The diazoxide derivative 7-chloro-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-S,S-dioxide augments AMPA- and GABA-mediated synaptic responses in cultured hippocampal neurons.
The diazoxide derivative 7-chloro-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-S,S-dioxide (IDRA21) enhances memory and learning in rodents, most likely by potentiating AMPAergic synaptic activity. We examined IDRA21's effect upon AMPAergic synaptic currents and whole-cell glutamate currents in cultured rat hippocampal neurons to determine whether IDRA21 was a partial modulator of AMPA receptor desensitization and deactivation. Comparable to cyclothiazide, IDRA21 prolonged AMPAergic autaptic currents (5.6 times control, EC50 150 microM) and slowed the rate of AMPA deactivation (3 times control) following 1-ms applications of 1 mM glutamate to excised, outside-out membrane patches. IDRA21 also augmented autaptic GABA currents by 27 +/- 8.1%, although it had two opposing effects, reducing the peak amplitude versus prolonging autaptic GABA currents. IDRA21 (200 microM) inhibited whole-cell GABA currents elicited by exogenously applied 1 mM GABA by 41 +/- 11%. At sufficient concentrations, IDRA21 reduced AMPA receptor desensitization and slowed the rate of deactivation, most consistent with full agonist activity with lower potency compared to cyclothiazide. IDRA21 slightly augments GABAergic synaptic currents.
Yamada
K A
KA
Center for the Study of Nervous System Injury, St. Louis Children's Hospital, Missouri, USA.
Hill
M W
MW
Hu
Y
Y
Covey
D F
DF
D000818:Animals; D000831:Animals, Newborn; D000959:Antihypertensive Agents / Q000494:pharmacology; D001581:Benzothiadiazines / Q000737:chemistry* / Q000494:pharmacology*; D002478:Cells, Cultured; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology; D009433:Neural Inhibition / Q000187:drug effects; D009474:Neurons / Q000737:chemistry* / Q000166:cytology / Q000187:drug effects; D009498:Neurotoxins / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D018091:Receptors, AMPA / Q000502:physiology*; D018079:Receptors, GABA / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects
D000959:Antihypertensive Agents; D001581:Benzothiadiazines; D018691:Excitatory Amino Acid Antagonists; D009498:Neurotoxins; D011810:Quinoxalines; D018091:Receptors, AMPA; D018079:Receptors, GABA; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; C091420:IDRA 21; D018698:Glutamic Acid; D016291:Dizocilpine Maleate; C004639:cyclothiazide