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-13 C]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 gaschromatography 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 cocultures of astrocytes and either glutamatergic or GABAergic neurons with [U-13 C]glucose or the glialselective substrate [1,[2][3][4][5][6][7][8][9][10][11][12][13] C]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. V C 2017Wiley Periodicals, Inc.