Editorial [Hot Topic: GABA and Glutamate as Targets in Medicinal Chemistry (Guest Editor: Dr. Julianna Kardos)]

The inhibitory γ-aminobutyrate (GABA) and the excitatory glutamate (Glu) are physiologically and therapeutically important major signaling amino acids within the brain. A strong interest in the drug discovery community is directed to interplaying GABAergic and Gluergic processes, as reflected in the large number of publications devoted to this subject from the 1990's. In this issue of Current Topics in Medicinal Chemistry, a selection of reviews on the recent developments in this area is presented by researchers who have been active in the field over many years. The topic of this issue is "GABA and glutamate as targets in medicinal chemistry", with emphasis on glial-neuronal metabolic coupling, synaptic vs. nonsynaptic and direct vs. indirect co-signaling performed by GABA and/or Glu and the elucidation of its physiological and pathological significance. Several lines of functional and analytical evidence are reviewed which cover co-existence of GABA and Glu within the synapse and nonsynaptically. In this way, medicinal chemists have an updated survey of the fundamentals of the complex problem of therapeutic intervention associated with signaling by GABA and/or Glu. The first contribution in this issue describes the function of astroglia in the modulation of availability, release and clearance of Glu and GABA within the central nervous system (CNS). Arne Schousboe and Helle Waagepetersen give an overview of the metabolic coupling between neurons and astroglia. The GABA-Glu-Gln cycle ramifies astroglia and neurons at the expense of the tricarboxilic acid cycle involving the activation of astroglial Glu transporters. Specific strategy aimed at inhibiting terminal GABA transporter subtype GAT1 has been successfully applied in the development of the antiepileptic tiagabine. The second review by Gabriella Nyitrai et al discusses and evaluates methodological details and problems associated with brain tissue microdyalisis. These in vivo measurements are very important for monitoring changes in the extracellular level of GABA and Glu under control and pathological conditions such as ischemia and epilepsy. Reflecting extracellular concentrations, the alterations of the amount of GABA and Glu in dyalisate samples independent of neuronal activity precipitate a role for glia in nonsynaptic communication. The third review by Sylvester Vizi and Árpád Mike investigate whether the archetypical synaptic neurotransmitters GABA and Glu can operate via nonsynaptic transmission. The authors collect evidence for different forms of nonsynaptic transmission performed by the extrasynaptic GABA and Glu receptors (GluRs). In the light of recent progress in the field theoretical predictions of the concept of nonsynaptic transmission have also been investigated. Extrasynaptic receptors and the ambient neurotransmitters or drugs are expected to interact with higher affinity. This feature may enable extrasynaptic receptors to serve useful pharmacological targets. Highlighted by Katalin Schlett, proliferative effects should be distinguished from those which affect cell fate commitment and/or survival. Glu actions on neurogenesis show distinct differences in the developing and adult brain. Glu acts nonsynaptically on dividing progenitors and can influence proliferation and neuronal commitment. Pathological conditions including ischemia, epilepsy and stress induce cell loss in the brain providing a clue for therapeutic interventions aimed at enhancing neuronal replacement. Rewived by Robert Balazs, GluR activation may directly initiates a cascade of events primarily involving Ca2+ ion-mediated signaling and consecutive gene expression changes. Indirect effects of GluR stimulation are due to the production and release of neurotrophic factors, such as brain-derived neurotrophic factor and also involve glia-neuronal interaction. Neuronal loss can occur during development as well as in the adult brain. Contrasting physiological and excessive stimulations, usually associated with either trophic effects promoting neuronal plasticity or neurotoxicity, respectively, may compromise the therapeutic manipulation of GluRs. Salient features of the co-transmission by GABA and Glu in neural signaling are reviewed by József Somogyi. Several brain areas, including granule cells of the Dentate Gyrus, hippocampal mossy fibre terminals and their termination zone in the CA3 subfield, retina, brain stem and spinal cord are highlighted. The vesicular Glu (VGLUT3) and GABA (VIAAT) transporters are functionally compatible making possible package and release of Glu and GABA from the same terminals. His new hypothesis on combinatorial neural code gives a possible reason for the functional significance of co-transmission by GABA and Glu in nerve terminals...........