Mycophenolic acid downregulates inducible nitric oxide synthase induction in astrocytes.
Free radical nitric oxide (NO), generated by inducible nitric oxide synthase (iNOS) in astrocytes and macrophages, has been implicated in CNS inflammatory disorders such as multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE). Mycophenolic acid (MPA), a selective inhibitor of inosine monophosphate dehydrogenase (IMPDH), inhibited interferon-gamma (IFN-gamma) + lipopolysaccharide (LPS)-induced NO production dose-dependently in astrocytes, but not in macrophages. The effect of MPA was not mediated through interference with IMPDH-dependent synthesis of iNOS cofactor BH4 and subsequent suppression of iNOS enzymatic activity, as direct BH4 precursor sepiapterin failed to block the action of the drug. However, MPA markedly inhibited IFN-gamma + LPS-triggered astrocyte expression of mRNA for iNOS and its transcription factor IRF-1, while the expression of tumor necrosis factor-alpha (TNF-alpha) gene was not altered. The observed MPA suppression of NO release and iNOS and IRF-1 induction in astrocytes were efficiently prevented by exogenous guanosine, indicating that the drug acted through reduction of IMPDH-dependent synthesis of guanosine nucleotides. This IRF-1-dependent inhibition of iNOS activation might be partly responsible for the protective effect of MPA in EAE, prompting investigation of its potential use in multiple sclerosis.
Miljkovic
Djordje
D
Institute for Biological Research, Belgrade, Yugoslavia. georgije_zw@yahoo.com
Samardzic
Tatjana
T
Cvetkovic
Ivana
I
Mostarica Stojkovic
Marija
M
Trajkovic
Vladimir
V
D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects* / Q000201:enzymology*; D015536:Down-Regulation / Q000187:drug effects* / Q000502:physiology; D004790:Enzyme Induction / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology; D009173:Mycophenolic Acid / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D052247:Nitric Oxide Synthase Type II; D051381:Rats; D014407:Tumor Cells, Cultured
D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D009173:Mycophenolic Acid