title: TSPO PIGA Ligands Promote Neurosteroidogenesis and Human Astrocyte Well-Being.
abstract: The steroidogenic 18 kDa translocator protein (TSPO) is an emerging, attractive therapeutic tool for several pathological conditions of the nervous system. Here, 13 high affinity TSPO ligands belonging to our previously described N,N-dialkyl-2-phenylindol-3-ylglyoxylamide (PIGA) class were evaluated for their potential ability to affect the cellular Oxidative Metabolism Activity/Proliferation index, which is used as a measure of astrocyte well-being. The most active PIGA ligands were also assessed for steroidogenic activity in terms of pregnenolone production, and the values were related to the metabolic index in rat and human models. The results showed a positive correlation between the increase in the Oxidative Metabolism Activity/Proliferation index and the pharmacologically induced stimulation of steroidogenesis. The specific involvement of steroid molecules in mediating the metabolic effects of the PIGA ligands was demonstrated using aminoglutethimide, a specific inhibitor of the first step of steroid biosynthesis. The most promising steroidogenic PIGA ligands were the 2-naphthyl derivatives that showed a long residence time to the target, in agreement with our previous data. In conclusion, TSPO ligand-induced neurosteroidogenesis was involved in astrocyte well-being.
authors.affiliation: Department of Pharmacy, University of Pisa, Via Bonanno Pisano 6, 56126 Pisa, Italy. eleonora.dapozzo@unipi.it.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Da Pozzo
authors.affiliation: Department of Pharmacy, University of Pisa, Via Bonanno Pisano 6, 56126 Pisa, Italy. chiara.giacomelli@for.unipi.it.
authors.forename: Chiara
authors.initials: C
authors.lastname: Giacomelli
authors.affiliation: Department of Pharmacy, University of Pisa, Via Bonanno Pisano 6, 56126 Pisa, Italy. barbara.costa@unipi.it.
authors.forename: Barbara
authors.initials: B
authors.lastname: Costa
authors.affiliation: Department of Pharmacy, University of Pisa, Via Bonanno Pisano 6, 56126 Pisa, Italy. chiara.cavallini@farm.unipi.it.
authors.forename: Chiara
authors.initials: C
authors.lastname: Cavallini
authors.affiliation: Department of Pharmacy, University of Pisa, Via Bonanno Pisano 6, 56126 Pisa, Italy. sabrina.taliani@unipi.it.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Taliani
authors.affiliation: Department of Pharmacy, University of Pisa, Via Bonanno Pisano 6, 56126 Pisa, Italy. elisabetta.barresi@for.unipi.it.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Barresi
authors.affiliation: Department of Pharmacy, University of Pisa, Via Bonanno Pisano 6, 56126 Pisa, Italy. federico.dasettimo@unipi.it.
authors.forename: Federico
authors.initials: F
authors.lastname: Da Settimo
authors.affiliation: Department of Pharmacy, University of Pisa, Via Bonanno Pisano 6, 56126 Pisa, Italy. claudia.martini@unipi.it.
authors.forename: Claudia
authors.initials: C
authors.lastname: Martini
mesh_terms: D001253:Astrocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D055495:Neurogenesis / Q000187:drug effects; D010084:Oxidation-Reduction / Q000187:drug effects; D011284:Pregnenolone / Q000378:metabolism
chemical_list: D007211:Indoles; C503726:N,N-Di-n-butyl-5-chloro-2-(4-chlorophenyl)indol-3-ylglyoxylamide; D011284:Pregnenolone
keywords: PIGA ligands; astrocytes; cellular proliferation; neurosteroidogenesis; oxidative metabolism; translocator protein