Properties of NAX-5011: A Novel Systemically Available Galanin-Based Neuropeptide

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Publication Type dissertation
School or College School of Medicine
Department Neurology
Author Flynn, Sean Patrick
Title Properties of NAX-5011: A Novel Systemically Available Galanin-Based Neuropeptide
Date 2012-08
Description Epilepsy describes a spectrum of common and devastating neurological disorders characterized by recurrent unprovoked seizures. Approximately 70% of epilepsy patients achieve seizure freedom with the use of clinically available antiseizure drugs, while the remaining 30% of patients are considered drug-resistant. It has been proposed that in order to effectively treat drug-resistant patients, future research must focus on novel molecular targets that are capable of modifying the underlying pathology of epilepsy. Potential novel targets include the neuropeptide galanin and its cognate receptors. Hippocampal galanin expression is increased following seizure activity and experimentally increasing central galanin produces antiseizure activity in a number of animal models. However, the specific role of the galanin receptors (GalR1-3) in mediating the anti-seizure properties of galanin remains unclear. To address this issue a collaboration was established between the laboratories of Drs. H. Steve White and Grzegorz Bulaj to design, synthesize, and characterize novel, receptor-preferring, galanin-based neuropeptides. One analog generated from these studies, NAX-5055, displays a 15-fold preference for the GalR1 receptor and potent antiseizure activity in a battery of seizure and epilepsy models. The overall goal of this dissertation was to further characterize the properties of NAX-5055. Electrophysiological studies evaluated the mechanism of action of NAX- 5055. Resutlts from these studies demonstrate an inhibition of presynaptic glutamate iv v release in the CA3 region of the hippocampus. Interestingly, behavioral studies demonstrated that the antiseizure efficacy of NAX-5055 was markedly reduced following repeated systemic administration. As a result, we investigated the potential mechanism(s) that could account for this observation. Our studies suggest that the reduced efficacy of NAX-5055 is not likely due to an alteration in galanin receptor function, efflux transport by P-glycoprotein, or increased peripheral metabolism. The studies presented in this dissertation were able to rule out several candidate mechanisms for the reduced efficacy of NAX-5055; however, additional work will be required to fully understand this phenomenon. In addition, our functional studies provide the first indication that galanin can decrease hippocampal excitability through a presynaptic mechanism. Future studies with NAX-5055 will increase our understanding of galanin and its receptors in vivo and help guide the development of future neuropeptide-based theraputics.
Type Text
Publisher University of Utah
Subject MESH Galanin; Receptor, Galanin, Type 3; Receptors, Neuropeptide; Nerve Tissue Proteins; Epilepsy; Anticonvulsants; Kindling, Neurologic; Hippocampus; NAX-5055
Dissertation Institution University of Utah
Dissertation Name Doctor of Philosophy
Language eng
Relation is Version of Digital reproduction of Properties of NAX-5055: A Novel Systematically Available Galanin-Based Neuropeptide. Spencer S. Eccles Health Sciences Library. Print version available at J. Willard Marriott Library Special Collections.
Rights Management Copyright © Sean Patrick Flynn 2012
Format Medium application/pdf
Format Extent 13,305,012 bytes
Source Original in Marriott Library Special Collections,
ARK ark:/87278/s6d53w53
Setname ir_etd
Date Created 2014-04-10
Date Modified 2021-05-06
ID 196341
Reference URL https://collections.lib.utah.edu/ark:/87278/s6d53w53
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