Absence of 12/15 lipoxygenase reduces brain oxidative stress in apolipoprotein E-deficient mice

The enzyme 12/15 lipoxygenase (12/15LO) has been implicated in the oxidative modification of lipoproteins and phospholipids in vivo. In addition, mice deficient in apolipoprotein E (ApoE(-/-)) are characterized by spontaneous hypercholesterolemia and a systemic increase in oxidative stress. Whereas the absence of 12/15LO reduces lipid peroxidation in the plasma and urine of ApoE-/- mice, the relative contribution of this enzyme to oxidative stress in the central nervous system remains unknown. Here, we provide the first in vivo evidence that 12/15LO modulates brain oxidative stress reactions using ApoE-/- mice crossbred with 12/15LO-deficient (12/15LO(-/-)) mice (12/15LO(-/-)/ApoE(-/-)). in chow-fed 12-month-old 12/15LO-/-/ApoE-/- mice, the amount of brain isoprostane iPF(2 alpha)-VI, a marker of lipid peroxidation, and carbonyls, markers of protein oxidation, were significantly reduced when compared with 12/15LO-expressing controls (12/15LO(+/+)/ApoE(-/-)). These results were observed despite the fact that cholesterol, triglyceride, and lipoprotein levels were similar to those of ApoE(-/-) mice. These data indicate a functional role for 12/15LO in the modulation of oxidative reactions in the central nervous system, supporting the hypothesis that inhibition of this enzymatic pathway may be a novel therapeutic target in clinical settings involving increased brain oxidative stress.