title: Bumetanide alleviates epileptogenic and neurotoxic effects of sevoflurane in neonatal rat brain.
abstract: 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.
authors.affiliation: Department of Anesthesiology, University of Florida, Gainesville, Florida 32610-0254, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Edwards
authors.forename: Hina P
authors.initials: HP
authors.lastname: Shah
authors.forename: Wengang
authors.initials: W
authors.lastname: Cao
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Gravenstein
authors.forename: Christoph N
authors.initials: CN
authors.lastname: Seubert
authors.forename: Anatoly E
authors.initials: AE
authors.lastname: Martynyuk
mesh_terms: 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
chemical_list: D018685:Anesthetics, Inhalation; D004232:Diuretics; D008738:Methyl Ethers; D011963:Receptors, GABA-A; D002034:Bumetanide; D000077149:Sevoflurane; D053148:Caspase 3