NEUROSTEROID INHIBITION OF CELL-DEATH

Diverse gamma-aminobutyric acid (GABAA) receptor modulators exhibited novel cytoprotective effects and mechanisms of action in rabbit renal proximal tubules subjected to mitochondrial inhibition (antimycin A) o r hypoxia. Cytoprotective potencies (50% effective concentration, EC50 ) were 0.3 nM allopregnanolone (AP) > 0.4 nM 17 alpha-OH-allopregnanol one (17 alpha-OH-AP) > 30 nM dehydroepiandrosterone sulfate (DHEAS) = 30 nM pregnenolone sulfate (PS) > 500 nM pregnenolone (PREG) > 30 mu M muscimol > 10 mM GABA following antimycin A exposure. Maximal protect ion with AP and 17 alpha-OH-AP was 70%, whereas DHEAS, PS, PREG, and m uscimol produced 100% cytoprotection. Experiments with AP, PS, and mus cimol revealed the return of mitochondrial function and active Na+ tra nsport following hypoxia/reoxygenation. Muscimol inhibited the antimyc in A-induced influx of both extracellular Ca2+ and Cl- that occurs dur ing the late phase of cell injury, whereas the neurosteroids only inhi bited influx of Cl-. Radioligand binding studies with AP and PS did no t reveal a specific binding site; however, structural requirements wer e observed for cytoprotective potency and efficacy. In conclusion, we suggest that the GABAA receptor modulators muscimol and neurosteroids are cytoprotective at different cellular sites in the late phase of ce ll injury; muscimol inhibits Ca2+ and subsequent Cl- influx, whereas t he neurosteroids inhibit Cl- influx.