Regulation of inducible nitric oxide synthase and agmatine synthesis in macrophages and astrocytes.

Ann N Y Acad Sci

Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USA.

Published: December 2003

AI Article Synopsis

  • Agmatine is a compound derived from the amino acid arginine, showing potential benefits in protecting against ischemic injuries and chronic neuropathic pain, especially by influencing inflammation.
  • The study explored agmatine's effects on the production of nitric oxide, a proinflammatory molecule, in astroglial and RAW 264.7 (macrophage) cells, demonstrating that agmatine inhibits nitric oxide production in a dose-dependent manner.
  • Results indicate that agmatine reduces the activity and expression of nitric oxide synthase-2 (NOS-2) in these cells, providing insights into its neuroprotective and anti-inflammatory properties.

Article Abstract

Agmatine is a novel endogenous guanido amine synthesized from arginine by arginine decarboxylase. Among several biologic effects, the ability of agmatine to protect against ischemic injury and chronic neuropathic pain is particularly interesting. Because inflammation is a common contributor to these conditions, we sought to determine if agmatine acts by decreasing the production of proinflammatory molecules such as nitric oxide and if agmatine synthesis is regulated by inflammatory stimuli. We tested whether agmatine affects astroglial and macrophage (RAW 264.7 cell line) nitric oxide synthase-2 (NOS-2) expression. NOS-2 was induced in these cells by incubation with lipopolysaccharide (LPS) plus three cytokines for astrocytes and LPS alone for RAW 264.7 cells in the presence and absence of varying concentrations of agmatine. NOS-2 activity was assessed after 24 hours by nitrite accumulation in the culture media. Agmatine dose-dependently inhibited nitrite accumulation, and shorter incubation with agmatine (1 and 4 hours) also caused significant reduction. Agmatine decreased the expression of NOS-2 activity and NOS-2 protein as determined by immunoblot analysis. Incubation of astrocytes and RAW 264.7 cells with LPS/cytokines for 2 hours resulted in an increase in arginine decarboxylase (ADC) activity, whereas longer-term incubation (12-17 hours) lowered ADC activity. Agmatine levels in these cells are increased after 6-hour incubation with LPS/cytokines. These results show that agmatine inhibits the production of nitric oxide by decreasing the activity of NOS-2 in macrophages and astroglial cells by decreasing the levels of NOS-2 protein. These findings provide a molecular basis for the neuroprotective and anti-inflammatory actions of agmatine.

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Source
http://dx.doi.org/10.1196/annals.1304.002DOI Listing

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