title: IDRA-21, a positive AMPA receptor modulator, inhibits synaptic and extrasynaptic NMDA receptor mediated events in cultured cerebellar granule cells.
abstract: IDRA-21 (7-chloro-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide) reduces alpha-amino-3-hydroxy-5-methylisoxazolepropionic acid (AMPA) receptors desensitisation in vitro and restores learning and cognitive impairment in vivo. In this study, we show that in cerebellar granule cells (CGCs) in culture IDRA-21 reduces N-methyl-d-aspartate receptor (NMDAR) whole-cell currents. The effect is neither competitive nor voltage-dependent. The reduction of NMDA currents is stronger at low glycine concentrations suggesting an interaction with this site. IDRA-21 shortens miniature excitatory postsynaptic currents mediated by NMDARs (NMDA-mEPSCs) in CGCs grown in low potassium with no effect on peak amplitudes. By using fast glutamate application onto CGCs nucleated patches, we found that IDRA-21 decreases both decay time constant and amplitude of the current. Experiments performed on recombinant NMDAR expressed in HEK 293 cells showed that IDRA-21 was more effective on NR1a-NR2B than NR1a-NR2A receptors highlighting a subunit selectivity of the drug. Our findings make light on a novel target for IDRA-21: NMDA receptors function is negatively modulated and the different action at the level of extrasynaptic and synaptic receptors could be ascribed to a partial selectivity for NR2B subunits.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Modena e Reggio Emilia, Via Campi, 183, 41100 Modena, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Losi
authors.forename: Giulia
authors.initials: G
authors.lastname: Puia
authors.forename: Daniela
authors.initials: D
authors.lastname: Braghiroli
authors.forename: Mario
authors.initials: M
authors.lastname: Baraldi
mesh_terms: D000818:Animals; D001581:Benzothiadiazines / Q000494:pharmacology*; D002460:Cell Line; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology* / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D016202:N-Methylaspartate / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000819:agonists / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology
chemical_list: D001581:Benzothiadiazines; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; C091420:IDRA 21; D016202:N-Methylaspartate