Diphenyl Diselenide Prevents Cortico-cerebral Mitochondrial Dysfunction and Oxidative Stress Induced by Hypercholesterolemia in LDL Receptor Knockout Mice

Recent studies have indicated a causal link between high dietary cholesterol intake and brain oxidative stress. In particular, we have previously shown a positive correlation between elevated plasma cholesterol levels, cortico-cerebral oxidative stress and mitochondrial dysfunction in low density lipoprotein receptor knockout (LDLr-/-) mice, a mouse model of familial hypercholesterolemia. Here we show that the organoselenium compound diphenyl diselenide (PhSe)(2) (1 mg/kg; o.g., once a day for 30 days) significantly blunted the cortico-cerebral oxidative stress and mitochondrial dysfunction induced by a hypercholesterolemic diet in LDLr-/- mice. (PhSe)(2) effectively prevented the inhibition of complex I and II activities, significantly increased the reduced glutathione (GSH) content and reduced lipoperoxidation in the cerebral cortex of hypercholesterolemic LDLr-/- mice. Overall, (PhSe)(2) may be a promising molecule to protect against hypercholesterolemia-induced effects on the central nervous system, in addition to its already demonstrated antiatherogenic effects.