Enhancement of mitochondrial function using NO releasing nanoparticles; a potential approach for therapy of Alzheimer's disease

Abstract

Alzheimer's disease (AD) is the most common type of dementia. Increasing evidence is showing the important role of mitochondrial dysfunction in AD. Mitochondria based oxidative stress, decrease in respiratory chain activity and ATP production are all associated with AD, hence indicating that the enhancement of mitochondrial function and biogenesis present a promising therapeutic approach for AD. Nitric oxide (NO) is an initiator of mitochondrial biogenesis. However, its gaseous nature and very short half-life limit the realization of its therapeutic potential. Additionally, its uncontrolled in-vivo distribution results in generalized vasodilation, hypotension among other off-target effects. Diazeniumdiolates (NONOates) are NO donors that release NO in physiological temperature and pH. Their encapsulation within a hydrophobic matrix carrier system could control the release of NO, and at the same time enable its delivery to the brain. In this work, PAPANONOate (PN) a NO donor was encapsulated in small (92 ± 7 nm) poly (lactic-co-glycolic acid) (PLGA) NPs. These NPs did not induce hemolysis upon intravenous administration and were able to accumulate in the brains of lipopolysaccharides (LPS) induced neurodegeneration mouse models. The encapsulation of PN within a hydrophobic PLGA matrix enabled the sustained release of NO from NPs (≈ 3 folds slower relative to free PN) and successfully delivered PN to brain. As a result, PN-NPs but not free PN resulted in an enhancement in memory and cognition in animals with neurodegeneration as determined by the Y-maze test. The enhancement in cognition was a result of increased mitochondria function as indicated by the increased production of ATP and Cytochrome C oxidase enzyme activity.