Activation of cultured astrocytes by amphotericin B: Stimulation of NO and cytokines production and changes in neurotrophic factors production |
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Authors: | Akiko Motoyoshi-Yamashiro Mizuho Tamura Mitsuaki Moriyama Katsura Takano Kenji Kawabe Hidemitsu Nakajima Ritsuko Katoh-Semba Teiichi Furuichi Yoichi Nakamura |
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Institution: | 1. Laboratory of Integrative Physiology in Veterinary Sciences, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Japan;2. Laboratory of Veterinary Pharmacology, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Japan;3. Riken Brain Science Institute, Laboratory for Molecular Neurogenesis, Japan |
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Abstract: | Amphotericin B (AmB) is a polyene antibiotic and reported to be one of a few reagents having therapeutic effects on prion diseases, such as the delay in the appearing of the clinical signs and the prolongation of the survival time. In prion diseases, glial cells have been suggested to play important roles by proliferating and producing various factors such as nitric oxide, proinflammatory cytokines, and neurotrophic factors. However, the therapeutic mechanism of AmB on prion diseases remains elusive. We have previously reported that AmB changed the expression of neurotoxic and neurotrophic factors in microglia (Motoyoshi et al., 2008, Neurochem. Int. 52, 1290–1296). In the present study, we examined the effects of AmB on cellular functions of rat cultured astrocytes. We found that AmB could activate astrocytes to produce nitric oxide via inducible nitric oxide synthase induction. AmB also induced mRNA expression of interleukin-1β and tumor necrosis factor-α, and productions of their proteins in astrocytes. Moreover, AmB changed levels of neurotrophic factor mRNAs and proteins. Among three neurotrophic factors examined here, neurotrophin-3 mRNA expression and its protein production in the cells were down-regulated by AmB stimulation. On the other hand, AmB significantly enhanced the amounts of glial cell line-derived neurotrophic factor and brain-derived neurotrophic factor proteins in the cells and the medium. These results suggest that AmB might show therapeutic effects on prion diseases by controlling the expression and production of such mediators in astrocytes. |
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Keywords: | AmB amphotericin B BDNF brain-derived neurotrophic factor CNTF ciliary neurotrophic factor DAN 2 3-diaminonaphthalene DMEM Dulbecco&rsquo s modified Eagle medium FCS fetal calf serum GAPDH glyceraldehyde-3-phosphate dehydrogenase GDNF glial cell line-derived neurotrophic factor GFAP glial fibrillary acidic protein IL interleukin iNOS inducible NO synthase LPS lipopolysaccharide MTT 3-(4 5-dimethylthiazol-2-yl)-2 5-diphenyltetrazolium bromide NF-κB nuclear factor-kappa B NGF nerve growth factor L-NMMA NG-monomethyl-l-arginine NO nitric oxide NO2&ndash nitrite NT-3 neurotrophin-3 PrP prion potein PrPc cellular PrP PrPsc pathological PrP TNF tumor necrosis factor |
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