title: Framing Neuro-Glia Coupling in Antiepileptic Drug Design.
abstract: We delineate perspectives for the design and discovery of antiepileptic drugs (AEDs) with fewer side effects by focusing on astroglial modulation of spatiotemporal seizure dynamics. It is now recognized that the major inhibitory neurotransmitter of the brain, γ-aminobutyric acid (GABA), can be released through the reversal of astroglial GABA transporters. Synaptic spillover and subsequent glutamate (Glu) uptake in neighboring astrocytes evoke replacement of extracellular Glu for GABA, driving neurons away from the seizure threshold. Attenuation of synaptic signaling by this negative feedback through the interplay of Glu and GABA transporters of adjacent astroglia can result in shortened seizures. By contrast, long-range activation of astroglia through gap junctions may promote recurrent seizures on the model of pharmacoresistant temporal lobe epilepsy. From their first detection to our current understanding, we identify various targets that shape both short- and long-range neuro-astroglia coupling, as these are manifest in epilepsy phenomena and in the associated research promotions of AED.
authors.affiliation: Functional Pharmacology Research Group, Institute of Organic Chemistry, Research Centre for Natural Sciences, Hungarian Academy of Sciences, 1117 Budapest, Hungary.
authors.forename: Julianna
authors.initials: J
authors.lastname: Kardos
authors.affiliation: Functional Pharmacology Research Group, Institute of Organic Chemistry, Research Centre for Natural Sciences, Hungarian Academy of Sciences, 1117 Budapest, Hungary.
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Szabó
authors.affiliation: Functional Pharmacology Research Group, Institute of Organic Chemistry, Research Centre for Natural Sciences, Hungarian Academy of Sciences, 1117 Budapest, Hungary.
authors.forename: László
authors.initials: L
authors.lastname: Héja
mesh_terms: D000927:Anticonvulsants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D050485:GABA Plasma Membrane Transport Proteins / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D015394:Molecular Structure; D009457:Neuroglia / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D000927:Anticonvulsants; D050485:GABA Plasma Membrane Transport Proteins; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid