Expression of inducible nitric oxide synthase causes delayed neurotoxicity in primary mixed neuronal-glial cortical cultures

V. L. Dawson, H. P. Brahmbhatt, J. A. Mong, T. M. Dawson

Research output: Contribution to journalArticle

Abstract

Nitric oxide (NO) is a potent biological messenger molecule in the central nervous system (CNS). There are several potential sources of NO production in the CNS, including neurons and endothelial cells which express NO synthase (NOS) constitutively. Astrocytes and microglia can be induced by cytokines to express a NOS isoform similar to macrophage NOS (mNOS). Primary mixed glial cultures exposed to lipopolysaccharide (LPS) or a combination of LPS and γ-interferon (INF-γ) produce nitrite, a breakdown product of NO formation, in a dose-dependent manner. Nitrite production is detectable at 12 hr, peaks at 48 hr and is sustained for at least 96 hr. The NOS inhibitor, nitro-l-arginine (NArg), inhibits nitrite formation, but the immunosuppressant agent, FK506, does not. In mixed glial-neuronal cultures exposed to 50 ng LPS or 5 ng LPS and 1 μg INF-γ, neurons begin to die at 48 hr, approx. 24-36 hr after detectable nitrite production. Neurotoxicity is attenuated by 100 μM NArg. These data indicate that expression of inducible mNOS causes delayed neurotoxicity.

Original languageEnglish (US)
Pages (from-to)1425-1430
Number of pages6
JournalNeuropharmacology
Volume33
Issue number11
DOIs
StatePublished - Nov 1994

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Keywords

  • Macrophage nitric oxide synthase
  • astrocytes
  • gamma-interferon
  • lipopolysaccharide
  • microglia
  • neurodegeneration
  • nitric oxide

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience

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