The effect of sevoflurane on neuronal degeneration and GABAA subunit composition in a developing rat model of organotypic hippocampal slice cultures.
OBJECTIVE
The GABA(A) receptor subunit composition undergoes a switch from a predominantly alpha2 to a predominantly alpha1 around postnatal day (PND) 7 in a rat pup. This developmental switch in the GABA(A) receptor subunit composition changes the kinetics and pharmacologic properties of the GABA(A) receptor. Using a developmental organotypic hippocampal slice model, we hypothesized that the developmental changes in the GABA(A) receptor subunit composition may promote neurodegeneration after exposure to sevoflurane.


METHODS
Organotypic hippocampal slices (OHS) were prepared from rat pups on PND 4, 7, and 14 and exposed to 2.0% sevoflurane or air for 5 hours. Hippocampal CA1, CA3, and dentate gyrus neuronal survival and GABA(A) receptor subunit composition were assessed immediately, 24 and 72 hours after exposure and compared with air.


RESULTS
Early cell death immediately after exposure to sevoflurane was statistically significant in the PND14 (P<0.001). At 24 hours, cell death was not significant for any PND age-examined OHS. However, at 72 hours, cell death was significant in the OHS prepared from the PND7 and 4 rat pups (P<0.001). In further analysis, either a decrease in the alpha1 and/or increase in the alpha2 subunit composition promoted cell survival in the PND 4 and 7 OHS. On PND14, cell survival was promoted by an increase in the alpha1 subunit composition.


CONCLUSIONS
This in vitro investigation supports an age-dependent and GABA(A) receptor subunit composition relationship between 2.0% sevoflurane exposure and cell death.
Piehl
Estee
E
University of Colorado, Denver, CO, USA.
Foley
Lisa
L
Barron
Max
M
D'Ardenne
Chris
C
Guillod
Paul
P
Wise-Faberowski
Lisa
L
D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000502:physiology; D004396:Coloring Agents; D004789:Enzyme Activation / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism*; D008738:Methyl Ethers / Q000494:pharmacology*; D009410:Nerve Degeneration / Q000517:prevention & control*; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism*; D000077149:Sevoflurane
D018685:Anesthetics, Inhalation; D004396:Coloring Agents; C546242:Gabra1 protein, rat; C520011:Gabra2 protein, rat; D008738:Methyl Ethers; D011963:Receptors, GABA-A; D000077149:Sevoflurane; D053148:Caspase 3