title: The anticonvulsant action of the galanin receptor agonist NAX-5055 involves modulation of both excitatory- and inhibitory neurotransmission.
abstract: The endogenous neuropeptide galanin is ubiquitously expressed throughout the mammalian brain. Through the galanin receptors GalR1-3, galanin has been demonstrated to modulate both glutamatergic and GABAergic neurotransmission, and this appears to be important in epilepsy and seizure activity. Accordingly, galanin analogues are likely to provide a new approach to seizure management. However, since peptides are generally poor candidates for therapeutic agents due to their poor metabolic stability and low brain bioavailability, a search for alternative strategies for the development of galanin-based anti-convulsant drugs was prompted. Based on this, a rationally designed GalR1 preferring galanin analogue, NAX-5055, was synthesized. This compound demonstrates anti-convulsant actions in several animal models of epilepsy. However, the alterations at the cellular level leading to this anti-convulsant action of NAX-5055 are not known. Here we investigate the action of NAX-5055 at the cellular level by determining its effects on excitatory and inhibitory neurotransmission, i.e. vesicular release of glutamate and GABA, respectively, in cerebellar, neocortical and hippocampal preparations. In addition, its effects on cell viability and neurotransmitter transporter capacity were examined to evaluate potential cell toxicity mediated by NAX-5055. It was found that vesicular release of glutamate was reduced concentration-dependently by NAX-5055 in the range from 0.1 to 1000 nM. Moreover, exposure to 1 μM NAX-5055 led to a reduction in the extracellular level of glutamate and an elevation of the extracellular level of GABA. Altogether these findings may at least partly explain the anti-convulsant effect of NAX-5055 observed in vivo.
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, Copenhagen DK-2100, Denmark. Electronic address: abw@sund.ku.dk.
authors.forename: Anne B
authors.initials: AB
authors.lastname: Walls
authors.affiliation: Anticonvulsant Drug Development Program, Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, 417 Wakara Way, Suite 3211, Salt Lake City, UT 84108, USA.
authors.forename: Sean P
authors.initials: SP
authors.lastname: Flynn
authors.affiliation: Anticonvulsant Drug Development Program, Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, 417 Wakara Way, Suite 3211, Salt Lake City, UT 84108, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: West
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, Copenhagen DK-2100, Denmark; Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, UK.
authors.forename: Margit S
authors.initials: MS
authors.lastname: Müller
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, Copenhagen DK-2100, Denmark.
authors.forename: Lasse K
authors.initials: LK
authors.lastname: Bak
authors.affiliation: University of Utah, Department Medicinal Chemistry, College of Pharmacy, 30 S 2000 E RM 201, Salt Lake City, UT 84112, USA.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Bulaj
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, Copenhagen DK-2100, Denmark.
authors.forename: Arne
authors.initials: A
authors.lastname: Schousboe
authors.affiliation: Anticonvulsant Drug Development Program, Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, 417 Wakara Way, Suite 3211, Salt Lake City, UT 84108, USA.
authors.forename: H Steve
authors.initials: HS
authors.lastname: White
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000927:Anticonvulsants / Q000494:pharmacology*; D001921:Brain / Q000166:cytology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects*; D005260:Female; D019004:Galanin / Q000031:analogs & derivatives* / Q000494:pharmacology; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects*; D055666:Lipopeptides / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects*; D018377:Neurotransmitter Agents / Q000378:metabolism*; D009924:Organ Culture Techniques; D011247:Pregnancy; D013997:Time Factors; D014812:Vitamin K / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000927:Anticonvulsants; D018690:Excitatory Amino Acid Agonists; D055666:Lipopeptides; C000604069:NAX 5055; D018377:Neurotransmitter Agents; D014812:Vitamin K; D016202:N-Methylaspartate; D019004:Galanin; C023885:menadiol
keywords: GABA; Galanin; Glutamate; NAX-5055; Seizure activity; Toxicity; Vesicular neurotransmitter release; mEPSC