title: Suppression of ERK phosphorylation through oxidative stress is involved in the mechanism underlying sevoflurane-induced toxicity in the developing brain.
abstract: In animal models, neonatal exposure to general anesthetics significantly increased neuronal apoptosis with subsequent behavioral deficits in adulthood. Although the underlying mechanism is largely unknown, involvement of extracellular signal-regulated kinases (ERKs) is speculated since ERK phosphorylation is decreased by neonatal anesthetic exposure. Importance of ERK phosphorylation for neuronal development is underscored by our recent finding that transient suppression of ERK phosphorylation during the neonatal period significantly increased neuronal apoptosis and induced behavioral deficits. However, it is still unknown as to what extent decreased ERK phosphorylation contributes to the mechanism underlying anesthetic-induced toxicity. Here we investigated the causal relationship of decreased ERK phosphorylation and anesthetic-induced toxicity in the developing brain. At postnatal day 6 (P6), mice were exposed to sevoflurane (2%) or the blood-brain barrier-penetrating MEK inhibitor, α-[amino[(4-aminophenyl)thio]methylene]-2-(trifluoromethyl)benzeneacetonitrile (SL327) (50 mg/kg). Transient suppression of ERK phosphorylation by an intraperitoneal injection of SL327 at P6 significantly increased apoptosis similar to sevoflurane-induced apoptosis. Conversely, SL327 administration at P14 or P21 did not induce apoptosis, even though ERK phosphorylation was inhibited. Restoring ERK phosphorylation by administration of molecular hydrogen ameliorated sevoflurane-induced apoptosis. Together, our results strongly suggests that suppressed ERK phosphorylation is critically involved in the mechanism underlying anesthetic-induced toxicity in the developing brain.
authors.affiliation: Department of Anesthesiology, National Defense Medical College, 3-2 Namiki, Tokorozawa 359-8513, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Yufune
authors.affiliation: Department of Anesthesiology, National Defense Medical College, 3-2 Namiki, Tokorozawa 359-8513, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Satoh
authors.affiliation: Department of Anesthesiology, National Defense Medical College, 3-2 Namiki, Tokorozawa 359-8513, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Akai
authors.affiliation: Department of Obstetrics and Gynecology, Japan Self-Defense Forces Central Hospital, 1-2-24 Ikejiri, Setagaya, Tokyo 154-8532, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Yoshinaga
authors.affiliation: Department of Anatomy and Neurobiology, National Defense Medical College, 3-2 Namiki, Tokorozawa 359-8513, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kobayashi
authors.affiliation: Aging Neuroscience Research Team, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, 35-2 Sakaecho, Itabashi, Tokyo 173-0015, Japan.
authors.forename: Shogo
authors.initials: S
authors.lastname: Endo
authors.affiliation: Department of Anesthesiology, National Defense Medical College, 3-2 Namiki, Tokorozawa 359-8513, Japan.
authors.forename: Tomiei
authors.initials: T
authors.lastname: Kazama
mesh_terms: D000607:Aminoacetonitrile / Q000031:analogs & derivatives / Q000494:pharmacology; D018685:Anesthetics, Inhalation / Q000633:toxicity*; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D006859:Hydrogen / Q000494:pharmacology; D008738:Methyl Ethers / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077149:Sevoflurane; D013997:Time Factors
chemical_list: D018685:Anesthetics, Inhalation; D008738:Methyl Ethers; D017382:Reactive Oxygen Species; C424127:SL 327; D000607:Aminoacetonitrile; D000077149:Sevoflurane; D006859:Hydrogen; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D053148:Caspase 3