Divergence of brain prostaglandin H synthase activity and oxidative damagein mice with encephalitis

Several lines of evidence point to inflammation and increased oxidant injur y 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 hypoth esis that pro-inflammatory signals in AD brain induce PGHS-2 that in turn c ontributes to brain oxidant injury. Here we have tested directly this 2-ste p hypothesis in a murine reovirus type 3 encephalitis model by measuring ce rebral PGHS activity and quantifying oxidant injury. Our results showed a r obust chronic inflammatory infiltrate and a 2-fold increase in PGHS activit y in encephalitic mice compared with controls. Despite these changes, there was no significant increase in F-2-isoprostanes or F-4-neuroprostanes, acc urate in vivo biomarkers of oxidant injury, and only minimal accumulation o f protein adducts from the lipid peroxidation product 4-hydroxy-2-nonenal i n the most intensely inflamed brain regions. These results challenge the pr oposal of others that pro-inflammatory induction of PGHS activity significa ntly contributes to oxidant injury in brain.