Defense Date

6-12-2013

Graduation Date

2013

Availability

Immediate Access

Submission Type

dissertation

Degree Name

PhD

Department

Pharmacology

School

School of Pharmacy

Committee Chair

Jane Cavanaugh

Committee Member

Jelena Janjic

Committee Member

Agnes Rimando

Committee Member

Christopher Surratt

Committee Member

Paula Witt-Enderby

Keywords

Aging, Dopamine, Motor deficits, Pinostilbene, Resveratrol, Wild blueberries

Abstract

With age, there is a loss of motor coordination leading to an increase in falls. Currently, there are limited therapeutic regimens for age-related motor deficits. However, L-DOPA is used for motor dysfunction in Parkinson's disease (PD). Therefore, we investigated the effect of L-DOPA on motor deficits in young (2 mo) and old (20 mo) mice. We found that L-DOPA reversed age-related motor decline.

Chronic L-DOPA use produces involuntary movements or dyskinesias. Interestingly, natural foods, such as wild blueberries (WBB), and isolated compounds, such as resveratrol and pinostilbene, have beneficial effects on several physiological processes with few side effects. Therefore, to examine the effect of these natural products on motor function, mice (2, 10 and 20 mo) were fed resveratrol, pinostilbene, or WBB containing diet. The age-related loss of motor coordination was attenuated in animals fed resveratrol and WBB diets, while pinostilbene diet increased spontaneous activity.

To investigate the mechanism that may underlie this reversal of motor deficits, striatal dopamine (DA) and DA metabolite levels and the number of DA neurons in the substantia nigra were examined. None of these parameters changed with age or in animals fed resveratrol or pinostilbene diets. However, WBB increased the number of DA neurons in the substantia nigra in aged animals.

To further investigate the mechanism that may underlie the alleviation of motor deficits, the effects of resveratrol or pinostilbene on oxidative stress-induced cell death and the expression and activation of ERK1/2 and ERK5, kinases known to protect from oxidative stress, were examined in DA cells. Resveratrol and pinostilbene decreased DA-induced cell death and activated ERK1/2, but not ERK5. Pretreatment with U0126, an inhibitor of the ERK1/2 pathways, blocked the resveratrol- and pinostilbene-mediated neuroprotection.

Together, these data suggest that resveratrol, pinostilbene, and/or WBB may decrease age-related motor deficits by protecting DA neurons from oxidative stress via activation of the ERK1/2 pathway. As the use of natural supplements is on the rise, it is important to understand the therapeutic and physiological effects of these compounds. Moreover, this research may lead to the use of these natural compounds as novel therapies for age-related motor deficits.

Format

PDF

Language

English

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