5-nitro-gamma-tocopherol and linsidomine

Oxidative stress and quasi-inflammatory processes recently have been recognized as contributing factors in the pathogenesis of Alzheimer's disease (AD). Reactive nitrating species have specifically been implicated in AD based on immunochemical and instrumental detection of nitrotyrosine in AD brain protein. The significance of lipid-phase nitration has not been investigated in AD. This study documents a significant two- to threefold increase in the lipid nitration product 5-nitro-gamma-tocopherol in affected regions of the AD brain as determined by high-performance liquid chromatography with electrochemical detection. In a bioassay to compare the relative potency of alpha-tocopherol and gamma-tocopherol against nitrative stress, rat brain mitochondria were exposed to the peroxynitrite-generating compound SIN-1. The oxidation-sensitive Kreb's cycle enzyme alpha-ketoglutarate dehydrogenase was inactivated by SIN-1, in a manner that could be significantly attenuated by gamma-tocopherol (at <10 microM) but not by alpha-tocopherol. These data indicate that nitric oxide-derived species are significant contributors to lipid oxidation in the AD brain. The findings are discussed in reference to the neuroinflammatory hypothesis of AD and the possible role of gamma-tocopherol as a major lipid-phase scavenger of reactive nitrogen species.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Antioxidants; Brain; Female; gamma-Tocopherol; Humans; Ketoglutarate Dehydrogenase Complex; Lipid Metabolism; Male; Mitochondria; Molsidomine; Nitric Oxide Donors; Reactive Nitrogen Species