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Date of Award

2009

Document Type

Dissertation - Pacific Access Restricted

Degree Name

Doctor of Philosophy (Ph.D.)

Department

Physiology and Pharmacology

First Advisor

Robert Halliwell

First Committee Member

David Thomas

Second Committee Member

James Blankenship

Third Committee Member

James Uchizono

Fourth Committee Member

Dinah Misner

Abstract

The combination of fluoroquinolones and non-steroidal anti-inflammatory drugs (NSAIDs) in patients increases the incidence of convulsions. The molecular mechanism underlying this interaction is not fully understood. The primary aim of this study was to investigate the pharmacological mechanisms that might underlie convulsions associated with the use of fluoroquinolones and NSAIDs. In this study, the interaction of ciprofloxacin (cipro; a prototype fluoroquinolone) and biphenylacetic acid (BPAA; a NSAID) was investigated using patch-clamp recording techniques. The specific aims of this study were to investigate the actions of cipro and BPAA on: (1) neuronal GABA A receptors, (2) spontaneous synaptic activity in cultured neurons; (3) voltage-gated ion channels; (4) GABA-gated single channels, 5) the association and dissociation rate kinetics of cipro and BPAA at GABA A -receptors, and 6) their effects at different human GABA A receptor isoforms. BPAA acted as an allosteric modulator to enhance the antagonist effect of cipro at GABA A receptors. Cipro + BPAA abolished inhibitory synaptic activity, whereas excitatory synaptic events were enhanced. These data suggest that this combination of drugs inhibits GABA A receptor-mediated inhibition and secondarily increases excitability in neuronal networks. Cipro and BPAA had little or no effects at voltage-gated Na + , K + or Ca 2+ ion channels, which suggests that the main effects of cipro + BPAA are at GABA A receptors. The kinetics study showed that BPAA increased the stability of the cipro-receptor complex to enhance the action of cipro. Cipro + BPAA inhibited the GABA A receptor by decreasing channel opening frequency and increasing the mean channel closed time. Subunit selectivity studies suggest that the β1/2 or γ2 subunits of GABA A receptors may not be a critical for the interaction of cipro + BPAA. Interestingly, the potentiation of cipro by BPAA was significantly less (p < 0.001) in GABA A receptors containing the α6 subunit compared to potentiation in the non-α6 contained receptor. The α subunit, therefore, appear to be a critical site for the synergistic antagonism of GABA A receptors by Cipro + BPAA. These data also suggest that there may be a novel binding site for BPAA at the a subunit of GABA A receptors.

Pages

175

ISBN

9781109172065

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