Bumetanide alleviates epileptogenic and neurotoxic effects of sevoflurane in neonatal rat brain.
BACKGROUND
We tested the hypothesis that in newborn rats, sevoflurane may cause seizures, neurotoxicity, and impairment in synaptic plasticity-effects that may be diminished by the Na-K-2Cl cotransporter 1 inhibitor, bumetanide.


METHODS
Electroencephalography, activated caspase-3, and hippocampal long-term potentiation were measured in rats exposed to 2.1% sevoflurane for 0.5-6 h at postnatal days 4-17 (P4-P17).


RESULTS
Arterial blood gas samples drawn at a sevoflurane concentration of 2.1% showed no evidence of either hypoxia or hypoventilation in spontaneously breathing rats. Higher doses of sevoflurane (e.g., 2.9%) caused respiratory depression. During anesthesia maintenance, the electroencephalography exhibited distinctive episodes of epileptic seizures in 40% of P4-P8 rats. Such seizure-like activity was not detected during anesthesia maintenance in P10-P17 rats. Emergence from 3 h of anesthesia with sevoflurane resulted in tonic/clonic seizures in some P10-P17 rats but not in P4-P8 rats. Bumetanide (5 micromol/kg, intraperitoneally) significantly decreased seizures in P4-P9 rats but did not affect the emergence seizures in P10-P17 rats. Anesthesia of P4 rats with sevoflurane for 6 h caused a significant increase in activated caspase-3 and impairment of long-term potentiation induction measured at 1 and 14-17 days after exposure to sevoflurane, respectively. Pretreatment of P4 rats with bumetanide nearly abolished the increase in activated caspase-3 but did not alleviate impairment of long-term potentiation.


CONCLUSIONS
These results support the possibility that excitatory output of sevoflurane-potentiated gamma-aminobutyric acid type A/glycine systems may contribute to epileptogenic and neurotoxic effects in early postnatal rats.
Edwards
David A
DA
Department of Anesthesiology, University of Florida, Gainesville, Florida 32610-0254, USA.
Shah
Hina P
HP
Cao
Wengang
W
Gravenstein
Nikolaus
N
Seubert
Christoph N
CN
Martynyuk
Anatoly E
AE
D000769:Anesthesia, Inhalation; D018685:Anesthetics, Inhalation / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D002034:Bumetanide / Q000627:therapeutic use*; D053148:Caspase 3 / Q000378:metabolism; D004232:Diuretics / Q000627:therapeutic use*; D004569:Electroencephalography / Q000187:drug effects; D004594:Electrophysiology; D004789:Enzyme Activation / Q000187:drug effects; D004827:Epilepsy / Q000139:chemically induced* / Q000517:prevention & control*; D008738:Methyl Ethers / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D020258:Neurotoxicity Syndromes / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects / Q000502:physiology; D000077149:Sevoflurane
D018685:Anesthetics, Inhalation; D004232:Diuretics; D008738:Methyl Ethers; D011963:Receptors, GABA-A; D002034:Bumetanide; D000077149:Sevoflurane; D053148:Caspase 3