Bumetanide Alleviates Epileptogenic and Neurotoxic Effects of Sevoflurane in Neonatal Rat Brain

• DOI: 10.1097/aln.0b013e3181cf9138
• Publication Date: 2010-02-17T07:31:01Z
• Authors: David A. Edwards; Hina P. Shah; Wengang Cao; Nikolaus Gravenstein; Christoph N. Seubert; Anatoly E. Martynyuk
• Keywords: Methyl Ethers; Epilepsy; Caspase 3; Blotting, Western; Electroencephalography; Receptors, GABA-A; Rats; 3. Good health; Electrophysiology; Enzyme Activation; Rats, Sprague-Dawley; Sevoflurane; 03 medical and health sciences; 0302 clinical medicine; Animals, Newborn; Anesthetics, Inhalation; Animals; Neurotoxicity Syndromes; Anesthesia, Inhalation; Diuretics; Bumetanide

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.

Conclusion 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.