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 &mgr;mol/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. Conclusion:These results support the possibility that excitatory output of sevoflurane-potentiated &ggr;-aminobutyric acid type A/glycine systems may contribute to epileptogenic and neurotoxic effects in early postnatal rats.

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