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Inflammatory responses in aggregating rat brain cell cultures subjected to different demyelinating conditions.
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To study inflammatory reactions occurring in relation to demyelination, aggregating rat brain cell cultures were subjected to three different demyelinating insults, i.e., (i) lysophosphatidylcholine (LPC), (ii) interferon-gamma combined with lipopolysaccharide (IFN-gamma+LPS), and (iii) anti-MOG antibodies plus complement (alpha-MOG+C). Demyelination was assessed by measuring the expression of myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG), and the activity of 2',3'-cyclic nucleotide 3'-phosphohydrolase (CNP). The accompanying inflammatory reactions were examined by the quantification of microglia-specific staining, by immunostaining for glial fibrillary acidic protein (GFAP), and by measuring the mRNA expression of a panel of inflammation-related genes. It was found that all three demyelinating insults decreased the expression of MBP and MOG, and induced microglial reactivity. LPC and alpha-MOG+C, but not IFN-gamma+LPS, decreased CNP activity; they also caused the appearance of macrophagic microglia, and increased GFAP staining indicating astrogliosis. LPC affected also the integrity of neurons and astrocytes. LPC and IFN-gamma+LPS upregulated the expression of the inflammation-related genes IL-6, TNF-alpha, Ccl5, Cxcl1, and iNOS, although to different degrees. Other inflammatory markers were upregulated by only one of the three insults, e.g., Cxcl2 by LPC; IL-1beta and IL-15 by IFN-gamma+LPS; and IFN-gamma by alpha-MOG+C. These findings indicate that each of the three demyelinating insults caused distinct patterns of demyelination and inflammatory reactivity, and that of the demyelinating agents tested only LPC exhibited general toxicity.
2',3'-Cyclic-Nucleotide Phosphodiesterases/metabolism, Animals, Antibodies/pharmacology, Brain/cytology, Cells, Cultured, Choline O-Acetyltransferase/metabolism, Cytokines/genetics, Cytokines/metabolism, Demyelinating Diseases/metabolism, Demyelinating Diseases/physiopathology, Drug Interactions, Embryo, Mammalian, Glial Fibrillary Acidic Protein/genetics, Glial Fibrillary Acidic Protein/metabolism, Glutamate Decarboxylase/metabolism, Immunologic Factors/genetics, Immunologic Factors/metabolism, Interferon-gamma/pharmacology, Lectins/metabolism, Lysophosphatidylcholines/pharmacology, Myelin Basic Proteins/genetics, Myelin Basic Proteins/metabolism, Myelin-Associated Glycoprotein/immunology, Myelin-Associated Glycoprotein/metabolism, Neurons/drug effects, Neurons/metabolism, Polysaccharides/pharmacology, RNA, Messenger/metabolism, Rats, Tumor Necrosis Factor-alpha/metabolism, Up-Regulation/drug effects
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