title: The novel anticonvulsant neuropeptide and galanin analogue, NAX-5055, does not alter energy and amino acid metabolism in cultured brain cells.
abstract: A large body of evidence suggests that the neuropeptide galanin plays an important role in seizure control. In line with this, it was demonstrated that the galanin analogue, NAX-5055, exerts a potent anticonvulsant activity in animal seizure models. We recently found that the NAX-5055-mediated anticonvulsant action involves modulation of both excitatory and inhibitory neurotransmission. Since homeostasis of neurotransmitters and cerebral energy metabolism are intimately linked, it was investigated whether the effects of NAX-5055 on neurotransmission involve changes in energy metabolism and in particular glucose- and amino acid metabolism. With this aim, cultured neurons from mouse brain were incubated with [U-13C]glucose in absence or presence of NAX-5055. Since effects of NAX-5055 on neurotransmission were detected during repetitive stimulation, we tested potential metabolic effects while mimicking repetitive bursts of neurotransmitter release as occurring in the intact brain. The metabolic pathways were mapped using gas-chromatography coupled to mass-spectrometry. We found that NAX-5055 does not modify glucose metabolism in glutamatergic and GABAergic neurons. Furthermore, the effect of NAX-5055 on astrocyte-neuron metabolic interactions was investigated by incubating co-cultures of astrocytes and either glutamatergic or GABAergic neurons with [U-13C]glucose or the glial-selective substrate [1,2-13C]acetate, with or without NAX-5055. In the presence of NAX-5055, no changes in the metabolic landscape were traced. The findings suggest that the anticonvulsant action of NAX-5055 and the accompanying changes in neurotransmission do not involve alterations in energy and amino acid metabolism. Hence, NAX-5055 appears to be an anti-seizure drug candidate displaying no unwanted side effects concerning brain energy and amino acid homeostasis. © 2017 Wiley Periodicals, Inc.
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Blanca I
authors.initials: BI
authors.lastname: Aldana
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Helle S
authors.identifier: 0000-0003-4583-8379
authors.initials: HS
authors.lastname: Waagepetersen
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 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, Salt Lake City, Utah, USA.|Department of Pharmacy, School of Pharmacy, University of Washington, Seattle, Washington, USA.
authors.forename: H Steve
authors.initials: HS
authors.lastname: White
authors.affiliation: University of Utah, Department of Medicinal Chemistry, College of Pharmacy, Salt Lake City, Utah, 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, Copenhagen, Denmark.
authors.forename: Anne B
authors.identifier: 0000-0002-5234-5006
authors.initials: AB
authors.lastname: Walls
mesh_terms: D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D000927:Anticonvulsants / Q000494:pharmacology*; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D018920:Coculture Techniques; D004734:Energy Metabolism / Q000187:drug effects* / Q000502:physiology; D005260:Female; D019004:Galanin / Q000031:analogs & derivatives* / Q000494:pharmacology; D055666:Lipopeptides / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009479:Neuropeptides / Q000494:pharmacology
chemical_list: D000596:Amino Acids; D000927:Anticonvulsants; D055666:Lipopeptides; C000604069:NAX 5055; D009479:Neuropeptides; D019004:Galanin
keywords: acetate; astrocytes; cerebellum; cortex; glucose; neurons