Editors' ChoiceAnesthesiology

Milk of Amnesia

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Science Translational Medicine  07 Nov 2012:
Vol. 4, Issue 159, pp. 159ec201
DOI: 10.1126/scitranslmed.3005250

Propofol—a creamy white, intravenous anesthetic—is referred to as the “milk of amnesia.” Although therapeutically useful, propofol and other intravenous or inhaled anesthetics are suspected of being toxic to the brains of the very young and very old. Past studies have suggested that propofol can kill immature neurons. Now, Sall and colleagues demonstrate that the concentrations of propofol used clinically do not kill neural precursor cells, but they may influence cell fate.

Neural precursor cells were isolated from the hippocampus—a brain structure important for memory and cognition—of neonatal rat pups. When incubated with these cells, propofol did not affect the number of precursors in the S phase of the cell cycle, as measured by incorporation of the synthetic nucleoside bromodeoxyuridine into DNA of proliferating cells. Dose-dependent toxicity was apparent, however: The cells showed increased lactate dehydrogenase, indicating a shift to anaerobic metabolism. Nevertheless, this toxicity only occurred at doses outside of the clinically relevant range. In contrast to past studies of anesthetic effects on immature neurons, caspase-3/7 activity was not altered by any dose of propofol, excluding apoptosis as a mechanism of cell death—similarly, neither calcium nor the γ-aminobutyric acid type A receptor, the molecular target of propofol-mediated cell death. This suggests that different molecular mechanisms may account for the therapeutic and toxic effects of general anesthetics.

Although clinical doses of propofol had no effect on neural precursor cells, Sall and colleagues found that these concentrations did lead to an increase in differentiation of the neural precursors. Similar alterations of cell fate in differentiating neurons have been seen with the inhaled anesthetic isoflurane.

The article by Sall and colleagues clarifies the effects of a commonly used anesthetic on developing neurons. Given the toxic effect of propofol on immature neurons and its effect on the cell fate of neural precursor cells, the next translational challenge is to determine the net effect of anesthetics on brain development. Understanding these influences will be critical to achieving safe care for neonatal patients in surgery.

J. W. Sall, G. Stratmann, J. Leong, E. Woodward, P. E. Bickler, Propofol at clinically relevant concentrations increases neuronal differentiation but is not toxic to hippocampal neural precursor cells in vitro. Anesthesiology 117, 1080–1090 (2012). [Abstract]

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