Numerous studies from the clinical and preclinical literature indicate that general anesthetic agents have toxic effects on the developing brain, but the mechanism of this toxicity is still unknown. Previous studies have focused on the effects of anesthetics on cell survival, dendrite elaboration, and synapse formation, but little attention has been paid to possible effects of anesthetics on the developing axon. Using dissociated mouse cortical neurons in culture, we found that isoflurane delays the acquisition of neuronal polarity by interfering with axon specification. The magnitude of this effect is dependent on isoflurane concentration and exposure time over clinically relevant ranges, and it is neither a precursor to nor the result of neuronal cell death. Propofol also seems to interfere with the acquisition of neuronal polarity, but the mechanism does not require activity at GABAA receptors. Rather, the delay in axon specification likely results from a slowing of the extension of prepolarized neurites. The effect is not unique to isoflurane as propofol also seems to interfere with the acquisition of neuronal polarity. These findings demonstrate that anesthetics may interfere with brain development through effects on axon growth and specification, thus introducing a new potential target in the search for mechanisms of pediatric anesthetic neurotoxicity.
*Department of Anesthesiology, Columbia University
†Fishberg Department of Neuroscience, The Mount Sinai School of Medicine, New York, NY
Supported by the Department of Anesthesiology at Columbia University and the National Institutes of Health Grants GM008464 and NS050634.
The authors have no conflicts of interest to disclose.
Reprints: Cyrus David Mintz, MD, PhD, Department of Anesthesiology, Columbia University, 622 West 168th St., P&S Building, P.O. Box 46, New York, NY 10032 (e-mail: firstname.lastname@example.org).
Received July 16, 2012
Accepted July 16, 2012