Defense Date

3-12-2012

Graduation Date

Spring 2012

Availability

Immediate Access

Submission Type

thesis

Degree Name

MS

Department

Pharmacology

School

School of Pharmacy

Committee Chair

Jane E. Cavanaugh

Committee Member

Patrick Flaherty

Committee Member

Lauren O'Donnell

Committee Member

Christopher K. Surratt

Keywords

Lipopolysaccharide, Resveratrol

Abstract

Neuroinflammation is a common pathology found in patients with Parkinson's disease (PD). PD involves a loss of dopamine (DA) neurons and an increase in activated microglia with subsequent proinflammatory cytokine secretion in the substantia nigra (SN) and striatum. A loss of DA neurons is found in the offspring of animals exposed prenatally to the bacteriotoxin, lipopolysaccharide (LPS) (Ling et al., 2002). Activation of the extracellular regulated kinases, ERK1/2 and ERK5, the downstream targets in the mitogen-activated protein kinase (MAPK) pathway, has been shown to be involved in the dysregulation of the inflammatory process (Cuschieri and Maier, 2005). Consequently, LPS-induced activation of ERK1/2 and ERK5 may cause an increase in production and secretion of proinflammatory cytokines in activated microglia. LPS-mediated activation of ERK1/2 has been shown to be decreased by the phytochemical resveratrol (Zhang et al., 2010). However, the effect of LPS or resveratrol on ERK5 signaling has not been explored. The purpose of this study was to determine (1) the effect of resveratrol on LPS-induced dopaminergic deficits in pups exposed prenatally to LPS, (2) the impact of resveratrol on LPS-induced BV-2 microglial cell activation and (3) the roles of ERK1/2 and ERK5 in resveratrol mediated inhibition of LPS-induced BV-2 cell activation. To test our hypothesis, pregnant rats received an intraperitoneal (i.p.) injection 10, 000 EU/kg LPS at gestational day 10.5 (E10.5) and were fed a resveratrol-enriched diet for 20 days (E3 - E22.5). LPS-induced dopaminergic deficits in pups exposed prenatally at postnatal day 21 (P21), but not at P10 or P40. These deficits were exhibited by a loss of striatal 3, 4-dihydroxyphenylacetic acid (DOPAC) and DA content and tyrosine hydroxylase (TH) expression in the P21 animals. However, dietary resveratrol supplementation increased TH expression, DA and DOPAC levels in the P21 pups following prenatal exposure to LPS. Thus, these data suggest that resveratrol treatment may restore the homeostasis of the DA neuronal system in vivo. However, contrary to previous reports it was determined in vitro that LPS-mediated BV-2 activation and ERK1/2 phosphorylation was not inhibited by resveratrol pretreatment. Interestingly, at 6 hours the MEK inhibitor U0126 decreased LPS-mediated ERK1/2 activation and TNF-α release. ERK5 was not activated by LPS, but preliminary data suggest that the MEK5 inhibitor BIX02189 inhibited LPS-induced TNF-α release. Therefore, BIX02189 may be inhibiting a distinct pathway in our model. Overall, these studies suggest that the use of dietary resveratrol supplementation may be protective against LPS-induced loss of striatal dopaminergic deficits in a time-dependent manner and inhibition of ERK signaling may reduce LPS-mediated microglial activation.

Format

PDF

Language

English

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