Divergence of brain prostaglandin H synthase activity and oxidative damage in mice with encephalitis.
Several lines of evidence point to inflammation and increased oxidant injury in brain regions of patients with Alzheimer disease (AD). Prostaglandin H synthase (PGHS) catalyzes the limiting step in prostaglandin synthesis and generates a potent oxidizing agent as by-product. One form of PGHS, PGHS-2, is induced by pro-inflammatory signals; thus leading to the 2-step hypothesis that pro-inflammatory signals in AD brain induce PGHS-2 that in turn contributes to brain oxidant injury. Here we have tested directly this 2-step hypothesis in a murine reovirus type 3 encephalitis model by measuring cerebral PGHS activity and quantifying oxidant injury. Our results showed a robust chronic inflammatory infiltrate and a 2-fold increase in PGHS activity in encephalitic mice compared with controls. Despite these changes, there was no significant increase in F2-isoprostanes or F4-neuroprostanes, accurate in vivo biomarkers of oxidant injury, and only minimal accumulation of protein adducts from the lipid peroxidation product 4-hydroxy-2-nonenal in the most intensely inflamed brain regions. These results challenge the proposal of others that pro-inflammatory induction of PGHS activity significantly contributes to oxidant injury in brain.
Valyi-Nagy
T
T
Department of Pathology, Elizabeth B. Lamb Center for Pediatric Research, Nashville, Tennessee, USA.
Sidell
K R
KR
Marnett
L J
LJ
Roberts
L J
LJ
Dermody
T S
TS
Morrow
J D
JD
Montine
T J
TJ
D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002460:Cell Line; D018792:Encephalitis, Viral / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology / Q000821:virology*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008054:Lipid Peroxides / Q000378:metabolism; D051379:Mice; D010084:Oxidation-Reduction; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D012088:Reoviridae Infections
D000447:Aldehydes; D008054:Lipid Peroxides; D011451:Prostaglandin-Endoperoxide Synthases; C027576:4-hydroxy-2-nonenal