Delay of neurodegenerative disease by Nano-PSO (GranaGard) is associated with restoring normal mitochondrial function

Neurodegenerative diseases are associated with the accumulation of specific misfolded proteins, and with severe oxidative damage, leading to mitochondrial malfunction. Previous work in our lab has shown that long term administration of Nano-PSO, a brain targeted antioxidant composed of a Nano-droplet formulation of pomegranate seed oil (PSO) to TgMHu2ME199K mice, modeling for genetic prion disease, significantly delayed disease advance and neuronal death. These mice are born healthy, then start to demonstrated neurological abnormalities at 5-6 months of age and subsequently deteriorate to full paralysis at around 12-14 months. To elucidate the mechanism of action of Nano-PSO, we compared brain mitochondrial enzyme activity and ROS/ATP production at different time points of the model mice. Concomitantly, we looked in parallel brain samples for the expression of mitochondrial enzymes and oxidation response factors. We found that while brain mitochondrial respiratory chain enzymatic activates and ATP/ROS production, were abnormally elevated in asymptomatic mice and then reduced in old and sick Tg mice, the same parameters in the samples of Nano-PSO treated Tg brains were always similar to those of wt mice. Similar results were obtained when brain slices of wt, untreated and Nano-PSO treated Tg mice were immunostained for Cytochrome c oxidase (COX) subunit IV isoform 1(Cox IV-1) as compared to Cox IV isoform 2, an isoform that operates in oxidative neuronal conditions. While in untreated Tgs COX IV1 was mostly replaced by COX IV2, in Nano-PSO treated mice COX IV1 expression was even higher than in wt mice. Similar results were obtained for additional oxidation markers, demonstrating that administration of Nano-PSO significantly corrected functional and biochemical mitochondrial abnormalities, concomitant with delaying disease advance. Our results indicate that brain targeted antioxidants can correct mitochondrial function in neurodegenerative conditions.