The diazoxide derivative IDRA 21 enhances ischemic hippocampal neuron injury.
The diazoxide derivative IDRA 21 and other positive modulators of (AMPA)-type glutamate receptors are considered potential memory-enhancing agents. However, AMPA receptor activation contributes to CA1 hippocampal neuron damage from global ischemia in rodents, raising the possibility that 7-chloro-3-methyl-3-4-dihydro-2H-1,2,4 benzothiadiazine S,S-dioxide (IDRA 21) or drugs with similar actions may worsen ischemic neuronal injury. Here we demonstrate that glutamate plus IDRA 21 kills cultured rat hippocampal neurons by AMPA receptor activation, and, in vivo, 12 and 24 mg/kg of IDRA 21 given orally increases CA1 neuron loss produced by 10 minutes of global ischemia. Treating patients with drugs that potentiate AMPA receptor activation will have to consider these potential effects, particularly when coexistent with conditions in which excessive activation of AMPA receptors may occur (eg, stroke, seizures).
Yamada
K A
KA
Department of Neurology, St Louis Children's Hospital, MO, USA.
Covey
D F
DF
Hsu
C Y
CY
Hu
R
R
Hu
Y
Y
He
Y Y
YY
D000818:Animals; D001581:Benzothiadiazines / Q000737:chemistry / Q000494:pharmacology*; D002545:Brain Ischemia / Q000188:drug therapy*; D002478:Cells, Cultured; D003981:Diazoxide / Q000737:chemistry; D004232:Diuretics; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology; D009410:Nerve Degeneration / Q000188:drug therapy*; D009474:Neurons / Q000737:chemistry / Q000187:drug effects*; D009498:Neurotoxins / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D018091:Receptors, AMPA / Q000502:physiology; D049993:Sodium Chloride Symporter Inhibitors / Q000737:chemistry
D001581:Benzothiadiazines; D004232:Diuretics; D018691:Excitatory Amino Acid Antagonists; D009498:Neurotoxins; D011810:Quinoxalines; D018091:Receptors, AMPA; D049993:Sodium Chloride Symporter Inhibitors; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; C091420:IDRA 21; D018698:Glutamic Acid; D003981:Diazoxide