Induction of glial fibrillary acidic protein expression in astrocytes by nitric oxide

Saurav Brahmachari, Yiu K. Fung, Kalipada Pahan

Research output: Contribution to journalArticle

210 Scopus citations

Abstract

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 (NO) in the expression of GFAP. Bacterial lipopolysachharides (LPSs) induced the production of NO and the expression of GFAP in mouse primary astrocytes. Either a scavenger of NO [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 NO production such as interferon-γ, interleukin-1β, human immunodeficiency virus type 1 gp120, fibrillar amyloid β peptides, and double-stranded RNA (polyinosinic-polycytidilic acid) also induced the expression of GFAP through NO. The role of NO in the expression of GFAP was supported further by increased expression of GFAP by S-nitroso glutathione (GSNO), an NO donor. Interestingly, inhibition of nuclear factor κB (NF-κB) suppressed LPS- but not GSNO-induced expression of GFAP, suggesting that NO does not require NF-κB to induce GFAP and that NF-κB functions upstream of NO 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 NO induces GFAP via GC-cGMP-PKG. This study illustrates a novel biological role of NO in regulating the expression of GFAP in astrocytes through the GC-cGMP-PKG pathway that may participate in the pathogenesis of neurodegenerative disorders.

Original languageEnglish (US)
Pages (from-to)4930-4939
Number of pages10
JournalJournal of Neuroscience
Volume26
Issue number18
DOIs
StatePublished - Sep 7 2006

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Keywords

  • Astroglial activation
  • GFAP
  • Guanylate cyclase
  • Neurotoxins
  • Nitric oxide
  • cGMP

ASJC Scopus subject areas

  • Neuroscience(all)

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