PMID- 9435674
OWN - NLM
STAT- MEDLINE
DCOM- 19980209
LR  - 20190510
IS  - 0002-9513 (Print)
IS  - 0002-9513 (Linking)
VI  - 273
IP  - 6
DP  - 1997 Dec
TI  - Neurosteroid inhibition of cell death.
PG  - F869-76
LID - 10.1152/ajprenal.1997.273.6.F869 [doi]
AB  - 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) or hypoxia. Cytoprotective 
      potencies (50% effective concentration, EC50) were 0.3 nM allopregnanolone (AP) > 
      0.4 nM 17 alpha-OH-allopregnanolone (17 alpha-OH-AP) > 30 nM 
      dehydroepiandrosterone sulfate (DHEAS) = 30 nM pregnenolone sulfate (PS) > 500 nM 
      pregnenolone (PREG) > 30 microM muscimol > 10 mM GABA following antimycin A 
      exposure. Maximal protection with AP and 17 alpha-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 GABAA 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.
FAU - Waters, S L
AU  - Waters SL
AD  - Department of Pharmacology and Toxicology, University of Arkansas for Medical 
      Sciences, Little Rock 72205, USA.
FAU - Miller, G W
AU  - Miller GW
FAU - Aleo, M D
AU  - Aleo MD
FAU - Schnellmann, R G
AU  - Schnellmann RG
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Am J Physiol
JT  - The American journal of physiology
JID - 0370511
RN  - 0 (Alkaloids)
RN  - 0 (Benzylisoquinolines)
RN  - 0 (Isoxazoles)
RN  - 0 (Pregnanes)
RN  - 0 (Receptors, GABA-A)
RN  - 2763-96-4 (Muscimol)
RN  - 56-12-2 (gamma-Aminobutyric Acid)
RN  - 57B09Q7FJR (Dehydroepiandrosterone Sulfate)
RN  - 642-15-9 (Antimycin A)
RN  - 8890V3217X (hydrastine)
RN  - EC 1.1.1.27 (L-Lactate Dehydrogenase)
RN  - K1M5RVL18S (gaboxadol)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Alkaloids/pharmacology
MH  - Animals
MH  - Antimycin A/pharmacology
MH  - Benzylisoquinolines
MH  - Calcium/metabolism
MH  - Cell Death/drug effects
MH  - *Cell Hypoxia
MH  - Cells, Cultured
MH  - Dehydroepiandrosterone Sulfate/pharmacology
MH  - Female
MH  - Isoxazoles/pharmacology
MH  - Kidney Tubules, Proximal/*cytology/drug effects
MH  - Kinetics
MH  - L-Lactate Dehydrogenase
MH  - Mitochondria/drug effects/metabolism
MH  - Muscimol/chemistry/pharmacology
MH  - Oxygen Consumption/drug effects
MH  - Pregnanes/chemistry/*pharmacology
MH  - Rabbits
MH  - Receptors, GABA-A/drug effects/*physiology
MH  - gamma-Aminobutyric Acid/*pharmacology
EDAT- 1998/01/22 00:00
MHDA- 1998/01/22 00:01
CRDT- 1998/01/22 00:00
PHST- 1998/01/22 00:00 [pubmed]
PHST- 1998/01/22 00:01 [medline]
PHST- 1998/01/22 00:00 [entrez]
AID - 10.1152/ajprenal.1997.273.6.F869 [doi]
PST - ppublish
SO  - Am J Physiol. 1997 Dec;273(6):F869-76. doi: 10.1152/ajprenal.1997.273.6.F869.