenças Cerebelares/patologia , Doenças Cerebelares/terapia , Feminino , Humanos , Pessoa de Meia-Idade , Solventes/química , Resultado do TratamentoRESUMO
INTRODUCTION: Methanol intoxication is an infrequent cause of poisoning in the United Sates. It can present with prominent stroke-like features and acute kidney injury. Despite the life-threatening nature of this condition, it is poorly identified by clinicians. We aim to present a case of rapidly progressive mental decline and renal involvement, discuss a diagnostic work-up and provide a critical review on therapeutic strategies. CASE PRESENTATION: A 24-year-old patient presented to the emergency department with acute encephalopathy and diffuse muscular rigidity. His studies were relevant for severe anion gap metabolic acidosis, extensive brain infarction, and acute kidney injury. After excluding infections, drug intoxication, and environmental exposure, his serum methanol levels were found to be high. The patient was effectively treated with renal replacement therapy and survived with residual neurological sequelae. CONCLUSIONS: Methanol intoxication should be in the differential diagnosis of patients with brain infarction and high anion gap metabolic acidosis. Early use of renal replacement therapy may be life-saving and should be tailored on an individual basis.â©.
Assuntos
Acidose/induzido quimicamente , Injúria Renal Aguda/induzido quimicamente , Infarto Encefálico/induzido quimicamente , Metanol/intoxicação , Diálise Renal , Acidose/terapia , Injúria Renal Aguda/terapia , Infarto Encefálico/terapia , Humanos , Masculino , Resultado do Tratamento , Adulto JovemRESUMO
Hyperbaric oxygen (HBO) therapy and neural stem cell (NSC) transplantation can improve traumatic brain injury (TBI) clinically. This study aimed to investigate the mechanism of HBO promoting NSC proliferation and neurological recovery after TBI. Twenty-four Sprague-Dawley rats were divided randomly into three groups: a sham group, a TBI group (constructed using Feeney's free-fall method), and an HBO-treated TBI group. Neurological function was evaluated by Neurological Severity Scores on days 1, 3, and 7, and we found that TBI-induced poor neurological function was improved by HBO. On day 7 after TBI, we observed that TBI promoted NSC proliferation, migration to the lesion area, and the levels of vascular endothelial growth factor (VEGF), VEGFR2, Raf-1, MEK1/2, and phospho-extracellular signal-regulated kinase (ERK) 1/2 protein, which were further boosted by HBO, from immunohistochemistry, immunofluorescence, and Western blot experiments. In vitro, cell injury was applied to NSCs isolated from neonatal Sprague-Dawley rats by the Cell Injury Controller II system. Moreover, data from the BrdU Kit and Western blot showed that in-vitro HBO significantly accelerated NSC proliferation and the levels of proteins related to cell cycle and the VEGF/ERK pathway after cell injury, which was suppressed by the VEGFR2 inhibitor. Taken together, this study indicated that HBO may promote NSC proliferation by activating VEGF/ERK signaling and play a crucial role in neuroprotection after TBI.
Assuntos
Lesões Encefálicas Traumáticas , Proliferação de Células/fisiologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Células-Tronco Neurais/fisiologia , Transdução de Sinais/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Infarto Encefálico/induzido quimicamente , Infarto Encefálico/diagnóstico , Lesões Encefálicas Traumáticas/metabolismo , Lesões Encefálicas Traumáticas/patologia , Lesões Encefálicas Traumáticas/terapia , Bromodesoxiuridina/metabolismo , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Oxigenoterapia Hiperbárica/métodos , Masculino , Células-Tronco Neurais/efeitos dos fármacos , Exame Neurológico , Oxigênio/farmacologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/fisiologia , Fatores de TempoRESUMO
Tissue plasminogen activator (tPA), the only approved drug for the treatment of ischemic stroke, increases the risk of cerebral hemorrhage. Here, we investigated whether the newly identified gaso-transmitter hydrogen sulfide (H2S), when used in combination with tPA, reduced the hemorrhagic transformation following stroke. In a mouse model of middle cerebral artery occlusion (MCAO), intravenous injection of tPA enhanced cerebral hemorrhage, which was significantly attenuated by the co-administration of two structurally unrelated H2S donors, ADT-OH and NaHS. By assessing extravasation of Evans blue into the ischemic hemisphere as well as brain edema following MCAO, we further showed that a tPA-exacerbated BBB disruption was significantly ameliorated by the co-administration of ADT-OH. In the mouse MCAO model, tPA upregulated Akt activation, vascular endothelial growth factor (VEGF) expression, and metalloproteinase 9 (MMP9) activity in the ischemic brain, which was remarkably attenuated by ADT-OH. In the in vitro glucose-oxygen deprivation (OGD) model, ADT-OH markedly attenuated tPA-enhanced Akt activation and VEGF expression in brain microvascular endothelial cells. Finally, ADT-OH improved functional outcomes in mice subjected to MCAO and tPA infusion. In conclusion, H2S donors reduced tPA-induced cerebral hemorrhage by possibly inhibiting the Akt-VEGF-MMP9 cascade. Administration of H2S donors has potential as a novel modality to improve the safety of tPA following stroke.
Assuntos
Hemorragia Cerebral/induzido quimicamente , Hemorragia Cerebral/tratamento farmacológico , Fibrinolíticos/efeitos adversos , Sulfeto de Hidrogênio/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Ativador de Plasminogênio Tecidual/efeitos adversos , Análise de Variância , Animais , Edema Encefálico/tratamento farmacológico , Edema Encefálico/etiologia , Infarto Encefálico/induzido quimicamente , Infarto Encefálico/tratamento farmacológico , Células Cultivadas , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Glucose/deficiência , Hipóxia/tratamento farmacológico , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Exame Neurológico , Índice de Gravidade de Doença , Acidente Vascular Cerebral/tratamento farmacológicoRESUMO
Polysialic acid (PSA), a carbohydrate polymer associated with the neural cell adhesion molecule (NCAM), plays an important role in the migration, differentiation and maturation of neuroblasts. Endoneuraminidase-N (Endo-N) can specifically cleave PSA from NCAM. The objective of the present study was to examine: the effect of Endo-N on characteristics of subventricular zone (SVZ)-derived neural progenitor cells (NPCs) in vitro; whether intraventricular administration of Endo-N could increase ectopic migration of SVZ-derived NPCs into 6-hydroxydopamine (6-OHDA)-lesioned striatum, and whether migrated NPCs could differentiate into neuronal and glial cells. In in vitro study, Endo-N was found to inhibit the migration of NPCs, and to enhance the differentiation of NPCs. In in vivo study, mice sequentially received injections of 6-OHDA into the right striatum, Endo-N into the right lateral ventricle, and bromodeoxyuridine (BrdU) intraperitoneally. The data showed that intraventricular injections of Endo-N disorganized the normal structure of the rostral migratory stream (RMS), and drastically increased the number of BrdU-immunoreactive (IR) cells in 6-OHDA-lesioned striatum. In addition, a number of BrdU-IR cells were double labeled for doublecortin (DCX), NeuN or glial fibrillary acidic protein (GFAP). The results suggest that interruption of neuroblast chain pathway with Endo-N facilitates ectopic migration of SVZ-derived NPCs into the lesioned striatum, and migrated NPCs can differentiate into neurons and astrocytes.
Assuntos
Infarto Encefálico/patologia , Movimento Celular/efeitos dos fármacos , Corpo Estriado/patologia , Glicosídeo Hidrolases/farmacologia , Ventrículos Laterais/citologia , Células-Tronco Neurais/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Infarto Encefálico/induzido quimicamente , Ciclo Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Proteína Duplacortina , Proteína Glial Fibrilar Ácida/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Oxidopamina/toxicidade , Ácidos Siálicos/metabolismo , Fatores de Tempo , Tubulina (Proteína)/metabolismoRESUMO
Clinical stroke usually results from a cerebral ischaemic event, and is frequently a debilitating condition with limited treatment options. A significant proportion of clinical strokes result from specific damage to the subcortical white matter (SWM), but currently there are few animal models available to investigate the pathogenesis and potential therapeutic strategies to promote recovery. Granulocyte macrophage colony-stimulating factor (GM-CSF) is a cytokine that has been previously shown to promote neuroprotective effects after brain damage; however, the mechanisms mediating this effect are not known. Here, it is reported that GM-CSF treatment results in dramatic functional improvement in a white matter model of stroke in mice. SWM stroke was induced in mice by unilateral injections of the vasoconstrictor, endothelin-1 (ET-1). The results reveal that ET-1-induced stroke impairs skilled motor function on the single pellet-reaching task and results in forelimb asymmetry, in adult mice. Treatment with GM-CSF, after stroke, restores motor function and abolishes forelimb asymmetry. The results also indicate that GM-CSF promotes its effects by activating mammalian target of rapamycin signalling mechanisms in the brain following stroke injury. Additionally, a significant increase in GM-CSF receptor expression was found in the ipsilateral hemisphere of the ET-1-injected brain. Taken together, the present study highlights the use of an under-utilized mouse model of stroke (using ET-1) and suggests that GM-CSF treatment can attenuate ET-1-induced functional deficits.
Assuntos
Infarto Encefálico/complicações , Corpo Caloso/efeitos dos fármacos , Corpo Caloso/patologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Atividade Motora/efeitos dos fármacos , Recuperação de Função Fisiológica/efeitos dos fármacos , Substância Branca/efeitos dos fármacos , Substância Branca/patologia , Animais , Infarto Encefálico/induzido quimicamente , Corpo Caloso/lesões , Modelos Animais de Doenças , Endotelina-1 , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Córtex Sensório-Motor/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Substância Branca/lesõesRESUMO
Age is associated with poor outcome and impaired functional recovery after stroke. Fluoxetine, which is widely used in clinical practice, can regulate hippocampal neurogenesis in young rodents. As the rate of neurogenesis is dramatically reduced during aging, we studied the effect of post-stroke fluoxetine treatment on neurogenesis in the subventricular zone (SVZ) and subgranular zone (SGZ) of dentate gyrus (DG) and whether this would be associated with any behavioral recovery after the cortical infarct in aged rats. Aged rats were randomly assigned to four groups: sham-operated rats, sham-operated rats treated with fluoxetine, rats subjected to cerebral ischemia, and rats with ischemia treated with fluoxetine. Focal cortical ischemia was induced by intracranial injection of vasoconstrictive peptide, endothelin-1 (ET-1). Fluoxetine was administered in the drinking water for 3 weeks starting 1 week after ischemia at a dose of 18 mg/kg/day. Behavioral recovery was evaluated on post-stroke days 29 to 31 after which the survival rate and fate of proliferating cells in the SVZ and DG were assessed by immunohistochemistry. Apoptosis was measured with the TUNEL assay. The results indicated that chronic fluoxetine treatment after stroke enhanced the proliferation of newborn neurons in the SVZ, but not in SGZ, and it suppressed perilesional apoptosis. Fluoxetine treatment did not affect the survival or differentiation of newly generated cells in the SVZ i.e., the enhanced neurogenesis was not translated into a behavioral outcome.
Assuntos
Antidepressivos de Segunda Geração/uso terapêutico , Infarto Encefálico/tratamento farmacológico , Córtex Cerebral/efeitos dos fármacos , Fluoxetina/uso terapêutico , Locomoção , Neurogênese , Fármacos Neuroprotetores/uso terapêutico , Animais , Antidepressivos de Segunda Geração/farmacologia , Apoptose , Infarto Encefálico/induzido quimicamente , Córtex Cerebral/crescimento & desenvolvimento , Endotelina-1/toxicidade , Fluoxetina/farmacologia , Masculino , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Sprague-DawleyRESUMO
Acidic fibroblast growth factor (aFGF) is a neurotrophic factor which is a powerful neuroprotective and neuroregenerative factor of the nervous system. Prior study had shown that levels of FGFs significantly increase following ischemic injury, reflecting a physiological protection mechanism. However, few reports demonstrated the efficacy of applying aFGF in cerebral ischemia. A recent report showed that the intranasal aFGF treatment improved neurological functional recovery; however, it did not significantly reduce the lesion size in ischemic rats. The present study examines the neuroprotective effect of aFGF on cortical neuron-glial cultures under oxygen glucose deprivation (OGD)-induced cell damage and investigates whether epidural application of slow-released aFGF could improve benefit on ischemic stroke injury in conscious rats. We used a topical application of aFGF mixed in fibrin glue, a slow-release carrier, over the peri-ischemic cortex and examined such treatment on cerebral infarction and behavioral impairments of rats subjected to focal cerebral ischemia (FCI). Results demonstrate that aFGF effectively protected cortical neuron-glial cultures from OGD-induced neuronal damage. Neurite extension from cortical neurons was significantly enhanced by aFGF, mediated through activation of AKT and ERK. In addition, topical application of fibrin glue-mixed aFGF dose-dependently reduced ischemia-induced brain infarction and improved functional restoration in ischemic stroke rats. Slow-released aFGF not only protected hippocampal and cortical cell loss but reduced microglial infiltration in FCI rats. Our results suggest that aFGF mixed in fibrin glue could prolong the protective/regenerative efficacy of aFGF to the damaged brain tissue and thus improve the functional restorative effect of aFGF.
Assuntos
Fator 1 de Crescimento de Fibroblastos/uso terapêutico , Infarto da Artéria Cerebral Média/patologia , Neuritos/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/patologia , Fármacos Neuroprotetores/uso terapêutico , Animais , Infarto Encefálico/induzido quimicamente , Infarto Encefálico/tratamento farmacológico , Hipóxia Celular/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Embrião de Mamíferos , Fator 1 de Crescimento de Fibroblastos/farmacologia , Lateralidade Funcional , Glucose/deficiência , Infarto da Artéria Cerebral Média/complicações , Infarto da Artéria Cerebral Média/tratamento farmacológico , MAP Quinase Quinase Quinase 3/metabolismo , Masculino , Transtornos dos Movimentos/tratamento farmacológico , Transtornos dos Movimentos/etiologia , Neuroglia/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Long-Evans , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacosAssuntos
Infarto Encefálico/induzido quimicamente , Técnicas Cosméticas/efeitos adversos , Ácido Hialurônico/efeitos adversos , Oclusão da Artéria Retiniana/induzido quimicamente , Viscossuplementos/efeitos adversos , Adulto , Cegueira/induzido quimicamente , Feminino , Humanos , Imageamento por Ressonância Magnética , NarizRESUMO
BACKGROUND: Most ischemic strokes in humans are caused by ruptured arterial atheroma, which activate platelets and produce thrombi that occlude cerebral vessels. METHODS: To simulate these events, we threaded a catheter through the internal carotid artery toward the middle cerebral artery (MCA) orifice and injected collagen directly into the cerebral circulation of male C57Bl/6 mice and Wistar rats. RESULTS: Laser-Doppler flowmetry demonstrated reductions in cerebral blood flow (CBF) of â¼80% in mice and â¼60% in rats. CBF spontaneously increased but remained depressed after catheter withdrawal. Magnetic resonance imaging showed that ipsilateral CBF was reduced at 3h after collagen injection and markedly improved at 48 h. Micro-computed tomography revealed reduced blood vessel density in the ipsilateral MCA territory at 3 h. Gross examination of excised brains revealed thrombi within ipsilateral cerebral arteries at 3 h, but not 24 h, after collagen injection. Immunofluorescence microscopy confirmed that platelets and fibrinogen/fibrin were major components of these thrombi at both macrovascular and microvascular levels. Cerebral infarcts comprising â¼30% of hemispheric volume and neurobehavioral deficits were observed 48 h after ischemic injury in both mice and rats. COMPARISON WITH EXISTING METHODS: Collagen injection caused brain injury that was similar in magnitude and variability to mechanical MCA occlusion or injection of a pre-formed clot; however, alterations in CBF and the mechanism of vascular occlusion were more consistent with clinical ischemic stroke. CONCLUSION: This novel rodent model of ischemic stroke has pathophysiologic characteristics consistent with clinical atherothrombotic stroke, is technically feasible, and creates reproducible brain injury.
Assuntos
Isquemia Encefálica/induzido quimicamente , Isquemia Encefálica/complicações , Circulação Cerebrovascular/efeitos dos fármacos , Colágeno/toxicidade , Modelos Animais de Doenças , Acidente Vascular Cerebral/etiologia , Animais , Infarto Encefálico/induzido quimicamente , Circulação Cerebrovascular/fisiologia , Lateralidade Funcional , Fluxometria por Laser-Doppler , Imageamento por Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Doenças do Sistema Nervoso/etiologia , Neutrófilos/patologia , Ratos , Ratos Wistar , Estatísticas não Paramétricas , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/patologia , Fatores de Tempo , Tomografia Computadorizada por Raios XAssuntos
Cisplatino/efeitos adversos , Seminoma/tratamento farmacológico , Neoplasias Testiculares/tratamento farmacológico , Trombose/induzido quimicamente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bleomicina/administração & dosagem , Infarto Encefálico/induzido quimicamente , Infarto Encefálico/reabilitação , Cisplatino/administração & dosagem , Etoposídeo/administração & dosagem , Humanos , Masculino , Trombose/terapiaRESUMO
BACKGROUND: The multiple prominent hypointense veins on susceptibility-weighted imaging (SWI) have been found in the ischemic territory of patients with acute ischemic stroke. Venous side is the unknown area in the hemodynamics of brain infarction. PURPOSE: To evaluate the venous aspect in acute brain infarction through an animal study. MATERIAL AND METHODS: The acute infarction in cat brains was induced with a bolus infusion of 0.25 mL of triolein through one side of the common carotid artery. The magnetic resonance (MR) images, including diffusion-weighted imaging (DWI), apparent diffusion coefficient (ADC) map, SW, and perfusion-weighted (PWI) images, were obtained serially at 2 h (n = 17), 1 day (n = 11), and 4 days (n = 4) after triolein infusion. The obtained MR images were evaluated qualitatively and quantitatively. For qualitative assessment, the signal intensity of the serial MR images was evaluated. The presence or absence and the location with serial changes of infarction were identified on DWI and ADC map images. The presence or absence of prominent hypointense veins and the serial changes of cortical veins were also evaluated on SWI. Quantitative assessment was performed by comparing the relative cerebral blood volume (rCBV), cerebral blood flow (rCBF), and mean transit times (MTT) of the lesions with those of the contralateral normal side calculated on PWI. The serial changes of rCBV, rCBF, and MTT ratio were also evaluated. RESULTS: Acute infarction in the first and second medial gyrus of lesion hemisphere was found by qualitative evaluation of DWI and ADC map images. On the serial evaluation of SWI, the cortical veins of cat brain with infarction were obscured at 2 h and then re-appeared at 1 day. The hemorrhage transformation and prominent hypointense veins were seen at 4 days on SWI. The quantitative evaluation revealed increased MTT ratios and decreased rCBV and rCBF ratios on PWIs in the acute infarction of cat brain. CONCLUSION: The prominent hypointense veins on SWI were seen in the half of the acute infarction at 4 days. The prominent hypointense veins on SWI may have good agreement with the increased MTT ratio.