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1.
J Neurosci ; 31(25): 9323-31, 2011 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-21697382

RESUMO

Immunization against amyloid-ß (Aß) can reduce amyloid accumulation in vivo and is considered a potential therapeutic approach for Alzheimer's disease. However, it has been associated with meningoencephalitis thought to be mediated by inflammatory T-cells. With the aim of producing an immunogenic vaccine without this side effect, we designed CAD106 comprising Aß1-6 coupled to the virus-like particle Qß. Immunization with this vaccine did not activate Aß-specific T-cells. In APP transgenic mice, CAD106 induced efficacious Aß antibody titers of different IgG subclasses mainly recognizing the Aß3-6 epitope. CAD106 reduced brain amyloid accumulation in two APP transgenic mouse lines. Plaque number was a more sensitive readout than plaque area, followed by Aß42 and Aß40 levels. Studies with very strong overall amyloid reduction showed an increase in vascular Aß, which atypically was nonfibrillar. The efficacy of Aß immunotherapy depended on the Aß levels and thus differed between animal models, brain regions, and stage of amyloid deposition. Therefore, animal studies may not quantitatively predict the effect in human Alzheimer's disease. Our studies provided no evidence for increased microhemorrhages or inflammatory reactions in amyloid-containing brain. In rhesus monkeys, CAD106 induced a similar antibody response as in mice. The antibodies stained amyloid deposits on tissue sections of mouse and human brain but did not label cellular structures containing APP. They reacted with Aß monomers and oligomers and blocked Aß toxicity in cell culture. We conclude that CAD106 immunization is suited to interfere with Aß aggregation and its downstream detrimental effects.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/uso terapêutico , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/imunologia , Imunoterapia/métodos , Doença de Alzheimer/imunologia , Peptídeos beta-Amiloides/efeitos adversos , Animais , Células Cultivadas , Camundongos , Camundongos Transgênicos , Resultado do Tratamento
2.
ACS Chem Neurosci ; 13(8): 1296-1314, 2022 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-35357812

RESUMO

Neurodegenerative proteinopathies are characterized by the intracellular formation of insoluble and toxic protein aggregates in the brain that are closely linked to disease progression. In Alzheimer's disease and in rare tauopathies, aggregation of the microtubule-associated tau protein leads to the formation of neurofibrillary tangles (NFT). In Parkinson's disease (PD) and other α-synucleinopathies, intracellular Lewy bodies containing aggregates of α-synuclein constitute the pathological hallmark. Inhibition of the glycoside hydrolase O-GlcNAcase (OGA) prevents the removal of O-linked N-acetyl-d-glucosamine (O-GlcNAc) moieties from intracellular proteins and has emerged as an attractive therapeutic approach to prevent the formation of tau pathology. Like tau, α-synuclein is known to be modified with O-GlcNAc moieties and in vitro these have been shown to prevent its aggregation and toxicity. Here, we report the preclinical discovery and development of a novel small molecule OGA inhibitor, ASN90. Consistent with the substantial exposure of the drug and demonstrating target engagement in the brain, the clinical OGA inhibitor ASN90 promoted the O-GlcNAcylation of tau and α-synuclein in brains of transgenic mice after daily oral dosing. Across human tauopathy mouse models, oral administration of ASN90 prevented the development of tau pathology (NFT formation), functional deficits in motor behavior and breathing, and increased survival. In addition, ASN90 slowed the progression of motor impairment and reduced astrogliosis in a frequently utilized α-synuclein-dependent preclinical rodent model of PD. These findings provide a strong rationale for the development of OGA inhibitors as disease-modifying agents in both tauopathies and α-synucleinopathies. Since tau and α-synuclein pathologies frequently co-exist in neurodegenerative diseases, OGA inhibitors represent unique, multimodal drug candidates for further clinical development.


Assuntos
Doença de Parkinson , Sinucleinopatias , Tauopatias , Animais , Camundongos , Doença de Parkinson/metabolismo , Preparações Farmacêuticas , Tauopatias/metabolismo , alfa-Sinucleína/metabolismo , beta-N-Acetil-Hexosaminidases , Proteínas tau/metabolismo
3.
Mov Disord ; 26(9): 1593-604, 2011 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-21618611

RESUMO

Parkinson's disease is associated with mutations in the glucocerebrosidase gene, which result in the enzyme deficiency causing Gaucher disease, the most common lysosomal storage disorder. We have performed an exhaustive literature search and found that additional lysosomal storage disorders might be associated with Parkinson's disease, based on case reports, the appearance of pathological features such as α-synuclein deposits in the brain, and substantia nigra pathology. Our findings suggest that the search for biochemical and cellular pathways that link Parkinson's disease with lysosomal storage disorders should not be limited exclusively to changes that occur in Gaucher disease, such as changes in glucocerebrosidase activity or in glucosylceramide levels, but rather include changes that might be common to a wide variety of lysosomal storage disorders. Moreover, we propose that additional genetic, epidemiological, and clinical studies should be performed to check the precise incidence of mutations in genes encoding lysosomal proteins in patients displaying Parkinson's symptoms.


Assuntos
Doença de Gaucher/epidemiologia , Doença de Gaucher/genética , Glucosilceramidase/genética , Doenças por Armazenamento dos Lisossomos/genética , Doença de Parkinson/genética , Doença de Gaucher/etiologia , Glucosilceramidase/deficiência , Humanos , Doenças por Armazenamento dos Lisossomos/epidemiologia
4.
Brain Res ; 1185: 293-300, 2007 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-18028883

RESUMO

In ischemic stroke, cytosolic death pathways are activated in injured neurons destined to die. Neuronal injury is modulated by cell surface receptors, among which the tumor necrosis factor receptor family obtained particular interest. Cytokine response modifier A (CrmA) is a cowpox virus-derived caspase inhibitor, which interferes with the so-called death-inducing signaling complex, thereby blocking receptor-mediated apoptosis. To elucidate CrmA's therapeutic potential in ischemic stroke, we characterized a transgenic mouse line expressing CrmA under a Thy1 promoter, which we subjected to intraluminal middle cerebral artery (MCA) occlusion. Using in situ hybridization histochemistry and Western blots, we show that the crmA gene integrated into chromosome 8 of the mouse genome, CrmA being expressed in the cerebral cortex and striatum. Although robustly expressed, transgenic CrmA did not influence ischemic injury, both when relatively long-lasting (90 min) and mild (30 min) MCA occlusions were imposed. As such, neither infarct volume, brain swelling or neurological deficits following 90-min ischemia, nor disseminated neuronal injury or caspase-3 activation following 30-min ischemia were influenced by CrmA. Our data argue against a therapeutic effect of CrmA in ischemic stroke.


Assuntos
Regulação da Expressão Gênica/fisiologia , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/prevenção & controle , Serpinas/metabolismo , Proteínas Virais/metabolismo , Animais , Animais Recém-Nascidos , Comportamento Animal , Encéfalo/metabolismo , Encéfalo/patologia , Edema Encefálico/etiologia , Edema Encefálico/patologia , Caspase 3/metabolismo , Caspase 8/metabolismo , Sobrevivência Celular , Modelos Animais de Doenças , Ativação Enzimática , Regulação da Expressão Gênica/genética , Técnicas In Vitro , Infarto da Artéria Cerebral Média/genética , Infarto da Artéria Cerebral Média/patologia , Camundongos , Camundongos Transgênicos , Serpinas/genética , Antígenos Thy-1/metabolismo , Proteínas Virais/genética
5.
J Cereb Blood Flow Metab ; 22(3): 308-17, 2002 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-11891436

RESUMO

Inflammatory processes have been implicated in the pathogenesis of brain damage after stroke. In rodent stroke models, focal ischemia induces several proinflammatory chemokines, including monocyte chemoattractant protein-1 (MCP-1). The individual contribution to ischemic tissue damage, however, is largely unknown. To address this question, the authors subjected MCP-1-deficient mice (MCP-1-/-) to permanent middle cerebral artery occlusion (MCAO). Measurement of basal blood pressure, cerebral blood flow, and blood volume revealed no differences between wild-type (wt) and MCP-1-/- mice. MCAO led to similar cerebral perfusion deficits in wt and MCP-1-/- mice, excluding differences in the MCA supply territory and collaterals. However, compared with wt mice, the mean infarct volume was 29% smaller in MCP-1-/- mice 24 hours after MCAO (P = 0.022). Immunostaining showed a reduction of phagocytic macrophage accumulation within infarcts and the infarct border in MCP-1-/- mice 2 weeks after MCAO. At the same time point, the authors found an attenuation of astrocytic hypertrophy in the infarct border and thalamus in MCP-1-/- mice. However, these effects on macrophages and astrocytes in MCP-1-/- mice occurred too late to suggest a protective role in acute infarct growth. Of note: at 6 hours after MCAO, MCP-1-/- mice produced significantly less interleukin-1beta in ischemic tissue; this might be related to tissue protection. The results of this study indicate that inhibition of MCP-1 signaling could be a new acute treatment approach to limit infarct size after stroke.


Assuntos
Infarto Cerebral/patologia , Circulação Cerebrovascular/fisiologia , Quimiocina CCL2/deficiência , Acidente Vascular Cerebral/prevenção & controle , Animais , Pressão Sanguínea , Quimiocina CCL2/genética , Quimiocina CCL2/fisiologia , Cruzamentos Genéticos , Imageamento por Ressonância Magnética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Artéria Cerebral Média , Valores de Referência , Acidente Vascular Cerebral/patologia , Tálamo/patologia
6.
J Cereb Blood Flow Metab ; 23(2): 154-65, 2003 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-12571447

RESUMO

Nogo-A is a myelin-associated neurite outgrowth inhibitory protein limiting recovery and plasticity after central nervous system injury. In this study, a purified monoclonal anti-Nogo-A antibody (7B12) was evaluated in two rat stroke models with a time-to-treatment of 24 hours after injury. After photothrombotic cortical injury (PCI) and intraventricular infusion of a control mouse immunoglobulin G for 2 weeks, long-term contralateral forepaw function was reduced to about 55% of prelesion performance until the latest time point investigated (9 weeks). Forepaw function was significantly better in the 7B12-treated group 6 to 9 weeks after PCI, and reached about 70% of prelesion levels. Cortical infarcts were also produced in spontaneously hypertensive rats (SHR) by permanent middle cerebral artery occlusion (MCAO). In the control group, forepaw function remained between 40% and 50% of prelesion levels 4 to 12 weeks after MCAO. In contrast, 7B12-treated groups showed significant improvement between 4 and 7 weeks after MCAO from around 40% of prelesion levels at week 4 to about 60% to 70% at 7 to 12 weeks after MCAO. Treatment in both models was efficacious without influencing infarct volume or brain atrophy. Neuroanatomically in the spinal cord, a significant increase of midline crossing corticospinal fibers originating in the unlesioned sensorimotor cortex was found in 7B12-treated groups, reaching 2.3 +/- 1.5% after PCI (control group: 1.1 +/- 0.5%) and 4.5 +/- 2.2% after MCAO in SHR rats (control group: 1.8 +/- 0.8%). Behavioral outcome and the presence of midline crossing fibers in the cervical spinal cord correlated significantly, suggesting a possible contribution of the crossing fibers for forepaw function after PCI and MCAO. The results suggest that specific anti-Nogo-A antibodies bear potential as a new rehabilitative treatment approach for ischemic stroke with a prolonged time-to-treatment window.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Comportamento Animal/efeitos dos fármacos , Hipertensão/complicações , Proteínas da Mielina/imunologia , Acidente Vascular Cerebral/fisiopatologia , Acidente Vascular Cerebral/psicologia , Animais , Anticorpos Monoclonais/farmacocinética , Arteriopatias Oclusivas/complicações , Encéfalo/metabolismo , Artérias Cerebrais , Infarto Cerebral/etiologia , Infarto Cerebral/patologia , Infarto Cerebral/psicologia , Esquema de Medicação , Injeções Intraventriculares , Masculino , Plasticidade Neuronal/efeitos dos fármacos , Proteínas Nogo , Tratos Piramidais/patologia , Tratos Piramidais/fisiopatologia , Ratos , Ratos Endogâmicos F344 , Ratos Endogâmicos SHR , Acidente Vascular Cerebral/etiologia , Distribuição Tecidual
7.
Neurol Res ; 24(8): 822-4, 2002 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-12500707

RESUMO

To determine if MRI can predict intracerebral plasminogen activation after focal cerebral ischemia (FCI), ischemic regions detected by MRI after 48 h of permanent FCI in rats were compared with areas of increased plasminogen activation, defined by histological zymography after 72 h of ischemia. The overlap between areas of MRI alterations (64.5% +/- 5.4% of total ischemic hemisphere) and areas with increased plasminogen activation (62.2% +/- 3.6%) was significant for the hemisphere (p < 0.001), the cortex (p < 0.05), and the basal ganglia (p < 0.05). Thus, MRI can predict the extent of increased plasminogen activation, which may play a role in BBB-mediated post-ischemic brain edema and secondary hemorrhage.


Assuntos
Isquemia Encefálica/metabolismo , Hemorragia Cerebral/metabolismo , Infarto Cerebral/metabolismo , Imageamento por Ressonância Magnética , Plasminogênio/metabolismo , Telencéfalo/metabolismo , Regulação para Cima/fisiologia , Animais , Edema Encefálico/metabolismo , Edema Encefálico/patologia , Edema Encefálico/fisiopatologia , Isquemia Encefálica/patologia , Isquemia Encefálica/fisiopatologia , Hemorragia Cerebral/patologia , Hemorragia Cerebral/fisiopatologia , Infarto Cerebral/patologia , Infarto Cerebral/fisiopatologia , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Masculino , Metaloproteinases da Matriz/metabolismo , Ativadores de Plasminogênio/metabolismo , Valor Preditivo dos Testes , Ratos , Ratos Endogâmicos F344 , Estatística como Assunto , Telencéfalo/patologia , Telencéfalo/fisiopatologia
8.
PLoS One ; 6(6): e21519, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21738687

RESUMO

Genetic variants of Leucine-Rich Repeat Kinase 2 (LRRK2) are associated with a significantly enhanced risk for Parkinson disease, the second most common human neurodegenerative disorder. Despite major efforts, our understanding of LRRK2 biological function and regulation remains rudimentary. In the present study we analyze LRRK2 mRNA and protein expression in sub-populations of human peripheral blood mononuclear cells (PBMCs). LRRK2 mRNA and protein was found in circulating CD19(+) B cells and in CD14(+) monocytes, whereas CD4(+) and CD8(+) T cells were devoid of LRRK2 mRNA. Within CD14(+) cells the CD14(+)CD16(+) sub-population of monocytes exhibited high levels of LRRK2 protein, in contrast to CD14(+)CD16(-) cells. However both populations expressed LRRK2 mRNA. As CD14(+)CD16(+) cells represent a more mature subset of monocytes, we monitored LRRK2 expression after in vitro treatment with various stress factors known to induce monocyte activation. We found that IFN-γ in particular robustly increased LRRK2 mRNA and protein levels in monocytes concomitant with a shift of CD14(+)CD16(-) cells towards CD14(+)CD16(+) cells. Interestingly, the recently described LRRK2 inhibitor IN-1 attenuated this shift towards CD14(+)CD16(+) after IFN-γ stimulation. Based on these findings we speculate that LRRK2 might have a role in monocyte maturation. Our results provide further evidence for the emerging role of LRRK2 in immune cells and regulation at the transcriptional and translational level. Our data might also reflect an involvement of peripheral and brain immune cells in the disease course of PD, in line with increasing awareness of the role of the immune system in PD.


Assuntos
Leucócitos Mononucleares/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Células Cultivadas , Humanos , Interferon gama/farmacologia , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Leucócitos Mononucleares/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/genética , Receptores de IgG/metabolismo
9.
PLoS One ; 5(4): e10014, 2010 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-20368804

RESUMO

BACKGROUND: Aggregation and misfolded alpha-synuclein is thought to be central in the pathogenesis of Parkinson's disease (PD). Heat-shock proteins (HSPs) that are involved in refolding and degradation processes could lower the aggregate load of alpha-synuclein and thus be beneficial in alpha-synucleinopathies. METHODOLOGY/PRINCIPAL FINDINGS: We co-overexpressed human A53T point-mutated alpha-synuclein and human HSP70 in mice, both under the control of Thy1 regulatory sequences. Behavior read-outs showed no beneficial effect of HSP70 expression in mice. In contrast, motor coordination, grip strength and weight were even worse in the alpha-synucleinopathy model in the presence of HSP70 overexpression. Biochemical analyses revealed no differences in alpha-synuclein oligomers/aggregates, truncations and phosphorylation levels and alpha-synuclein localization was unchanged in immunostainings. CONCLUSION/SIGNIFICANCE: Overexpressing HSP70 in a mouse model of alpha-synucleinopathy did not lower the toxic load of alpha-synuclein species and had no beneficial effect on alpha-synuclein-related motor deficits.


Assuntos
Proteínas de Choque Térmico HSP70/uso terapêutico , Doença de Parkinson/terapia , alfa-Sinucleína/efeitos adversos , Animais , Peso Corporal , Modelos Animais de Doenças , Terapia Genética , Proteínas de Choque Térmico HSP70/administração & dosagem , Proteínas de Choque Térmico HSP70/genética , Força da Mão , Humanos , Camundongos , Camundongos Transgênicos , Atividade Motora , Doença de Parkinson/patologia , Mutação Puntual , Dobramento de Proteína , Multimerização Proteica , Falha de Tratamento , alfa-Sinucleína/administração & dosagem , alfa-Sinucleína/genética
10.
Brain Res ; 1243: 124-33, 2008 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-18823960

RESUMO

Genetic abnormalities in amyloid precursor protein (APP) are associated with Down's syndrome and familial Alzheimer's disease where hallmark plaques contain A beta peptides derived from APP. Both APP and its derivatives are implicated in neurodegenerative processes and may play important physiological and pathophysiological roles in synaptic function. Here, we show that young APP23 transgenic mice overexpressing human APP with the Swedish double mutation display altered novelty seeking behavior before the age of plaque onset. Using short interfering RNA (siRNA) targeted against APP, we investigate the direct contribution of APP and its derivatives to this behavioral deficit. After validating siRNAs targeting human APP in vitro, siRNAs were infused directly into the brain of APP23 mice for 2 weeks. Behavioral analysis shows that infusion of siRNA targeted against APP completely reverses increased exploratory activity in APP23 mice. Collectively, these data suggest that excessive APP and/or its derivatives, causes a hyperactive phenotype in APP23 mice when placed in a novel environment, which is fully reversible and not linked to plaque deposits.


Assuntos
Precursor de Proteína beta-Amiloide/antagonistas & inibidores , Comportamento Animal/fisiologia , Encéfalo/metabolismo , Comportamento Exploratório/fisiologia , Agitação Psicomotora/genética , RNA Interferente Pequeno/farmacologia , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Precursor de Proteína beta-Amiloide/genética , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Células CHO , Cricetinae , Cricetulus , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Meio Ambiente , Comportamento Exploratório/efeitos dos fármacos , Terapia Genética/métodos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Transgênicos , Mutação/genética , Placa Amiloide/genética , Placa Amiloide/metabolismo , Agitação Psicomotora/metabolismo , Agitação Psicomotora/fisiopatologia , Interferência de RNA/fisiologia , RNA Interferente Pequeno/uso terapêutico
11.
Mol Cell Neurosci ; 32(1-2): 161-73, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-16697217

RESUMO

Neutralizing antibodies against the neurite growth inhibitory protein Nogo-A are known to induce regeneration, enhance compensatory growth, and enhance functional recovery. In intact adult rats and monkeys or spinal cord injured adult rats, antibodies reached the entire spinal cord and brain through the CSF circulation from intraventricular or intrathecal infusion sites. In the tissue, anti-Nogo antibodies were found inside Nogo-A expressing oligodendrocytes and neurons. Intracellularly, anti-Nogo-A antibodies were colocalized with endogenous Nogo-A in large organels, some of which containing the lysosomal marker cathepsin-D. This suggests antibody-induced internalization of cell surface Nogo-A. Total Nogo-A tissue levels in spinal cord were decreased in intact adult rats following 7 days of antibody infusion. This mechanism was confirmed in vitro; cultured oligodendrocytes and neurons had lower Nogo-A contents in the presence of anti-Nogo-A antibodies. These results demonstrate that antibodies against a CNS cell surface protein reach their antigen through the CSF and can induce its downregulation.


Assuntos
Anticorpos/farmacologia , Inibidores do Crescimento/antagonistas & inibidores , Proteínas da Mielina/antagonistas & inibidores , Traumatismos da Medula Espinal/tratamento farmacológico , Medula Espinal/efeitos dos fármacos , Animais , Anticorpos/imunologia , Anticorpos/metabolismo , Células Cultivadas , Líquido Cefalorraquidiano/imunologia , Líquido Cefalorraquidiano/metabolismo , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/imunologia , Endocitose/efeitos dos fármacos , Endocitose/imunologia , Feminino , Inibidores do Crescimento/imunologia , Inibidores do Crescimento/metabolismo , Injeções Espinhais , Macaca fascicularis , Masculino , Proteínas da Mielina/imunologia , Proteínas da Mielina/metabolismo , Regeneração Nervosa/efeitos dos fármacos , Regeneração Nervosa/imunologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Proteínas Nogo , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/metabolismo , Ratos , Ratos Endogâmicos F344 , Ratos Endogâmicos Lew , Medula Espinal/citologia , Medula Espinal/metabolismo , Traumatismos da Medula Espinal/imunologia , Traumatismos da Medula Espinal/fisiopatologia , Espaço Subaracnóideo/metabolismo
12.
Ann Neurol ; 58(6): 950-3, 2005 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16315284

RESUMO

Stroke is a prevalent and devastating disorder, and no treatment is currently available to restore lost neuronal function after stroke. One unique therapy that improves recovery after stroke is neutralization of the neurite inhibitory protein Nogo-A. Here, we show, in a clinically relevant model, improved functional recovery and brain reorganization in the aged and adult rat when delayed anti-Nogo-A therapy is given after ischemic injury. These results support the efficacy of Nogo-A neutralization as treatment for ischemic stroke, even in the aged animal and after a 1-week delay, and implicate neuronal plasticity from unlesioned areas of the central nervous system as a mechanism for recovery.


Assuntos
Anticorpos Monoclonais/farmacologia , Proteínas da Mielina/antagonistas & inibidores , Recuperação de Função Fisiológica , Acidente Vascular Cerebral/fisiopatologia , Acidente Vascular Cerebral/terapia , Fatores Etários , Animais , Isquemia Encefálica/fisiopatologia , Isquemia Encefálica/terapia , Modelos Animais de Doenças , Proteínas da Mielina/imunologia , Neuritos/fisiologia , Plasticidade Neuronal , Proteínas Nogo , Ratos
13.
NMR Biomed ; 16(5): 252-6, 2003 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-14648884

RESUMO

In this study we investigated the potential of in vivo MRI detection of axonal Mn2+ transport for tracing neuronal projections originating in the sensorimotor cortex in healthy and lesioned rat brains. Special attention was given to the potential of visualizing neuronal sprouting of central nervous system across the midline. After injecting unchelated MnCl2 into the forelimb area of sensorimotor cortex of 18 healthy and 10 lesioned rats corticofugal projections could be traced through the internal capsule to the cerebral peduncle and the pyramidal decussation. Although the neuronal tract was visible as early as 6 h after MnCl2 injection, best contrast was achieved after 24-48 h. Beside the cortico-spinal tract, the cortico-thalamic fibres were also visualized by anterograde Mn2+ transport. Cortico-striatal fibres were partially masked by the very high signal near the MnCl2 injection site but could be discerned as well. Slight, diffuse signal enhancement of cortical tissue contralateral to the MnCl2 injection site in healthy rat brains suggests interhemispheric connections or passive diffusion of Mn2+. However, enhanced fibre tract contrast connecting both hemispheres was visible 16 weeks after onset of focal photothrombotic cortical injury. In conclusion our study has shown that we were able to visualize reproducibly the main descending corticofugal projections and interhemispheric connections by non-invasive MRI after localized injection of MnCl2. The appearance of interhemispheric Mn2+-enhanced fibres after photothrombotic focal injury indicates that the method may bear potential to follow non-invasively gross plastic changes of connectivity in the brain after injury.


Assuntos
Trombose Intracraniana/patologia , Cloreto de Magnésio , Imageamento por Ressonância Magnética/métodos , Córtex Motor/patologia , Vias Neurais/patologia , Córtex Somatossensorial/patologia , Animais , Estudos de Viabilidade , Trombose Intracraniana/metabolismo , Cloreto de Magnésio/administração & dosagem , Cloreto de Magnésio/farmacocinética , Masculino , Microinjeções/métodos , Córtex Motor/metabolismo , Vias Neurais/metabolismo , Ratos , Ratos Endogâmicos F344 , Córtex Somatossensorial/metabolismo , Distribuição Tecidual
14.
Expert Opin Ther Targets ; 7(1): 35-48, 2003 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-12556201

RESUMO

Monocyte chemoattractant protein-1 (MCP-1) has been implicated in many inflammatory and autoimmune diseases. The G-protein-coupled receptor CCR-2B is probably the most important MCP-1 receptor in vivo, and loss of MCP-1 effector function alone is sufficient to impair monocytic trafficking in inflammation models. MCP-1 signalling appears to be a relevant target, especially in rheumatoid arthritis (RA). In RA patients, MCP-1 is produced by synovial cells and infiltrating monocytes, plasma MCP-1 concentrations correlate with swollen joint count, and elevated serum MCP-1 concentrations were found in juvenile RA in patients with active disease. Modulation of MCP-1 signalling in experimental RA showed beneficial effects on inflammation and joint destruction. With respect to chronic neuroinflammation, a critical role for MCP-1 has been established in animal models for multiple sclerosis. In acute neuroinflammation, experimental evidence for a detrimental role of MCP-1 in stroke and excitotoxic injury has been found. Several selective small molecular weight CCR-2B antagonists and MCP-1-blocking antibodies have been described. The proof for the validity of targeting MCP-1 signalling in disease, however, has yet to be established in clinical trials.


Assuntos
Quimiocina CCL2/antagonistas & inibidores , Desenho de Fármacos , Doença de Alzheimer/tratamento farmacológico , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Antirreumáticos/farmacologia , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/fisiopatologia , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/lesões , Quimiocina CCL2/deficiência , Quimiocina CCL2/genética , Quimiocina CCL2/fisiologia , Encefalomielite Autoimune Experimental/tratamento farmacológico , Humanos , Inflamação/tratamento farmacológico , Camundongos , Camundongos Endogâmicos MRL lpr , Camundongos Knockout , Modelos Moleculares , Estrutura Molecular , Esclerose Múltipla/tratamento farmacológico , Obesidade/tratamento farmacológico , Receptores CCR2 , Receptores de Quimiocinas/antagonistas & inibidores , Receptores de Quimiocinas/deficiência , Receptores de Quimiocinas/genética , Receptores de Quimiocinas/fisiologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
15.
Metab Brain Dis ; 17(3): 131-8, 2002 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12322783

RESUMO

The present study investigated the activation of extracellular-signal-regulated kinase (ERK) and the potential role of interleukin-1 beta (IL-1beta) in the brain's response to focal brain ischemia in the permanent middle cerebral artery occlusion (pMCAO) model. Phosphorylated ERK p44 and p42 were increased time-dependently and significantly 18- and 28-fold, respectively, at 24-h post-pMCAO. Similarly, IL-1beta protein levels were significantly increased with the peak at 24 h in the lesioned core of the ischemic hemisphere compared to the contralateral side. Previous studies using various stimuli have shown ERK-dependent IL-1 induction. The results from our study suggest that this relation may also exist in vivo in ischemic brain tissue. Based on the progressive nature of IL-1 induction, we hypothetized that inhibition of interleukin-converting enzyme (ICE) could provide an extended time-window for neuroprotection. Therefore, we applied N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD x fmk), an ICE blocker 3 or 6 h after pMCAO. Reductions of infarct volume, however, were not observed. Taken together with previous results, where we showed protective activity of zVAD x fmk when given immediately after pMCAO, we conclude that the time window for zVAD x fmk is less than 3 h.


Assuntos
Isquemia Encefálica/metabolismo , Interleucina-1/antagonistas & inibidores , Interleucina-1/biossíntese , Proteínas Quinases JNK Ativadas por Mitógeno , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Clorometilcetonas de Aminoácidos/farmacologia , Animais , Isquemia Encefálica/enzimologia , Caspase 1/metabolismo , Inibidores de Caspase , Ativação Enzimática/fisiologia , Inibidores Enzimáticos/farmacologia , Ensaio de Imunoadsorção Enzimática , Immunoblotting , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Cinética , Ligadura , MAP Quinase Quinase 4 , Imageamento por Ressonância Magnética , Masculino , Artéria Cerebral Média/fisiologia , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Ratos , Ratos Endogâmicos F344 , Proteínas Quinases p38 Ativadas por Mitógeno
16.
Ann Neurol ; 51(6): 790-3, 2002 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12112090

RESUMO

We studied the impact of cerebral amyloid angiopathy on tissue plasminogen activator-induced cerebral hemorrhages in APP23 transgenic mice. Results show that the intravenous administration of tissue plasminogen activator in APP23 mice leads to an increase in cerebral amyloid angiopathy-associated microhemorrhages and can provoke parenchymal and subarachnoidal hematomas. We conclude that cerebral amyloid angiopathy is a risk factor for cerebral hemorrhage caused by tissue plasminogen activator administration in mice and stress the need for more comprehensive studies of the relation between cerebral amyloid angiopathy and tissue plasminogen activator-induced cerebral hemorrhages in elderly and Alzheimer's disease patients.


Assuntos
Angiopatia Amiloide Cerebral/fisiopatologia , Córtex Cerebral/efeitos dos fármacos , Hemorragia Cerebral/etiologia , Terapia Trombolítica/efeitos adversos , Ativador de Plasminogênio Tecidual/farmacologia , Animais , Córtex Cerebral/patologia , Contraindicações , Modelos Animais de Doenças , Fibrinolíticos/efeitos adversos , Fibrinolíticos/farmacologia , Fibrinolíticos/uso terapêutico , Humanos , Imageamento por Ressonância Magnética , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Ativador de Plasminogênio Tecidual/efeitos adversos , Ativador de Plasminogênio Tecidual/uso terapêutico
17.
Anesthesiology ; 99(1): 112-21, 2003 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12826850

RESUMO

BACKGROUND: Global cerebral ischemia is associated with delayed neuronal death. Given the role of caspases in apoptosis, caspase inhibitors may provide neuronal protection after cardiac arrest. To this end, the authors generated a transgenic rat line expressing baculovirus p35, a broad-spectrum caspase inhibitor, in central neurons. Its effects were evaluated on neuronal cell death and outcome after global cerebral ischemia. METHODS: Global cerebral ischemia was induced by cardiocirculatory arrest. After 6 min, animals were resuscitated by controlled ventilation, extrathoracic cardiac massage, epinephrine, and electrical countershocks. Neuronal death was assessed after 7 days by histologic evaluation of the hippocampal cornu ammonis 1 sector. Postischemic outcome was assessed by determination of overall survival and according to neurologic deficit scores 24 h, 3 days, and 7 days after resuscitation. RESULTS: The rate of 7-day survival after cardiac arrest for the transgenic rats (85%) was significantly higher than that for the nontransgenic controls (52%; P < 0.05). However, no differences were observed either in the number of terminal deoxynucleotidyltransferase-mediated d-uracil triphosphate-biotin nick end-labeling-positive cells or viable neurons in the cornu ammonis 1 sector or in the neurologic deficit score when comparing surviving transgenic and nontransgenic rats. These findings suggest that neuronal apoptosis after cardiac arrest is not primarily initiated by activation of caspases. CONCLUSION: Expression of baculovirus p35 can improve survival after cardiac arrest in rats, but the mode and site of action remain to be elucidated.


Assuntos
Baculoviridae/metabolismo , Reanimação Cardiopulmonar , Inibidores de Caspase , Inibidores Enzimáticos/metabolismo , Parada Cardíaca/fisiopatologia , Proteínas Virais/fisiologia , Animais , Animais Geneticamente Modificados , Northern Blotting , Southern Blotting , Western Blotting , Química Encefálica/genética , Isquemia Encefálica/patologia , Morte Celular/fisiologia , Eletrochoque , Hipocampo/patologia , Hibridização In Situ , Marcação In Situ das Extremidades Cortadas , Proteínas Inibidoras de Apoptose , Microinjeções , Doenças do Sistema Nervoso/etiologia , Doenças do Sistema Nervoso/genética , Doenças do Sistema Nervoso/patologia , Neurônios/patologia , Ratos , Ratos Wistar , Sobrevida , Proteínas Virais/biossíntese , Proteínas Virais/genética
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