Neurosteroid inhibition of cell death

Shayla L. Waters, Gary W. Miller, Michael D. Aleo, Rick G. Schnellmann

Research output: Contribution to journalArticlepeer-review

37 Scopus citations


Diverse γ-aminobutyric acid (GABA(A)) receptor modulators exhibited novel cytoprotective effects and mechanisms of action in rabbit renal proximal tubules subjected to mitochondrial inhibition (antimycin A) or hypoxia. Cytoprotective potencies (50% effective concentration, EC50) were 0.3 nM allopregnanolone (AP) > 0.4 nM 17α-OH-allopregnanolone (17α-OH-AP) > 30 nM dehydroepiandrosterone sulfate (DHEAS) = 30 nM pregnenolone sulfate (PS) > 500 nM pregnenolone (PREG) > 30 μM museimol > 10 mM GABA following antimycin A exposure. Maximal protection with AP and 17α-OH-AP was 70%, whereas DHEAS, PS, PREG, and muscimol produced 100% cytoprotection. Experiments with AP, PS, and muscimol revealed the return of mitochondrial function and active Na+ transport following hypoxia/reoxygenation. Muscimol inhibited the antimycin A-induced influx of both extracellular Ca2+ and Cl- that occurs during the late phase of cell injury, whereas the neurosteroids only inhibited influx of Cl-. Radioligand binding studies with AP and PS did not reveal a specific binding site; however, structural requirements were observed for cytoprotective potency and efficacy. In conclusion, we suggest that the GABA(A) receptor modulators muscimol and neurosteroids are cytoprotective at different cellular sites in the late phase of cell injury; muscimol inhibits Ca2+ and subsequent Cl- influx, whereas the neurosteroids inhibit Cl- influx.

Original languageEnglish (US)
Pages (from-to)F869-F876
JournalAmerican Journal of Physiology - Renal Physiology
Issue number6 42-6
StatePublished - Dec 1997
Externally publishedYes


  • Anoxia
  • Calcium influx
  • Chloride influx
  • Renal proximal tubules
  • γ- aminobutyric acid receptor

ASJC Scopus subject areas

  • Physiology
  • Urology


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