| 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. Results from these studies demonstrate an inhibition of presynaptic glutamate 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 therapeutics. |
