title: Role of microglia in the pathogenesis of osmotic-induced demyelination.
abstract: Osmotic demyelination is a serious disease caused by rapid correction of hyponatremia. In humans, demyelinative lesions occur preferentially in the central pons, and thus are termed central pontine myelinolysis. Although accumulation of microglia has been reported in such demyelinative lesions, their role in the pathogenesis of osmotic demyelination remains unclear. We examined the expression of cytokines in microglia that accumulated in the demyelinative lesions in a rat model of osmotic demyelination. Hyponatremia was induced in rats by a combination of dDAVP infusion and liquid diet feeding. After 7 days, serum sodium levels were rapidly corrected by hypertonic saline injection. The rats developed severe motor deficits, and marked demyelinative lesions were found in the midbrain and cerebral cortex. In the area of the demyelinative lesions, massive accumulations of microglia were observed that expressed the proinflammatory cytokines TNF-alpha and IFN-gamma as well as iNOS. In contrast, in hyponatremia corrected rats treated with lovastatin, which is known to inhibit microglial infiltration in various animal models of CNS disease, neurological impairments and the degree of demyelination were significantly ameliorated. Lovastatin also reduced the accumulation of microglia and decreased the expression of TNF-alpha in the demyelinative lesions. These results indicate that microglia play a detrimental role in the pathogenesis of osmotic demyelination by producing proinflammatory cytokines, and further suggest that lovastatin may be useful in repressing the demyelination.
authors.affiliation: Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan.
authors.forename: Seiko
authors.initials: S
authors.lastname: Takefuji
authors.forename: Takashi
authors.initials: T
authors.lastname: Murase
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Sugimura
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Takagishi
authors.forename: Shizu
authors.initials: S
authors.lastname: Hayasaka
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Oiso
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Murata
mesh_terms: D000818:Animals; D001927:Brain Diseases / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D016207:Cytokines / Q000378:metabolism*; D003711:Demyelinating Diseases / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D007010:Hyponatremia / Q000503:physiopathology; D018836:Inflammation Mediators / Q000378:metabolism; D007267:Injections; D007371:Interferon-gamma / Q000378:metabolism; D008148:Lovastatin / Q000494:pharmacology; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009995:Osmosis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012462:Saline Solution, Hypertonic / Q000008:administration & dosage / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D012462:Saline Solution, Hypertonic; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D008148:Lovastatin; D052247:Nitric Oxide Synthase Type II