PMID- 1319167
OWN - NLM
STAT- MEDLINE
DCOM- 19920730
LR  - 20161123
IS  - 0893-133X (Print)
IS  - 0893-133X (Linking)
VI  - 6
IP  - 2
DP  - 1992 Feb
TI  - Cellular regulation of the benzodiazepine/GABA receptor: arachidonic acid, 
      calcium, and cerebral ischemia.
PG  - 119-25
AB  - The effects of cellular mediators that contribute to ischemia-induced neuronal 
      degeneration on gamma-aminobutyric acid (GABAA)-receptor function were studied. 
      In vitro, phospholipase A2 (PLA2) inhibited muscimol-induced 36Cl- uptake in 
      cerebral cortical synaptoneurosomes. The major hydrolysis product of PLA2 
      activity, arachidonic acid, also inhibited GABA-mediated 36Cl- uptake. The 
      unsaturated nature of arachidonic acid makes it (and its metabolites) highly 
      susceptible to peroxidation by oxygen radicals. Incubation of synaptoneurosomes 
      with the superoxide radical-generating system, xanthine and xanthine oxidase, 
      decreased muscimol-induced 36Cl- uptake, suggesting that the peroxidation of 
      arachidonic acid and/or its metabolites interferes with GABAA-receptor function. 
      Another factor involved in ischemia-induced neuronal degeneration is an increase 
      in intracellular Ca2+. Calcium also inhibited GABA-mediated 36Cl- flux, 
      consistent with its ability to activate PLA2. In contrast, Mg2+, which blocks 
      Ca2+ channels, enhanced muscimol-induced 36Cl- uptake, consistent with its 
      neuroprotective effects. Each of these cellular processes is activated during 
      cerebral ischemia and can lead to neuronal degeneration. We used a model of 
      transient forebrain ischemia in gerbils to determine if GABAA-receptor regulation 
      is altered in vivo at a time when CA1 hippocampal cells have degenerated. Four 
      days after a 5 minute bilateral carotid artery occlusion, receptor 
      autoradiography was performed to measure the binding of 
      [35S]t-butylbicyclophosphorothionate (TBPS) to the GABA-gated chloride channel. 
      Significant decreases in TBPS binding were observed only in the dendritic layers 
      (stratum oriens and lacunosem moleculare) of the CA1 hippocampus. The results 
      suggest that ischemia-induced cellular processes that contribute to cell death 
      can decrease GABA-gated chloride channels on dendrites of CA1 pyramidal cells, 
      and that GABAA receptors may also reside on neurons afferent to or intrinsic to 
      the dendritic layers of CA1 hippocampus.
FAU - Schwartz, R D
AU  - Schwartz RD
AD  - Department of Pharmacology, Duke University Medical Center, Durham, NC 27710.
FAU - Yu, X
AU  - Yu X
FAU - Wagner, J
AU  - Wagner J
FAU - Ehrmann, M
AU  - Ehrmann M
FAU - Mileson, B E
AU  - Mileson BE
LA  - eng
GR  - NS 24577/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - England
TA  - Neuropsychopharmacology
JT  - Neuropsychopharmacology : official publication of the American College of 
      Neuropsychopharmacology
JID - 8904907
RN  - 0 (Bridged Bicyclo Compounds)
RN  - 0 (Bridged Bicyclo Compounds, Heterocyclic)
RN  - 0 (Convulsants)
RN  - 0 (Receptors, GABA-A)
RN  - 27YG812J1I (Arachidonic Acid)
RN  - 70636-86-1 (tert-butylbicyclophosphorothionate)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Animals
MH  - Arachidonic Acid/*physiology
MH  - Autoradiography
MH  - Brain/pathology
MH  - Brain Ischemia/pathology/*physiopathology
MH  - Bridged Bicyclo Compounds
MH  - *Bridged Bicyclo Compounds, Heterocyclic
MH  - Calcium/*physiology
MH  - Convulsants/pharmacology
MH  - Gerbillinae
MH  - Hippocampus/cytology/physiology
MH  - In Vitro Techniques
MH  - Male
MH  - Nerve Degeneration
MH  - Neurons/physiology/ultrastructure
MH  - Rats
MH  - Rats, Inbred Strains
MH  - Receptors, GABA-A/*physiology
MH  - Synaptosomes/physiology
EDAT- 1992/02/01 00:00
MHDA- 1992/02/01 00:01
CRDT- 1992/02/01 00:00
PHST- 1992/02/01 00:00 [pubmed]
PHST- 1992/02/01 00:01 [medline]
PHST- 1992/02/01 00:00 [entrez]
PST - ppublish
SO  - Neuropsychopharmacology. 1992 Feb;6(2):119-25.