title: Role of Steroids in Hyperexcitatory Adverse and Anesthetic Effects of Sevoflurane in Neonatal Rats.
abstract: Recent studies have demonstrated that long-term developmental effects of neonatal anesthesia were more prominent in males. We tested whether steroids, in general, and sex steroids, in particular, are involved in the mediation of sevoflurane-caused paradoxical cortical seizures during the early postnatal period.
  
  
  
  Cortical electroencephalograms, hippocampal synaptic activity, serum levels of steroids and the loss of the righting reflex (LORR), a marker of anesthetic effect, were measured on postnatal days 4-6 in Sprague Dawley rats of both genders exposed to 2.1% sevoflurane.
  
  
  
  Episodes of seizures, persistent spikes in electroencephalograms and increases in serum corticosterone were similar in both genders. In the order of increasing potency, the corticosteroid receptor antagonist RU 28318, the estradiol receptor antagonist ICI 182780 and the estradiol synthesis inhibitor formestane decreased sevoflurane-induced seizures. Exogenous estradiol increased sevoflurane-caused seizures, spikes and serum levels of corticosterone. These estradiol-enhanced seizures and spikes were depressed by ICI 182780 and the NKCC1 inhibitor, bumetanide, while RU 28318 decreased seizures only. In hippocampal CA1 neurons, estradiol increased the amplitude, rise time and area under the curve of gamma-aminobutyric acid type A receptor (GABAAR)-mediated miniature postsynaptic currents. Exogenous estradiol shortened, while ICI 182780 and formestane lengthened the time needed for sevoflurane to induce LORR.
  
  
  
  These findings provide evidence for gender-independent acute electroencephalographic effects of sevoflurane at this age. Corticosterone and estradiol are involved in the mediation of sevoflurane-induced seizures. Estradiol, but not corticosterone, also contributes to sevoflurane-caused spikes, by enhancing GABAAR-mediated excitation in the cortex. By increasing GABAAR-mediated inhibition in more mature caudal regions of the brain, estradiol contributes to sevoflurane-induced LORR.
authors.forename: Jiaqiang
authors.initials: J
authors.lastname: Zhang
authors.forename: Changqing
authors.initials: C
authors.lastname: Xu
authors.forename: Dyanet L
authors.initials: DL
authors.lastname: Puentes
authors.forename: Christoph N
authors.initials: CN
authors.lastname: Seubert
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Gravenstein
authors.forename: Anatoly E
authors.initials: AE
authors.lastname: Martynyuk
mesh_terms: D000777:Anesthetics / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D058256:Brain Waves / Q000187:drug effects*; D002034:Bumetanide / Q000494:pharmacology; D004347:Drug Interactions; D004958:Estradiol / Q000031:analogs & derivatives / Q000097:blood / Q000494:pharmacology; D065171:Estrogen Receptor Antagonists / Q000494:pharmacology; D005260:Female; D000077267:Fulvestrant; D006624:Hippocampus / Q000166:cytology; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008738:Methyl Ethers / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D057897:Reflex, Righting / Q000187:drug effects; D000077149:Sevoflurane; D049994:Sodium Potassium Chloride Symporter Inhibitors / Q000494:pharmacology; D013148:Spironolactone / Q000031:analogs & derivatives / Q000494:pharmacology; D013256:Steroids / Q000009:adverse effects* / Q000097:blood
chemical_list: D000777:Anesthetics; D065171:Estrogen Receptor Antagonists; D008738:Methyl Ethers; D049994:Sodium Potassium Chloride Symporter Inhibitors; D013256:Steroids; D002034:Bumetanide; D000077267:Fulvestrant; D013148:Spironolactone; D000077149:Sevoflurane; D004958:Estradiol; C041006:RU 28318