Defense Date

5-2-2018

Graduation Date

Summer 8-11-2018

Availability

One-year Embargo

Submission Type

dissertation

Degree Name

PhD

Department

Pharmacology-Toxicology

School

School of Pharmacy

Committee Chair

Jane E Cavanaugh

Committee Member

Lauren O'Donnell

Committee Member

Christopher Surratt

Committee Member

Matthew Kostek

Committee Member

Zhengui Xia

Keywords

Resveratrol, Obesity, Dopamine, Cognition, Motor function

Abstract

Aging is a universal phenomenon. One of the greatest challenges faced by the elderly population is to sustain a healthy standard of living. Advancing age is associated with increased motor and cognitive deficits. Loss of balance, falls, hip fractures, and poor memory all contribute to a decline in the quality of life of the aging population. While ongoing research is making advances to find therapeutic interventions for neurodegenerative disorders like Parkinson’s and Alzheimer’s diseases, there is a pressing need to address deficits associated with normal aging.

Increase in oxidative stress and a decline of antioxidant mechanisms with aging have been attributed to the incidence of deteriorated physical function, which is purported to commence in middle age. Therefore, in this study, we explored natural antioxidants that may have the potential to combat rising oxidative stress and weakening of physiological systems, thereby improving motor and cognitive function of the older population. We supplemented the diet of middle-aged mice with resveratrol, a phytoalexin found in grapes, peanuts, wild blueberry and red wine. Resveratrol is known for its antioxidant, anti-inflammatory, anti-cancer properties and is also shown to be neuroprotective. During the course of our study, an unexpected confounding factor in the form of weight gain was introduced. However, by controlling for the increased bodyweight, we were able to evaluate resveratrol-mediated behavioral and molecular changes in a novel over-eating induced obesity and aging model. Our results indicated that prolonged resveratrol supplementation affected molecular changes in the brain, muscle and bone that may be potentially be beneficial for combating obesity and aging related deficits.

In addition to resveratrol, we also tested its naturally occurring analog, piceid in an in vitro model of oxidative-stress induced cell death in a dopaminergic-like cell line. Piceid afforded neuroprotection against oxidative-stress induced toxicity via activation of ERK1/2 and ERK5 (extracellular signal-regulated kinases) as well as inhibition of cellular apoptosis.

In conclusion, our data suggest that natural antioxidants may combat physiological deficits induced by obesity and aging and maybe potential therapeutic interventions for improving the quality of life of the elderly.

Language

English

Additional Citations

Potdar, S., Parmar, M.S., Ray, S.D. et al. Arch Toxicol (2018) 92: 669. https://doi.org/10.1007/s00204-017-2073-z

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