Document Detail

The inhaled anesthetic, isoflurane, enhances Ca2+-dependent survival signaling in cortical neurons and modulates MAP kinases, apoptosis proteins and transcription factors during hypoxia.
MedLine Citation:
PMID:  16861427     Owner:  NLM     Status:  MEDLINE    
We tested whether the protection of hypoxic neurons by the inhaled anesthetic isoflurane is related to the Ca2+-dependent phosphorylation of MAP kinases and anti-apoptotic co-factors. In cultures of mouse cortical neurons we measured changes in the phosphorylation of Ca2+-dependent and Ca2+-independent MAP kinases, transcription factors, and apoptosis regulators after hypoxia or hypoxia combined with isoflurane (1% in gas phase). In hypoxic neurons, isoflurane reduced cell death and TUNEL staining by >80%. Isoflurane released Ca2+ from intracellular stores, increasing [Ca2+]i in oxygenated neurons by approximately 20%. Neuroprotection was associated with a smaller increase in [Ca2+]i in hypoxic neurons and required IP3 receptors and phospholipase C. In hypoxic neurons, isoflurane increased the phosphorylation of the Ca2+-dependent MAP kinases Pyk2 and p42/44 (ERK). The Ca2+-independent MAP kinase p38 pathway showed increased phosphorylation with isoflurane but not with ionomycin, a Ca2+ ionophore. JNK was phosphorylated in hypoxic neurons in the presence of isoflurane, as was the transcription factor c-Jun; JNK inhibition with SP600125 prevented both phosphorylation of c-Jun and neuroprotection. Isoflurane decreased phosphorylation of the pro-apoptotic cofactors Bad and p90RSK and increased Akt phosphorylation. However, with the exception of c-Jun, transcription factors (Elk-1, GSK-3, Forkhead, p90RSK) decreased or remained unchanged. We conclude that isoflurane's protection of hypoxic cortical neurons involves signaling that includes changes in intracellular Ca2+ regulation, several MAP kinase pathways and modulation of apoptosis regulators.
Philip E Bickler; Christian S Fahlman
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Anesthesia and analgesia     Volume:  103     ISSN:  1526-7598     ISO Abbreviation:  Anesth. Analg.     Publication Date:  2006 Aug 
Date Detail:
Created Date:  2006-07-24     Completed Date:  2006-08-09     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  1310650     Medline TA:  Anesth Analg     Country:  United States    
Other Details:
Languages:  eng     Pagination:  419-29, table of contents     Citation Subset:  AIM; IM    
Severinghaus-Radiometer Research Laboratories, Department of Anesthesia and Perioperative Care, University of California at San Francisco, San Francisco, California 94143-0542, USA.
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MeSH Terms
Anesthetics, Inhalation / pharmacology*
Apoptosis / drug effects*
Calcium / metabolism*
Cell Hypoxia
Cells, Cultured
Cerebral Cortex / drug effects*
Extracellular Signal-Regulated MAP Kinases / physiology
In Situ Nick-End Labeling
Isoflurane / pharmacology*
MAP Kinase Signaling System / drug effects*
Neuroprotective Agents / pharmacology*
Proto-Oncogene Proteins c-akt / physiology
Transcription Factors / metabolism*
Type C Phospholipases / physiology
p38 Mitogen-Activated Protein Kinases / physiology
Grant Support
Reg. No./Substance:
0/Anesthetics, Inhalation; 0/Neuroprotective Agents; 0/Transcription Factors; 26675-46-7/Isoflurane; 7440-70-2/Calcium; EC Proteins c-akt; EC Signal-Regulated MAP Kinases; EC Mitogen-Activated Protein Kinases; EC 3.1.4.-/Type C Phospholipases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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