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Date of Award

2007

Document Type

Thesis - Pacific Access Restricted

Degree Name

Master of Science (M.S.)

Department

Pharmaceutical and Chemical Sciences

First Advisor

Robert P. Halliwell

First Committee Member

James W. Blankenship

Second Committee Member

Patrick R. Jones

Third Committee Member

Timothy J. Smith

Abstract

Resveratrol and catechin have behavioral and neuroprotective effects that may be due to their interaction with neuronal ion channels. It was hypothesized that the grape compounds, resveratrol and catechin modulate GABAAA receptors. To address this hypothesis, the effects of resveratrol and catechin were investigated on human recombinant GABAA receptors expressed in HEK-293 cells using electrophysiological techniques.<.p>

HEK-293 cells were cultured and transfected using eDNA encoding human GABAA receptors. GABA-evoked currents were recorded from HEK cells 24-48 hours following transfection. Cells were voltage clamped in the whole cell configuration at -60mV using the patch-clamp technique. Ligand-activated currents were recorded and stored, using Win WCP software, on a desktop computer.

Resveratrol (1- 100μM) dose-dependently potentiated GABA-evoked currents recorded from α1β2< /sup>γ2 and α1β2 GABAA receptors. Resveratrol did not modulate a α1β2< /sup>γ2 and α1β2 GABAA receptors. Furthermore, resveratrol did not act through the benzodiazepine binding site. The low efficacy and subunit selectivity of resveratrol is a promising discovery for the development of a highly specific GABAergic modulator. Conversely, catechin (1-100αM) dose-dependently inhibited GABA-evoked currents recorded from α1β2 and α1β1 GABAA receptors. The degree of inhibition was the same for both receptor subtypes. Catechin did not modulate α1β2 or α1β2 GABAA receptors. The selectivity of catechin for receptors lacking the γ subunit is similar to the effects of zinc and did not involve the benzodiazephine site on GABAA receptors.

This study has shown that catechin and resveratrol are subunit-selective modulators of human GABAA receptors. These compounds could lead to the development of novel agents to be used in treating neurological disorders. These data support the use and study of natural products for the development of agents that act selectively on the nervous system.

Pages

128

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