M-CSF deficiency leads to reduced metallothioneins I and II expression and increased tissue damage in the brain stem after 6-aminonicotinamide treatment.
6-Aminonicotinamide (6-AN) is a niacin antagonist, which leads to degeneration of gray-matter astrocytes followed by a vigorous inflammatory response. Macrophage colony stimulating factor (M-CSF) is important during inflammation, and in order to further clarify the roles for M-CSF in neurodegeneration and brain cell death, we have examined the effect of 6-AN on osteopetrotic mice with genetic M-CSF deficiency (op/op mice). The 6-AN-induced degeneration of gray-matter areas was comparable in control and op/op mice, but the numbers of reactive astrocytes, macrophages, and lymphocytes in the damaged areas were significantly decreased in op/op mice relative to controls. The levels of oxidative stress (as determined by using immunoreactivity for inducible nitric oxide synthase, nitrotyrosine, and malondialdehyde) and apoptotic cell death (as determined by using TUNEL and immunoreactivity for caspases and cytochrome c) were significantly increased in 6-AN-injected op/op mice relative to controls. From a number of antioxidant factors assayed, only metallothioneins I and II (MT-I+II) were decreased in op/op mice in comparison to controls. Thus, the present results indicate that M-CSF is an important growth factor for coping with 6-AN-induced central nervous system damage and suggest that MT-I+II are likely to have a significant role.
D015120:6-Aminonicotinamide / Q000633:toxicity*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001933:Brain Stem / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D020169:Caspases / Q000378:metabolism; D004660:Encephalitis / Q000139:chemically induced / Q000473:pathology*; D005455:Fluorescent Antibody Technique; D005904:Glial Fibrillary Acidic Protein / Q000096:biosynthesis; D006720:Homozygote; D020287:In Situ Nick-End Labeling; D008214:Lymphocytes / Q000473:pathology; D016173:Macrophage Colony-Stimulating Factor / Q000172:deficiency* / Q000235:genetics; D008264:Macrophages / Q000473:pathology; D008668:Metallothionein / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D017628:Microglia / Q000473:pathology; D009525:Niacin / Q000037:antagonists & inhibitors; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D018384:Oxidative Stress
D000975:Antioxidants; D005904:Glial Fibrillary Acidic Protein; D009525:Niacin; D015120:6-Aminonicotinamide; D016173:Macrophage Colony-Stimulating Factor; D008668:Metallothionein; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D020169:Caspases