Enhancement of GABA neurotransmission after cerebral ischemia in the rat reduces loss of hippocampal CA1 pyramidal cells.
Increased excitation may be involved in the development of delayed CA1 pyramidal cell death in hippocampus after global cerebral ischemia. Therefore we investigated the possible neuroprotective effect of the GABA uptake inhibitor, R-(-)-1-(4,4-(3-methyl-2-thienyl)-3-butenyl)-3-piperidine carboxylic acid (No-328), in a rat cerebral ischemia model of delayed CA1 pyramidal cell death. No-328 in doses of 36 mg/kg given 30 min before, and 1, 24, 48 and 72 h after ischemia significantly reduced the CA1 neuron loss. Doses of 50 mg/kg of No-328 given immediately before, 24 h and 48 h after ischemia, also reduced the CA1 neuron loss significantly. Furthermore, we demonstrated that postischemic treatment with diazepam (4 x 15 mg/kg) significantly reduced the CA1 neuron loss. However, postischemic treatment with several doses (5 x 12 mg/kg) of the GABA analog, 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP), offered no CA1 neuron protection when given alone, but when administrated together with diazepam (4 x 15 mg/kg) it significantly reduced the CA1 neuron loss. We conclude that enhancement of postischemic GABA neurotransmission, during the first 2-3 days after ischemia, may reduce the ischemic CA1 damage through a continuous increase in hippocampal GABA extracellular levels (No-328), or through an increase in sensitivity to GABA neurotransmission (diazepam).
Johansen
F F
FF
Institute of Neuropathology, University of Copenhagen, Denmark.
Diemer
N H
NH
D000818:Animals; D001143:Arousal / Q000187:drug effects / Q000502:physiology; D002545:Brain Ischemia / Q000503:physiopathology*; D002452:Cell Count; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D003975:Diazepam / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology*; D007555:Isoxazoles / Q000494:pharmacology; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009410:Nerve Degeneration / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009557:Nipecotic Acids / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D000078308:Tiagabine; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D007555:Isoxazoles; D009557:Nipecotic Acids; D005680:gamma-Aminobutyric Acid; C015542:gaboxadol; D003975:Diazepam; D000078308:Tiagabine