title: Anxiolytic properties of a 2-phenylindolglyoxylamide TSPO ligand: Stimulation of in vitro neurosteroid production affecting GABAA receptor activity.
abstract: A number of neurosteroids have been demonstrated to exert anxiolytic properties by means of a positive modulation of inhibitory GABAergic neurotransmission. The observation that neurosteroid synthesis can be pharmacologically regulated by ligands to the mitochondrial translocator protein (TSPO) has prompted the search for new, more selective TSPO ligands able to stimulate steroidogenesis with great efficacy. In the present study, the potential anxiolytic activity of a selective TSPO ligand, N,N-di-n-propyl-2-(4-methylphenyl)indol-3-ylglyoxylamide (MPIGA), was tested by means of the elevated plus maze paradigm. Moreover, the in vitro effects on synaptoneurosomal GABA(A) receptor (GABA(A)R) activity exerted by the conditioned salt medium from MPIGA-treated ADF human glial cells were investigated. MPIGA (30mg/kg) was found to affect rats' performance in the elevated plus maze test significantly, leading to an increase in both entries and time spent in the open arms. This same dose of MPIGA had no effect on rats' spontaneous exploratory activity. The conditioned salt medium from MPIGA-treated ADF cells potentiated the (36)Cl(-) uptake into cerebral cortical synaptoneurosomes. The exposure of ADF cells to MPIGA stimulated the production of pregnelonone derivatives including allopregnanolone, one of the major positive GABA(A)R allosteric modulator. In conclusion, the TSPO ligand MPIGA is a promising anxiolytic drug. The mechanism of action by which MPIGA exerts its anxiolytic activity was identified in the stimulation of endogenous neurosteroid production, which in turn determined a positive modulation of GABA(A)R activity, thus opening the way to the potential use of this TSPO ligand in anxiety and depressive disorders.
authors: Department of Human Morphology and Applied Biology, University of Pisa, via Volta, 4-56126 Pisa, Italy.
authors: Barbara
authors: B
authors: Costa
authors: Eleonora
authors: E
authors: Da Pozzo
authors: Beatrice
authors: B
authors: Chelli
authors: Nicola
authors: N
authors: Simola
authors: Micaela
authors: M
authors: Morelli
authors: Michele
authors: M
authors: Luisi
authors: Marco
authors: M
authors: Maccheroni
authors: Sabrina
authors: S
authors: Taliani
authors: Francesca
authors: F
authors: Simorini
authors: Federico
authors: F
authors: Da Settimo
authors: Claudia
authors: C
authors: Martini
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D004353:Drug Evaluation, Preclinical; D058785:GABA-A Receptor Agonists / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D008024:Ligands; D018377:Neurotransmitter Agents / Q000096:biosynthesis*; D011284:Pregnenolone / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018079:Receptors, GABA / Q000378:metabolism*; D011963:Receptors, GABA-A / Q000378:metabolism*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D014407:Tumor Cells, Cultured
chemical_list: D014151:Anti-Anxiety Agents; D058785:GABA-A Receptor Agonists; D007211:Indoles; D008024:Ligands; C558826:N,N-di-n-propyl-2-(4-methylphenyl)indol-3-ylglyoxylamide; D018377:Neurotransmitter Agents; D018079:Receptors, GABA; D011963:Receptors, GABA-A; C499229:TSPO protein, human; D011284:Pregnenolone