title: Isoflurane/nitrous oxide anesthesia induces increases in NMDA receptor subunit NR2B protein expression in the aged rat brain.
abstract: Postoperative cognitive dysfunction, POCD, afflicts a large number of elderly surgical patients following surgery with general anesthesia. Mechanisms of POCD remain unclear. N-methyl-D-aspartate (NMDA) receptors, critical in learning and memory, that display protein expression changes with age are modulated by inhalation anesthetics. The aim of this study was to identify protein expression changes in NMDA receptor subunits and downstream signaling pathways in aged rats that demonstrated anesthesia-induced spatial learning impairments. Three-month-old and 18-month-old male Fischer 344 rats were randomly assigned to receive 1.8% isoflurane/70% nitrous oxide (N(2)O) anesthesia for 4h or no anesthesia. Spatial learning was assessed at 2weeks and 3months post-anesthesia in Morris water maze. Hippocampal and cortical protein lysates of 18-month-old rats were immunoblotted for activated caspase 3, NMDA receptor subunits, and extracellular-signal regulated kinase (ERK) 1/2. In a separate experiment, Ro 25-6981 (0.5mg/kg dose) was administered by I.P. injection before anesthesia to 18-month-old rats. Immunoblotting of NR2B was performed on hippocampal protein lysates. At 3months post-anesthesia, rats treated with anesthesia at 18-months-old demonstrated spatial learning impairment corresponding to acute and long-term increases in NR2B protein expression and a reduction in phospho-ERK1/2 in the hippocampus and cortex. Ro 25-6981 pretreatment attenuated the increase in acute NR2B protein expression. Our findings suggest a role for disruption of NMDA receptor mediated signaling pathways in the hippocampus and cortex of rats treated with isoflurane/ N(2)O anesthesia at 18-months-old, leading to spatial learning deficits in these animals. A potential therapeutic intervention for anesthesia associated cognitive deficits is discussed.
authors.affiliation: Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Lana J
authors.initials: LJ
authors.lastname: Mawhinney
authors.forename: Juan Pablo
authors.initials: JP
authors.lastname: de Rivero Vaccari
authors.forename: Ofelia F
authors.initials: OF
authors.lastname: Alonso
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Jimenez
authors.forename: Concepción
authors.initials: C
authors.lastname: Furones
authors.forename: W Javier
authors.initials: WJ
authors.lastname: Moreno
authors.forename: Michael C
authors.initials: MC
authors.lastname: Lewis
authors.forename: W Dalton
authors.initials: WD
authors.lastname: Dietrich
authors.forename: Helen M
authors.initials: HM
authors.lastname: Bramlett
mesh_terms: D000375:Aging / Q000187:drug effects* / Q000378:metabolism; D000704:Analysis of Variance; D018685:Anesthetics, Inhalation / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000166:cytology / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D007530:Isoflurane / Q000494:pharmacology*; D008297:Male; D009474:Neurons / Q000378:metabolism; D009609:Nitrous Oxide / Q000494:pharmacology*; D010636:Phenols / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D011930:Reaction Time / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D013037:Spatial Behavior / Q000187:drug effects; D013997:Time Factors
chemical_list: D018685:Anesthetics, Inhalation; D018691:Excitatory Amino Acid Antagonists; C121001:NR2B NMDA receptor; D010636:Phenols; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; C109643:Ro 25-6981; D007530:Isoflurane; D053148:Caspase 3; D009609:Nitrous Oxide