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      Zymographic patterns of MMP-2 and MMP-9 in the CSF and cerebellum of dogs with subacute distemper leukoencephalitis

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          Distemper leukoencephalitis is a disease caused by the canine distemper virus (CDV) infection. It is a demyelinating disease affecting mainly the white matter of the cerebellum and areas adjacent to the fourth ventricle; the enzymes of the matrix metalloproteinases (MMPs) group, especially MMP-2 and MMP-9 have a key role in the myelin basic protein fragmentation and in demyelination, as well as in leukocyte traffic into the nervous milieu. To evaluate the involvement of MMPs during subacute distemper leukoencephalitis, we measured the levels of MMP-2 and MMP-9 by zymography in the cerebrospinal fluid (CSF) and in the cerebellum of 14 dogs naturally infected with CDV and 10 uninfected dogs. The infected dogs presented high levels of pro-MMP-2 in the CSF and elevated levels of pro-MMP-2 and pro-MMP-9 in the cerebellar tissue. Active MMP-2 was detected in the CSF of some infected dogs. As active MMP-2 and MMP-9 are required for cellular migration across the blood–brain barrier and any interference between MMPs and their inhibitors may result in an amplification of demyelination, this study gives additional support to the involvement of MMPs during subacute distemper leukoencephalitis and suggests that MMP-2 and MMP-9 may take part in the brain inflammatory changes of this disease.

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          Most cited references 24

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          Brain Endothelial Cell-Cell Junctions: How to “Open” the Blood Brain Barrier

          The blood-brain barrier (BBB) is a highly specialized structural and biochemical barrier that regulates the entry of blood-borne molecules into brain, and preserves ionic homeostasis within the brain microenvironment. BBB properties are primarily determined by junctional complexes between the cerebral endothelial cells. These complexes are comprised of tight and adherens junctions. Such restrictive angioarchitecture at the BBB reduces paracellular diffusion, while minimal vesicle transport activity in brain endothelial cells limits transcellular transport. Under normal conditions, this largely prevents the extravasation of large and small solutes (unless specific transporters are present) and prevents migration of any type of blood-borne cell. However, this is changed in many pathological conditions. There, BBB disruption (“opening”) can lead to increased paracellular permeability, allowing entry of leukocytes into brain tissue, but also contributing to edema formation. In parallel, there are changes in the endothelial pinocytotic vesicular system resulting in the uptake and transfer of fluid and macromolecules into brain parenchyma. This review highlights the route and possible factors involved in BBB disruption in a variety of neuropathological disorders (e.g. CNS inflammation, Alzheimer’s disease, Parkinson’s disease, epilepsy). It also summarizes proposed signal transduction pathways that may be involved in BBB “opening”.
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            Pathogenesis and immunopathology of systemic and nervous canine distemper.

            Canine distemper is a worldwide occurring infectious disease of dogs, caused by a morbillivirus, closely related to measles and rinderpest virus. The natural host range comprises predominantly carnivores. Canine distemper virus (CDV), an enveloped, negative-sense RNA virus, infects different cell types, including epithelial, mesenchymal, neuroendocrine and hematopoietic cells of various organs and tissues. CDV infection of dogs is characterized by a systemic and/or nervous clinical course and viral persistence in selected organs including the central nervous system (CNS) and lymphoid tissue. Main manifestations include respiratory and gastrointestinal signs, immunosuppression and demyelinating leukoencephalomyelitis (DL). Impaired immune function, associated with depletion of lymphoid organs, consists of a viremia-associated loss of lymphocytes, especially of CD4+ T cells, due to lymphoid cell apoptosis in the early phase. After clearance of the virus from the peripheral blood an assumed diminished antigen presentation and altered lymphocyte maturation cause an ongoing immunosuppression despite repopulation of lymphoid organs. The early phase of DL is a sequel of a direct virus-mediated damage and infiltrating CD8+ cytotoxic T cells associated with an up-regulation of pro-inflammatory cytokines such as interleukin (IL)-6, IL-8, tumor necrosis factor (TNF)-alpha and IL-12 and a lacking response of immunomodulatory cytokines such as IL-10 and transforming growth factor (TGF)-beta. A CD4+-mediated delayed type hypersensitivity and cytotoxic CD8+ T cells contribute to myelin loss in the chronic phase. Additionally, up-regulation of interferon-gamma and IL-1 may occur in advanced lesions. Moreover, an altered balance between matrix metalloproteinases and their inhibitors seems to play a pivotal role for the pathogenesis of DL. Summarized, DL represents a biphasic disease process consisting of an initial direct virus-mediated process and immune-mediated plaque progression. Immunosuppression is due to early virus-mediated lymphocytolysis followed by still poorly understood mechanisms affecting antigen presentation and lymphocyte maturation.
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              Quantitative zymography: detection of picogram quantities of gelatinases.

              Zymography is an electrophoretic technique used to identify proteolytic activity in enzymes separated in polyacrylamide gels under nonreducing conditions. It has been used extensively in the qualitative evaluation of proteases present in tumors and cell culture conditioned media. Using commercially available precast gels and a modern image analysis system, we have evaluated zymography as a quantitative technique. The degree of digestion of gelatin within the zymogram by purified gelatinase A, a matrix metalloprotease, is directly proportional to the amount of enzyme loaded over a 10- to 20-fold range. With an overnight (18 h) digestion period, the linear range of this assay extended from 10 to 120 pg of enzyme. The initial rate of digestion is proportional to the enzyme loading and varying the incubation time results in a shift in the linear range of the assay. Active and latent forms of gelatinase A show the same degree of digestion in this assay system. These results justify the use of zymography in the quantitative assessment of gelatinase activity as well as demonstrate its usefulness as a qualitative technique for the analysis of gelatinase species present.

                Author and article information

                Vet Immunol Immunopathol
                Vet. Immunol. Immunopathol
                Veterinary Immunology and Immunopathology
                Elsevier B.V.
                11 April 2013
                15 July 2013
                11 April 2013
                : 154
                : 1
                : 68-74
                [a ]Department of Animal Clinics, Surgery and Reproduction, College of Veterinary Medicine, UNESP – Univ. Estadual Paulista, Araçatuba, São Paulo, Brazil
                [b ]Department of Production and Animal Health, College of Veterinary Medicine, UNESP – Univ. Estadual Paulista, Araçatuba, São Paulo, Brazil
                Author notes
                [* ]Corresponding author at: Departamento de Clínica, Cirurgia e Reprodução Animal, Faculdade de Medicina Veterinária, Universidade Estadual Paulista “Júlio de Mesquita Filho” (UNESP), Rua Clóvis Pestana, 793, Araçatuba, SP, CEP 16050-680, Brazil. Tel.: +55 18 3636 1420; fax: +55 18 3636 1401. giselem@ di.melo@
                Copyright © 2013 Elsevier B.V. All rights reserved.

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