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NEUROSURGICAL ANESTHESIA

The Inhaled Anesthetic, Isoflurane, Enhances Ca²⁺-Dependent Survival Signaling in Cortical Neurons and Modulates MAP Kinases, Apoptosis Proteins and Transcription Factors During Hypoxia

From the Severinghaus-Radiometer Research Laboratories, Department of Anesthesia and Perioperative Care, University of California at San Francisco, San Francisco, California.

Address correspondence and reprint requests to Philip E. Bickler, Sciences 255, Box 0542, University of California Medical Center, 513 Parnassus Avenue, San Francisco, CA 94143-0542. Address e-mail to bicklerp{at}anesthesia.ucsf.edu.

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.

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Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999