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.
Anatomy and Neurobiology, Institute of Medical Biology, University of Southern Denmark, Winsløwparken 21, DK-5000 Odense C, Denmark. bkristensen@health.sdu.dk
Bjarne W
BW
Kristensen
Jens
J
Noraberg
Jens
J
Zimmer
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