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1.
Stroke ; 48(1): 187-194, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27879448

RESUMO

BACKGROUND AND PURPOSE: We sought to compare the effect of chronic treatment with commonly tolerated doses of Fasudil, a specific RhoA kinase (ROCK) inhibitor, and simvastatin (with pleiotropic effects including ROCK inhibition) on cerebral cavernous malformation (CCM) genesis and maturation in 2 models that recapitulate the human disease. METHODS: Two heterozygous murine models, Ccm1+/-Msh2-/- and Ccm2+/-Trp53-/-, were treated from weaning to 4 to 5 months of age with Fasudil (100 mg/kg per day), simvastatin (40 mg/kg per day) or with placebo. Mouse brains were blindly assessed for CCM lesion burden, nonheme iron deposition (as a quantitative measure of chronic lesional hemorrhage), and ROCK activity. RESULTS: Fasudil, but not simvastatin, significantly decreased mature CCM lesion burden in Ccm1+/-Msh2-/- mice, and in meta-analysis of both models combined, when compared with mice receiving placebo. Fasudil and simvastatin both significantly decreased the integrated iron density per mature lesion area in Ccm1+/-Msh2-/- mice, and in both models combined, compared with mice given placebo. ROCK activity in mature lesions of Ccm1+/-Msh2-/- mice was similar with both treatments. Fasudil, but not simvastatin, improved survival in Ccm1+/-Msh2-/- mice. Fasudil and simvastatin treatment did not affect survival or lesion development significantly in Ccm2+/-Trp53-/- mice alone, and Fasudil benefit seemed limited to males. CONCLUSIONS: ROCK inhibitor Fasudil was more efficacious than simvastatin in improving survival and blunting the development of mature CCM lesions. Both drugs significantly decreased chronic hemorrhage in CCM lesions. These findings justify the development of ROCK inhibitors and the clinical testing of commonly used statin agents in CCM.


Assuntos
1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , Neoplasias Encefálicas/tratamento farmacológico , Modelos Animais de Doenças , Hemangioma Cavernoso do Sistema Nervoso Central/tratamento farmacológico , Sinvastatina/uso terapêutico , Quinases Associadas a rho/antagonistas & inibidores , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/farmacologia , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/uso terapêutico , Animais , Neoplasias Encefálicas/patologia , Feminino , Hemangioma Cavernoso do Sistema Nervoso Central/patologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Masculino , Camundongos , Camundongos Transgênicos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Sinvastatina/farmacologia
2.
J Neurosci Methods ; 271: 14-24, 2016 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-27345427

RESUMO

BACKGROUND: Cerebral cavernous malformations (CCMs) are hemorrhagic brain lesions, where murine models allow major mechanistic discoveries, ushering genetic manipulations and preclinical assessment of therapies. Histology for lesion counting and morphometry is essential yet tedious and time consuming. We herein describe the application and validations of X-ray micro-computed tomography (micro-CT), a non-destructive technique allowing three-dimensional CCM lesion count and volumetric measurements, in transgenic murine brains. NEW METHOD: We hereby describe a new contrast soaking technique not previously applied to murine models of CCM disease. Volumetric segmentation and image processing paradigm allowed for histologic correlations and quantitative validations not previously reported with the micro-CT technique in brain vascular disease. RESULTS: Twenty-two hyper-dense areas on micro-CT images, identified as CCM lesions, were matched by histology. The inter-rater reliability analysis showed strong consistency in the CCM lesion identification and staging (K=0.89, p<0.0001) between the two techniques. Micro-CT revealed a 29% greater CCM lesion detection efficiency, and 80% improved time efficiency. COMPARISON WITH EXISTING METHOD: Serial integrated lesional area by histology showed a strong positive correlation with micro-CT estimated volume (r(2)=0.84, p<0.0001). CONCLUSIONS: Micro-CT allows high throughput assessment of lesion count and volume in pre-clinical murine models of CCM. This approach complements histology with improved accuracy and efficiency, and can be applied for lesion burden assessment in other brain diseases.


Assuntos
Encéfalo/diagnóstico por imagem , Modelos Animais de Doenças , Hemangioma Cavernoso do Sistema Nervoso Central/diagnóstico por imagem , Microtomografia por Raio-X/métodos , Animais , Proteínas Reguladoras de Apoptose , Meios de Contraste , Feminino , Técnicas Histológicas , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Iodo , Masculino , Camundongos , Camundongos Transgênicos , Variações Dependentes do Observador , Tamanho do Órgão , Reprodutibilidade dos Testes , Fatores de Tempo , Quinases Associadas a rho/genética , Quinases Associadas a rho/metabolismo
3.
J Neuroimmune Pharmacol ; 11(2): 369-77, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27086141

RESUMO

Cerebral cavernous malformations (CCMs) are relatively common vascular malformations, characterized by increased Rho kinase (ROCK) activity, vascular hyper-permeability and the presence of blood degradation products including non-heme iron. Previous studies revealed robust inflammatory cell infiltration, selective synthesis of IgG, in situ antigen driven B-cell clonal expansion, and deposition of immune complexes and complement proteins within CCM lesions. We aimed to evaluate the impact of suppressing the immune response on the formation and maturation of CCM lesions, as well as lesional iron deposition and ROCK activity. Two murine models of heterozygous Ccm3 (Pdcd10), which spontaneously develop CCM lesions with severe and milder phenotypes, were either untreated or received anti-mouse BR3 to deplete B cells. Brains from anti-mouse BR3-treated mice exhibited significantly fewer mature CCM lesions and smaller lesions compared to untreated mice. B cell depletion halted the progression of lesions into mature stage 2 lesions but did not prevent their genesis. Non-heme iron deposition and ROCK activity was decreased in lesions of B cell depleted mice. This represents the first report of the therapeutic benefit of B-cell depletion in the development and progression of CCMs, and provides a proof of principle that B cells play a critical role in CCM lesion genesis and maturation. These findings add biologics to the list of potential therapeutic agents for CCM disease. Future studies would characterize the putative antigenic trigger and further define the mechanism of immune response in the lesions.


Assuntos
Linfócitos B/imunologia , Neoplasias do Sistema Nervoso Central/imunologia , Neoplasias do Sistema Nervoso Central/prevenção & controle , Modelos Animais de Doenças , Hemangioma Cavernoso do Sistema Nervoso Central/imunologia , Hemangioma Cavernoso do Sistema Nervoso Central/prevenção & controle , Animais , Neoplasias do Sistema Nervoso Central/patologia , Feminino , Hemangioma Cavernoso do Sistema Nervoso Central/patologia , Masculino , Camundongos , Camundongos Transgênicos
4.
Genet Med ; 17(3): 188-196, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25122144

RESUMO

PURPOSE: The phenotypic manifestations of cerebral cavernous malformation disease caused by rare PDCD10 mutations have not been systematically examined, and a mechanistic link to Rho kinase-mediated hyperpermeability, a potential therapeutic target, has not been established. METHODS: We analyzed PDCD10 small interfering RNA-treated endothelial cells for stress fibers, Rho kinase activity, and permeability. Rho kinase activity was assessed in cerebral cavernous malformation lesions. Brain permeability and cerebral cavernous malformation lesion burden were quantified, and clinical manifestations were assessed in prospectively enrolled subjects with PDCD10 mutations. RESULTS: We determined that PDCD10 protein suppresses endothelial stress fibers, Rho kinase activity, and permeability in vitro. Pdcd10 heterozygous mice have greater lesion burden than other Ccm genotypes. We demonstrated robust Rho kinase activity in murine and human cerebral cavernous malformation vasculature and increased brain vascular permeability in humans with PDCD10 mutation. Clinical phenotype is exceptionally aggressive compared with the more common KRIT1 and CCM2 familial and sporadic cerebral cavernous malformation, with greater lesion burden and more frequent hemorrhages earlier in life. We first report other phenotypic features, including scoliosis, cognitive disability, and skin lesions, unrelated to lesion burden or bleeding. CONCLUSION: These findings define a unique cerebral cavernous malformation disease with exceptional aggressiveness, and they inform preclinical therapeutic testing, clinical counseling, and the design of trials.Genet Med 17 3, 188-196.


Assuntos
Proteínas Reguladoras de Apoptose/genética , Neoplasias do Sistema Nervoso Central/patologia , Hemangioma Cavernoso do Sistema Nervoso Central/patologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas de Membrana/genética , Mutação , Proteínas Proto-Oncogênicas/genética , Quinases Associadas a rho/metabolismo , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/farmacologia , Adolescente , Adulto , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Proteínas de Transporte/genética , Células Cultivadas , Neoplasias do Sistema Nervoso Central/enzimologia , Neoplasias do Sistema Nervoso Central/genética , Criança , Pré-Escolar , Modelos Animais de Doenças , Hemangioma Cavernoso do Sistema Nervoso Central/enzimologia , Hemangioma Cavernoso do Sistema Nervoso Central/genética , Células Endoteliais da Veia Umbilical Humana , Humanos , Lactente , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Queratina-1/genética , Proteínas de Membrana/metabolismo , Camundongos , Pessoa de Meia-Idade , Estudos Prospectivos , Proteínas Proto-Oncogênicas/metabolismo , Fibras de Estresse/efeitos dos fármacos , Fibras de Estresse/metabolismo , Adulto Jovem , Quinases Associadas a rho/antagonistas & inibidores
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