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The Journal of Neuroscience, September 15, 2000, 20(18):6862-6867
Peroxisome Proliferator-Activated Receptor- Ligands Reduce
Neuronal Inducible Nitric Oxide Synthase Expression and Cell Death
In Vivo
Michael T.
Heneka1, 2,
Thomas
Klockgether1, and
Douglas L.
Feinstein2
1 Department of Neurology, University of Bonn, 53105 Bonn, Germany, and 2 Department of Anesthesiology,
NeuroAnesthesia Research, University of Illinois at Chicago, Chicago,
Illinois 60607
Expression of the inducible form of nitric oxide synthase (iNOS) in
brain may contribute to neurotoxicity in Alzheimer's disease (AD).
Expression of iNOS can be induced in cerebellar granule cells (CGCs)
in vivo as well as in vitro, allowing
these cells to be used to study regulation of neuronal iNOS expression.
We report here that microinjection of bacterial lipopolysaccharide and
interferon gamma into rat cerebellum induced iNOS expression in CGCs
and subsequent cell death assessed by staining for DNA fragmentation.
Co-injection of three structurally distinct agonists of the peroxisome
proliferator-activated receptor gamma (PPAR ), including the
antidiabetic thiazolidinedione troglitazone, the nonsteroidal
anti-inflammatory drug (NSAID) ibuprofen, and the prostanoid
15-deoxy- 12,14 prostaglandin J2,
reduced both iNOS expression and cell death, whereas
co-injection of the selective cyclo-oxygenase inhibitor NS-398 had no
effect. These data demonstrate that PPAR agonists can modulate
inflammatory responses in brain. Because sustained medication with
NSAIDs reduces the risk and delays the onset of AD, these results
further suggest that NSAIDs provide therapeutic value by binding to
PPAR present in AD brain, thereby preventing iNOS expression and
neuronal cell death.
Key words:
iNOS; PPAR; cerebellar granule neurons; NSAIDs; Alzheimer's disease; apoptosis
Copyright © 2000 Society for Neuroscience 0270-6474/00/20186862-06$05.00/0
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