Abstract
(1) Background: Canine distemper virus (CDV)-induced demyelinating leukoencephalitis (CDV-DL) in dogs and Theiler’s murine encephalomyelitis (TME) virus (TMEV)-induced demyelinating leukomyelitis (TMEV-DL) are virus-induced demyelinating conditions mimicking Multiple Sclerosis (MS). Reactive oxygen species (ROS) can induce the degradation of lipids and nucleic acids to characteristic metabolites such as oxidized lipids, malondialdehyde, and 8-hydroxyguanosine. The hypothesis of this study is that ROS are key effector molecules in the pathogenesis of myelin membrane breakdown in CDV-DL and TMEV-DL. (2) Methods: ROS metabolites and antioxidative enzymes were assessed using immunofluorescence in cerebellar lesions of naturally CDV-infected dogs and spinal cord tissue of TMEV-infected mice. The transcription of selected genes involved in ROS generation and detoxification was analyzed using gene-expression microarrays in CDV-DL and TMEV-DL. (3) Results: Immunofluorescence revealed increased amounts of oxidized lipids, malondialdehyde, and 8-hydroxyguanosine in CDV-DL while TMEV-infected mice did not reveal marked changes. In contrast, microarray-analysis showed an upregulated gene expression associated with ROS generation in both diseases. (4) Conclusion: In summary, the present study demonstrates a similar upregulation of gene-expression of ROS generation in CDV-DL and TMEV-DL. However, immunofluorescence revealed increased accumulation of ROS metabolites exclusively in CDV-DL. These results suggest differences in the pathogenesis of demyelination in these two animal models.
Highlights
Reactive oxygen species (ROS) are chemically reactive molecules, which can cause severe damage to a vast variety of either intra- or extracellularly located macromolecules [1]
The histological presumption of demyelination in the subacute and chronic subgroups as compared to controls and acute Canine distemper virus (CDV)-DL lesions was substantiated by demonstrating a moderately decreased percentage of 2,3 -cyclic-nucleotide 3 -phosphodiesterase (CNPase)-positive oligodendrocytes as compared to the percentage of oligodendrocytes in the respective subgroups (Figure 2a)
The transcriptome analysis suggests that the NADPH oxidase system could potentially function as the main producer of ROS in both CDV-induced demyelinating leukoencephalitis (CDV-DL) and Theiler’s murine encephalomyelitis virus (TMEV)-DL
Summary
Reactive oxygen species (ROS) are chemically reactive molecules, which can cause severe damage to a vast variety of either intra- or extracellularly located macromolecules [1]. ROS-induced cell death may result from oxidation of important cellular components such as DNA, RNA, proteins, and lipids [5]. Different metabolites of oxidized lipids can be detected by various specific antibodies [7,8,9,10,11] One of these antibodies is a clone that was developed in apo E-deficient mice. The most commonly used markers for ROS-induced damage to DNA and RNA are 8-hydroxydeoxyguanosine (8-OHdG) and 8-hydroxyguanosine (8-OHG), respectively [6]. These products result from an oxidation of the carbon in the 8th position of the nucleoside guanosine [6]. Formation of 8-OHdG most commonly results from free radical-induced damage to DNA [12], and increases in both 8-OHdG/8-OHG generally point to an increase in free radical occurrence [12]
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