Date of Award

2016

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Chemistry and Biochemistry

First Advisor

Pandey, Siyaram

Rights

CC BY-NC-ND 4.0

Abstract

Neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) commonly affect people 60 years and above. Since the current treatment options only provide symptomatic relief and there is no effective way to halt the disease progression, there is a potential global socioeconomic crisis. Both PD and AD could be caused due to genetic disposition or environmental factors; however, oxidative stress has been implicated as a major contributor to the pathophysiology of the disease. Hence, an ideal way to halt the disease progression would be to use an antioxidant which can scavenge the reactive oxygen species and protect the neurons. In this study Ubisol–Q10, a water soluble formulation of the antioxidant Coenzyme Q10 (CoQ10) was tested on animal models of PD and AD. Ubisol–Q10 alleviated symptoms and halted loss of dopaminergic neurons when administered therapeutically to an environmental toxin paraquat rat model of PD, a model that mimics slow progressive neurodegeneration seen in PD. In the presence of Ubisol-Q10 treatment there was 16% loss of neurons in comparison to the PQ untreated group that suffered a significant 41% loss. Ubisol-Q10 also provides neuroprotection when administered prophylactically in a genetically susceptible DJ-1 deficient transgenic mouse model exposed to the neurotoxin 1-methyl-4-phenyl-1,2,3,6 acetic acid. In the MPTP injected DJ-1 mice there was a significant 49% loss in the number of dopaminergic neurons in comparison to the group that received prophylactic treatment group with Ubisol-Q10 which showed 19% loss of neurons. However, a short-term study conducted suggests that prolonged treatment with Ubisol-Q10 is necessary to sustain the neuroprotection. In vitro studies with Ubisol-Q10 reverse premature senescence in AD fibroblasts. Prophylactic studies were conducted with Ubisol-Q10 where it was administered over a 14 month period to a transgenic mouse model of AD containing human amyloid precursor protein and a mutant presenilin 1. Treatment showed improved long term memory in the Y-maze and was accompanied with decrease in the levels of plaques in brain sections, reduced circulating human amyloid-beta and altered glial cells morphology in comparison to the untreated group. The bioavailability of Ubisol-Q10 is high at small doses, 10 times lower than the FDA approved dose and the neuroprotection properties hold promise in providing effective treatment to those suffering from these diseases.

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