期刊
JOURNAL OF NEUROSCIENCE
卷 26, 期 18, 页码 4930-4939出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.5480-05.2006
关键词
neurotoxins; nitric oxide; astroglial activation; GFAP; guanylate cyclase; cGMP
资金
- NINDS NIH HHS [NS48923, R01 NS039940-05A1, R21 NS048923-01A2, R01 NS039940, R21 NS048923, NS39940] Funding Source: Medline
Increased expression of glial fibrillary acidic protein (GFAP) represents astroglial activation and gliosis during neurodegeneration. However, the molecular mechanism behind increased expression of GFAP in astrocytes is poorly understood. The present study was undertaken to explore the role of nitric oxide (N0) in the expression of GFAP. Bacterial lipopolysachharides (LPSs) induced the production of N0 and the expression of GFAP in mouse primary astrocytes. Either a scavenger of N0 [2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (PTIO)] or an inhibitor of inducible nitric oxide synthase [L-N6-(I-iminoethyl)-lysine hydrochloride] blocked this induction of GFAP expression. Similarly, other inducers of N0 production such as interferon-gamma, interleukin-1 beta, human immunodeficiency virus type 1 gp120, fibrillar amyloid beta peptides, and double-stranded RNA (polyinosinic-polycytidilic acid) also induced the expression of GFAP through N0. The role of NO in the expression of GFAP was supported further by increased expression of GFAP by S-nitroso glutathione (GSN0), an N0 donor. Interestingly, inhibition of nuclear factor kappa B (NF-kappa B) suppressed LPS- but not GSN0-induced expression of GFAP, suggesting that N0 does not require NF-kappa B to induce GFAP and that NF-kappa B functions upstream of N0 production. However, inhibition of LPS- and GSNO- induced expression of GFAP either by NS-2028 [a specific inhibitor of guanylate cyclase (GC)] or by KT5823 [a specific inhibitor of cGMP-activated protein kinase (PKG)], and induction of GFAP expression by either 8-BrcGMP(a cell-permeable cGMP analog) or MY-5445 (a specific inhibitor of cGMP phosphodiesterase) suggests that N0 induces GFAP via GC-cGMP-PKG. This study illustrates a novel biological role of N0 in regulating the expression of GFAP in astrocytes through the GC-cGMP-PKG pathway that may participate in the pathogenesis of neurodegenerative disorders.
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