BRAIN OXIDATIVE STRESS--A SIGN OF AGING OR EMINENT DEATH

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Brain oxidative stress is reported to play an important role in the process of aging and aging-related neurodegenerative diseases. Using conventional markers however, studies have produced conflicting data concerning the level of brain oxidative injury in aged animals. The purpose of this study is to further investigate the relationship between brain oxidative stress and aging, using novel sensitive markers which reflect differential contribution of various brain regions and cell types. Recently, F2-isoprostanes and F4-neuroprostanes, nonenzymatic oxidative products of arachidonic and docosahexaenoic acids, respectively, have been identified as novel and sensitive markers of oxidative injury. Preliminary data show that among all animal groups studied (Male Fischer 344 rats of 4,10,50, and 100 weeks old), only a subpopulation (4 out of 8) of 50 week old rats exhibited high brain neuroprostane levels. Based on these data, we hypothesize that brain oxidative damage is linked to death than to aging. This hypothesis is supported by the fact that the incidence of high brain neuroprostanes observed in 50 percent of studied animals is identical to the death rates reported for this strain at this age, and that mean brain neuroprostane levels were significantly lower in the 100 week old rats, compared with the 50 week old rat group. Our hypothesis will be tested by pursuing the following specific aims: (1) Confirm the exact incidence of high brain neuroprostane levels among male Fischer 344 rats of various ages, (2) Establish whether isoprostanes and neuroprostanes are more accurate and sensitive indicators, compared with conventional markers, of brain "oxidative status", and (3) Localize sources of oxidative stress mediators in the brain. Free and esterified brain isoprostanes and neuroprostanes will be quantified by mass spectroscopy. Levels of brain conventional oxidative markers as well as antioxidant enzyme activities will be assessed by established biochemical methods. Since the levels of arachidonic and docosahexaenoic acids, the precursors of isoprostanes and neuroprostanes, respectively, vary significantly between different regions of the brain (white vs gray matter), as well as among different cell types (neurones, astrocytes, oligodendrocytes) and subcellular fractions (myelin, synaptosomes), these two markers may help localize brain region and/or cell types exposed to oxidative injury. Furthermore, confirming that brain oxidative stress occurs earlier in life than previously reported would suggest that senescent animals may indeed arise from an oxidative damage-resistant subpopulation of the middle age group. Consequently, early diagnosis of this condition may present the opportunity to intervene to slow or halt neuronal degeneration and aging.