ABSTRACT
We investigated the effects of auraptene on mouse oligodendroglial cell lineage in an animal model of demyelination induced by cuprizone. Auraptene, a citrus coumarin, was intraperitoneally administered to mice fed the demyelinating agent cuprizone. Immunohistochemical analysis of the corpus callosum and/or Western blotting analysis of brain extracts revealed that cuprizone reduced immunoreactivity for myelin-basic protein, a marker of myelin, whereas it increased immunoreactivity to platelet derived-growth factor receptor-α, a marker of oligodendrocyte precursor cells. Administration of auraptene enhanced the immunoreactivity to oligodendrocyte transcription factor 2, a marker of oligodendrocyte precursor cells and oligodendrocyte lineage precursor cells, but had no effect on immunoreactivity to myelin-basic protein or platelet-derived growth factor receptor-α. These findings suggest that auraptene promotes the production of oligodendrocyte lineage precursor cells in an animal model of demyelination and may be useful for individuals with demyelinating diseases.
Subject(s)
Coumarins/pharmacology , Demyelinating Diseases/drug therapy , Neuroprotective Agents/pharmacology , Oligodendroglia/drug effects , Stem Cells/drug effects , Animals , Basic Helix-Loop-Helix Transcription Factors/metabolism , Brain/drug effects , Brain/metabolism , Brain/pathology , Cuprizone , Demyelinating Diseases/metabolism , Demyelinating Diseases/pathology , Disease Models, Animal , Drug Evaluation, Preclinical , Gene Expression/drug effects , Injections, Intraperitoneal , Male , Mice, 129 Strain , Mice, Inbred C57BL , Microglia/drug effects , Microglia/metabolism , Myelin Basic Protein/metabolism , Nerve Tissue Proteins/metabolism , Oligodendrocyte Transcription Factor 2 , Oligodendroglia/metabolism , Oligodendroglia/pathology , Receptor, Platelet-Derived Growth Factor alpha/metabolism , Stem Cells/physiologyABSTRACT
Two channel proteins, inwardly rectifying potassium channel 4.1 (Kir4.1) and water channel aquaporin-4 (AQP4), were recently identified as targets of an autoantibody response in patients with multiple sclerosis and neuromyelitis optica, respectively. In the present study, we examined the expression patterns of Kir4.1 and AQP4 in a mouse model of demyelination induced by cuprizone, a copper chelator. Demyelination was confirmed by immunohistochemistry using an anti-proteolipid protein antibody in various brain regions, including the corpus callosum, of cuprizone-fed mice. Activation of microglial and astroglial cells was also confirmed by immunohistochemistry, using an anti-ionized calcium binding adapter molecule and a glial fibrillary acidic protein antibody. Western blot analysis revealed the induction of Kir4.1 protein, but not AQP4, in the cortex of cuprizone-fed mice. Immunohistochemical analysis confirmed the Kir4.1 protein induction in microvessels of the cerebral cortex. Real-time polymerase chain reaction analysis revealed that mRNA levels of Kir4.1 and AQP4 in the cortex did not change during cuprizone administration. These findings suggest that enhanced accumulation of Kir4.1 protein in the brain with an inflammatory condition facilitates the autoantibody formation against Kir4.1 in patients with multiple sclerosis.
