NDLI: A novel mechanism of action of tetracyclines: Effects on nitric oxide synthases

Content Provider	PubMed Central
Author	Amin, Ashok r. Attur, Mukundan g. Thakker, Geeta d. Patel, Prakash d. Vyas, Pranav r. Patel, Rajesh n. Patel, Indravadan r. Abramson, Steven b.
Copyright Year	1996
Abstract	Tetracyclines have recently been shown to have “chondroprotective” effects in inflammatory arthritides in animal models. Since nitric oxide (NO) is spontaneously released from human cartilage affected by osteoarthritis (OA) or rheumatoid arthritis in quantities sufficient to cause cartilage damage, we evaluated the effect of tetracyclines on the expression and function of human OA-affected nitric oxide synthase (OA-NOS) and rodent inducible NOS (iNOS). Among the tetracycline group of compounds, doxycycline > minocycline blocked and reversed both spontaneous and interleukin 1β-induced OA-NOS activity in ex vivo conditions. Similarly, minocycline ≥ doxycycline inhibited both lipopolysaccharide- and interferon-γ-stimulated iNOS in RAW 264.7 cells in vitro, as assessed by nitrite accumulation. Although both these enzyme isoforms could be inhibited by doxycycline and minocycline, their susceptibility to each of these drugs was distinct. Unlike acetylating agents or competitive inhibitors of l-arginine that directly inhibit the specific activity of NOS, doxycycline or minocycline has no significant effect on the specific activity of iNOS in cell-free extracts. The mechanism of action of these drugs on murine iNOS expression was found to be, at least in part, at the level of RNA expression and translation of the enzyme, which would account for the decreased iNOS protein and activity of the enzyme. Tetracyclines had no significant effect on the levels of mRNA for β-actin and glyceraldehyde-3-phosphate dehydrogenase nor on levels of protein of β-actin and cyclooxygenase 2 expression. These studies indicate that a novel mechanism of action of tetracyclines is to inhibit the expression of NOS. Since the overproduction of NO has been implicated in the pathogenesis of arthritis, as well as other inflammatory diseases, these observations suggest that tetracyclines should be evaluated as potential therapeutic modulators of NO for various pathological conditions.
Starting Page	14014
File Format	PDF
ISSN	10916490
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	24
Volume Number	93
Language	English
Publisher	The National Academy of Sciences of the USA
Publisher Date	1996-11-26
Access Restriction	Open
Rights Holder	The National Academy of Sciences of the USA
Subject Keyword	Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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