Suppression of murine cerebral F2-isoprostanes and F4-neuroprostanes from excitotoxicity and innate immune response in vivo by alpha- or gamma-tocopherol.
Oxidative damage to brain is a featured shared by several destructive and degenerative diseases and is thought to contribute to disease pathogenesis. Two commonly proposed sources of the increased free radical stress that leads to oxidative damage in several of these diseases are excitotoxicity and activation of innate immunity, both of which are proposed pharmacologic targets. Here we used models of excitotoxicity, intracerebroventricular (ICV) kainate (KA), and innate immune activation, ICV lipopolysaccharide (LPS), to test the effectiveness of peripherally administered alpha-tocopherol (AT) and gamma-tocopherol (GT) as neuroprotectants. We quantified murine cerebral oxidative damage by measuring F(2)-isoprostanes (IsoPs) and F(4)-neuroprostanes (NeuroPs) using stable isotope dilution methods followed by gas chromatography-mass spectrometry with selective ion monitoring. Our data showed that peripherally administered AT and GT were equally effective at suppressing acute oxidative damage from direct excitotoxicity caused by KA. In contrast, peripherally administered AT, but not GT, was effective at suppressing delayed neuronal oxidative damage from activated glial innate immune response. These data imply that AT may be more broadly protective of cerebrum from oxidative damage in different disease contexts.
Milatovic
Dejan
D
Department of Pathology, University of Washington, Harborview Medical Center, Box 359791, Seattle, WA 98104, USA.
VanRollins
Mike
M
Li
Ke
K
Montine
Kathleen S
KS
Montine
Thomas J
TJ
D000818:Animals; D001921:Brain / Q000187:drug effects*; D004281:Docosahexaenoic Acids / Q000378:metabolism*; D028441:F2-Isoprostanes / Q000378:metabolism*; D007113:Immunity, Innate / Q000187:drug effects*; D007608:Kainic Acid; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020258:Neurotoxicity Syndromes / Q000209:etiology / Q000276:immunology*; D024502:alpha-Tocopherol / Q000494:pharmacology*; D024504:gamma-Tocopherol / Q000494:pharmacology*
D028441:F2-Isoprostanes; D008070:Lipopolysaccharides; D004281:Docosahexaenoic Acids; D024504:gamma-Tocopherol; D024502:alpha-Tocopherol; D007608:Kainic Acid