title: Reduced DNA oxidation in aged prostaglandin H synthase-1 knockout mice.
abstract: Prostaglandin H synthase (PHS)-2 (COX-2) is implicated in the neurodegeneration of Alzheimer and Parkinson diseases. Multiple mechanisms may be involved, including PHS-catalyzed bioactivation of neurotransmitters, precursors, and metabolites to neurotoxic free radical intermediates. Herein, in vitro studies with the purified PHS-1 (COX-1) isoform and in vivo studies of aging PHS-1 knockout mice were used to evaluate the potential neurodegenerative role of PHS-1-catalyzed bioactivation of endogenous neurotransmitters to free radical intermediates that enhance reactive oxygen species formation and oxidative DNA damage. The brains of 2-year-old wild-type (+/+) PHS-1 normal and heterozygous (+/-) and homozygous (-/-) PHS-1 knockout mice were analyzed for 8-oxo-2'-deoxyguanosine formation, characterized by high-performance liquid chromatography with electrochemical detection and by immunohistochemistry. Compared to aging PHS-1(+/+) normal mice, aging PHS-1(-/-) knockout mice had less oxidative DNA damage in the cortex, hippocampus, cerebellum, and brain stem. This PHS-1-dependent oxidative damage was not observed in young mice. In vitro incubation of purified PHS-1 and 2'-deoxyguanosine with dopamine, L-DOPA, and epinephrine, but not glutamate or norepinephrine, enhanced oxidative DNA damage. These results suggest that PHS-1-dependent accumulation of oxidatively damaged macromolecules including DNA may contribute to the mechanisms and risk factors of aging-related neurodegeneration.
authors.affiliation: Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada M5S 3M2.
authors.forename: Winnie
authors.initials: W
authors.lastname: Jeng
authors.forename: Annmarie
authors.initials: A
authors.lastname: Ramkissoon
authors.forename: Peter G
authors.initials: PG
authors.lastname: Wells
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000367:Age Factors; D000818:Animals; D001923:Brain Chemistry; D051545:Cyclooxygenase 1 / Q000235:genetics*; D004249:DNA Damage; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000096:biosynthesis / Q000737:chemistry; D004298:Dopamine / Q000737:chemistry; D004837:Epinephrine / Q000737:chemistry; D005260:Female; D005609:Free Radicals / Q000378:metabolism; D017353:Gene Deletion; D018698:Glutamic Acid / Q000737:chemistry; D007980:Levodopa / Q000737:chemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009638:Norepinephrine / Q000737:chemistry; D016877:Oxidants / Q000737:chemistry; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D005609:Free Radicals; D016877:Oxidants; D017382:Reactive Oxygen Species; D018698:Glutamic Acid; D007980:Levodopa; D000080242:8-Hydroxy-2'-Deoxyguanosine; D051545:Cyclooxygenase 1; D003849:Deoxyguanosine; D004298:Dopamine; D009638:Norepinephrine; D004837:Epinephrine