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Title	Lovastatin and phenylacetate inhibit the induction of nitric oxide synthase and cytokines in rat primary astrocytes, microglia, and macrophages
Alternative Title	Mevalonate inhibitors inhibit the induction of iNOS and cytokines
Author	Pahan, Kalipada Sheikh, Faruk G. Namboodiri, Aryan M.S. Singh, Inderjit
Contributor(s)	Journal of Clinical Investigation (Publisher)
Date	1997-12
Subject.MeSH	Alkyl and Aryl Transferases Anticholesteremic Agents Astrocytes Cells, Cultured Cytokines Enzyme Induction Enzyme Inhibitors Interleukin-1 Interleukin-6 Lipopolysaccharides Lovastatin Macrophages Mevalonic Acid Microglia Mitogens NF-kappa B Nitric Acid Nitric Oxide Synthase Phenylacetates Polyisoprenyl Phosphates Rats Sesquiterpenes Tumor Necrosis Factor-alpha
Subject.LCSH	Anticholesteremic agents Astrocytes Cell culture Cytology Cytokines Enzyme induction Enzyme inhibitors Interleukin-1 Interleukin-6 Macrophages Microglia Mitogens NF-kappa B (DNA-binding protein) Nitric acid Nitric-oxide synthase Phenylacetates Rats as laboratory animals Sesquiterpenes Tumor necrosis factor American Society for Clinical Investigation
Description	Article written by researchers from the Department of Pediatrics, Medical University of South Carolina. Published in the Journal of Clinical Investigation, December 1997, volume 100, number 11, pages 2671-2679. Includes abstract, references, tables, diagrams, and black-and-white photographic illustrations.
Collection	MUSC Faculty Journal Articles
Contributing Institution	Waring Historical Library (MUSC)
Rights	Copyright 1997, American Society for Clinical Investigation (ASCI).
Language	English
Type	Text
Format	application/pdf
Media Type	Periodicals
Resource Identifier	fja_0060_1997
Abstract	This study explores the role of mevalonate inhibitors in the activation of NF-k b and the induction of inducible nitric oxide synthase (iNOS) and cytokines (TNFa , IL-1 b , and IL-6) in rat primary astrocytes, microglia, and macrophages. Lovastatin and sodium phenylacetate (NaPA) were found to inhibit LPS- and cytokine-mediated production of NO and expression of iNOS in rat primary astrocytes;this inhibition was not due to depletion of end products of mevalonate pathway (e.g., cholesterol and ubiquinone). Reversal of the inhibitory effect of lovastatin on LPS-induced iNOS expression by mevalonate and farnesyl pyrophosphate and reversal of the inhibitory effect of NaPA on LPS-induced iNOS expression by farnesyl pyrophosphate, however, suggests a role of farnesylation in the LPS-mediated induction of iNOS. The inhibition of LPS-mediated induction of iNOS by FPT inhibitor II, an inhibitor of Ras farnesyl protein transferase, suggests that farnesylation of p21 ras or other proteins regulates the induction of iNOS. Inhibition of LPSmediated activation of NF-k b by lovastatin, NaPA, and FPT inhibitor II in astrocytes indicates that the observed inhibition of iNOS expression is mediated via inhibition of NF-k b activation. In addition to iNOS, lovastatin and NaPA also inhibited LPS-induced expression of TNFa, IL-1 b, and IL-6 in rat primary astrocytes, microglia, and macrophages. This study delineates a novel role of the mevalonate pathway in controlling the expression of iNOS and different cytokines in rat astrocytes, microglia, and macrophages that may be important in developing therapeutics against cytokineand NO-mediated neurodegenerative diseases. Keywords: lovastatin, phenylacetate, astrocytes, cytokines, and iNOS.

Lovastatin and phenylacetate inhibit the induction of nitric oxide synthase and cytokines in rat primary astrocytes, microglia, and macrophages

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