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In vitro studies on glial cell changes in canine distemper virus (CDV) infection could be useful for the understanding of the pathogenesis of demyelination in vivo in this disease.

Five Chow-Chow dogs from three different litters had generalized body tremors since birth. Histologically a severe myelin deficiency was found in the central nervous system. The peripheral nerves were normally myelinated. Electron microscopically abnormally thin myelin sheaths and completely naked nerve fibers were found. There were many astrocytes in the myelin deficient areas as well as cells with the characteristic features of oligodendrocytes but also containing fibrils. The present cases are compared to other dysmyelinating diseases and possible pathogenetic mechanisms are discussed.

Two young zebra siblings from consecutive pregnancies suffered from neurological disease, characterized by ventral deviation of the neck and tetraparesis which progressed to tetraplegia within a few weeks. On histological examination widespread neuronal degeneration was observed in the ventral horns of the spinal cord and in the lower brain stem. Ultrastructurally the neuronal degeneration was characterized by accumulation of neurofibrillary material resembling neurofilaments. The findings are compared to other diseases with neurofibrillary accumulation in man and animals.

The initial demyelinating lesions in canine distemper virus (CDV) infection develop during a period of severe immunosuppression in the absence of inflammation. In vitro and in vivo studies suggest that early demyelination is due to directly virus-induced oligodendroglial changes. In the present spatiotemporal study in experimentally CDV-infected dogs we observed diffuse up-regulation of T cells throughout the central nervous system (CNS) and T cell invasion in early demyelinating lesions. Invasion of T cells in the CNS occurred despite severe immunosuppression and without any perivascular cuffing. However, the major fraction of invading T cells correlated with sites of viral replication and coincided with the demonstration of an early immune response against the nucleocapsid protein of CDV. Activation of microglial cells was thought to have elicited the migration of T cells to the CNS by secretion of chemokines: marked IL-8 activity was found in the CSF of dogs with acute lesions. In areas of early demyelination, large numbers of CD3+cells accumulated in the tissue in the absence of any morphological sign of inflammation. Whether the T cells at lesion sites contribute to the development of acute demyelination remains uncertain at this stage. Antiviral cytotoxicity was not apparent since viral clearance in demyelinating lesions is only effective when B cells and concurring antiviral antibody production appeared in the subacute and chronic inflammatory stage of the disease. CD3+cells appear to persist for several weeks after infection since they were also found in recovered dogs that did not develop demyelination. Accumulation of immune cells, including a significant proportion of resting T cells (CD45RA+) in the CNS in the early stages of the disease may facilitate the later development of the intrathecal immune response and associated immunopathological complications.

Canine distemper virus (CDV) causes a multifocal demyelinating disease in dogs. The mechanism of acute demyelination in distemper is still poorly understood. The initial demyelinating lesion in distemper is directly virus induced, since there is a clear correlation between the occurrence of demyelination and CDV replication in the cells of the white matter. Yet, there is little evidence for oligodendroglial infection. Changes of these cells have been reported in vitro and in vivo. The in vitro studies showed that – in contrast to other cells such as astrocytes and macrophages – oligodendrocytes hardly express CDV protein. However, we could show that these cells underwent a restricted infection with transcription of CDV RNA and that this phenomenon correlated with down-regulation of myelin gene transcription. The extension of these in vitro findings in vivo was obscured by the lack of reliable oligodendrocyte labelling techniques in canine brain tissue sections. In this study we combined immunohistochemistry with in situ hybridization to examine oligodendrocytes in demyelinating lesions and to investigate the question of oligodendrocyte infection in vivo. We could demonstrate that CDV infection leads to massive down-regulation of myelin gene expression in demyelinating lesions and that this effect correlates in part with a restricted infection of oligodendrocytes.

Canine distemper is characterized mainly by respiratory, enteric, and nervous symptoms. Infection of the central nervous system results in demyelination, to which inflammation has been shown to contribute significantly. It has been proposed that macrophages play a major role as effector cells in this process. We report that cultured dog brain cells contain a population of macrophages capable of producing reactive oxygen species as measured by luminol-dependent chemiluminescence. In cultures infected with canine distemper virus, a burst of reactive oxygen is triggered by antiviral antibody. This response depends on the presence of viral antigens on the surfaces of infected cells and is mediated by the interaction of antigen-bound antibody with Fc receptors on the macrophages. Since there is no evidence in vitro or in vivo that oligodendrocytes, the cells forming myelin, are infected, our observation supports the hypothesis that "innocent bystander killing" is important in demyelination caused by canine distemper virus. Reactive oxygen species released from macrophages may contribute to destruction of myelin.

Background: Mivazerol (MIV) is anα2‐adrenoceptor agonist designed to prevent adverse cardiac outcome in perioperative patients. The present study was undertaken to determine whether the hyperdynamic state observed at emergence from halothane (HAL) anesthesia in rats could be modulated by MIV and to explore the mode of action of MIV under such conditions.

Canine distemper virus (CDV) induces oligodendroglial degeneration and multifocal demyelination in the central nervous system. The mechanism of oligodendrocyte degeneration is not understood but it has been shown that there is a restricted infection of these cells without viral protein production. Using a combination of immunocytochemistry and in situ hybridization we were able to demonstrate the transcription of the entire virus genome throughout the whole observation period (7–35 days after infection) in oligodendrocytes in CDV-infected brain cell cultures. Therefore, the lack of viral protein and particle production can not be explained on the basis of a defective viral transcription. The present study also shows that a restricted infection of oligodendrocytes with CDV down-regulates the transcription of the major myelin genes coding for proteolipid protein, myelin basic protein (MBP) and myelin-associated glycoprotein in a very similar way. Using densitometry for in situ hybridization products of MBP in populations of normal and infected oligodendrocytes, an effect could be observed long before morphological changes were detectable. The present results strongly suggest that demyelination in distemper is induced by a restricted CDV infection of oligodendrocytes which down-regulates the expression of a variety of cellular genes, in particular those coding for myelin proteins. Consequently, the infected cells are no longer able to synthesize all the membrane compounds which are necessary for maintaining their structural integrity.

Three female cats, littermates born from clinically normal parents, were examined at 8 to 10 weeks of age because of a slowly progressive posterior ataxia. Another cat from a previous litter from the same parents suffered from similar neurological symptoms. Histopathological examination of the nervous tissues of these animals revealed degeneration of axons and myelinopathy in a distal distribution pattern. Both peripheral nerves and central nervous system were involved. The central nervous system lesions were most prominent in the lateral pyramidal tracts of the spinal cord, the fasciculi gracili of the dorsal column in the cervical spinal cord and the cerebellar vermian white matter. In the PNS numerous degenerating nerve fibers were found in the sciatic nerves but not in the spinal nerve roots. Our findings show that these cats were suffering from a hereditary multisystem degeneration with a distribution pattern of the lesions suggestive of a distal axonopathy.

To study the pathomechanism of demyelination in canine distemper (CD), dog brain cell cultures were infected with virulent A75/17-CD virus (CDV) and examined ultrastructurally. Special attention was paid to the oligodendrocytes, which were specifically immunolabelled. In addition, cerebroside sulfotransferase (CST), an enzyme specific for oligodendrocyte activity was assayed during the course of the infection. Infection and maturation as well as CDV-induced changes were found in astrocytes and brain macrophages. Infection of oligodendrocytes was rarely seen, although CST activity of the culture markedly decreased and vacuolar degeneration of these cells occurred, resulting in their complete disappearance. We concluded that the degeneration of oligodendrocytes and demyelination is not due to direct virus-oligodendrocyte interaction, but due to CDV-induced events in other glial cells.

The mechanism of inflammatory demyelination in canine distemper encephalitis (CDE) is uncertain but macrophages are thought to play an important effector role in this lesion. Serum and cerebrospinal fluid (CSF), containing anti-canine distemper virus and anti-myelin antibodies from dogs with CDE were tested for their ability to generate reactive oxygen species (ROS) in macrophages in primary dog brain cell cultures using a chemiluminescence (CL) assay. The majority of serum samples and several CSF samples from animals with inflammatory demyelination elicited a CL signal in infected dog brain cell cultures. In contrast, none of these samples induced a positive response in uninfected cultures which contained large numbers of myelin antigen-presenting cells, although defined anti-myelin antibodies lead to a marked secretion of ROS in this system. It was concluded that antiviral antibody-induced secretion of ROS, known to be highly toxic for brain tissue, may play an important role in white matter damage in inflammatory lesions supporting a previous hypothesis of bystander demyelination in CDE. No evidence was found for a similar antibody-dependent cellular cytotoxicity-like mechanism mediated by anti-myelin antibodies in CDE, which does not support the concept of autoimmunity in this disease.