The GABAA receptor agonist THIP is neuroprotective in organotypic hippocampal slice cultures.
The potential neuroprotective effects of the GABA(A) receptor agonists THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) and muscimol, and the selective GluR5 kainate receptor agonist ATPA ((RS)-2-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl)propanoic acid), which activates GABAergic interneurons, were examined in hippocampal slice cultures exposed to N-methyl-D-aspartate (NMDA). The NMDA-induced excitotoxicity was quantified by densitometric measurements of propidium iodide (PI) uptake. THIP (100-1000 microM) was neuroprotective in slice cultures co-exposed to NMDA (10 microM) for 48 h, while muscimol (100-1000 microM) and ATPA (1-3 microM) were without effect. The results demonstrate that direct GABA(A) agonism can mediate neuroprotection in the hippocampus in vitro as previously suggested in vivo.
Kristensen
Bjarne W
BW
Anatomy and Neurobiology, Institute of Medical Biology, University of Southern Denmark, Winsløwparken 21, DK-5000 Odense C, Denmark. bkristensen@health.sdu.dk
Noraberg
Jens
J
Zimmer
Jens
J
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005968:Glutamate Decarboxylase / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000293:injuries / Q000378:metabolism; D007555:Isoxazoles / Q000494:pharmacology*; D007608:Kainic Acid / Q000009:adverse effects; D009118:Muscimol / Q000494:pharmacology*; D016202:N-Methylaspartate / Q000009:adverse effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009924:Organ Culture Techniques; D011419:Propidium / Q000378:metabolism; D017966:Pyramidal Cells / Q000187:drug effects / Q000293:injuries / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology*
D007555:Isoxazoles; D018696:Neuroprotective Agents; D009118:Muscimol; D011419:Propidium; D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D005968:Glutamate Decarboxylase; C015542:gaboxadol; D007608:Kainic Acid