Potential of xenon to induce or to protect against neuroapoptosis in the developing mouse brain
Davide Cattano1, Peter Williamson, Kimiko Fukui
1Department of Anestesiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Purpose:
Drugs that suppress neuronal activity, including all general anesthetics that have been tested thus far (ketamine, midazolam, isoflurane, propofol, and a cocktail of midazolam, nitrous oxide and isoflurane), trigger neuroapoptosis in the developing rodent brain. Combinations of nitrous oxide and isoflurane, or ketamine and propofol, cause more severe neuroapoptosis than any single agent by itself, which suggests a positive correlation between increased levels of anesthesia and increased severity of neuroapoptosis. In contrast, there is evidence that the rare gas, xenon, which has anesthetic properties, protects against isoflurane-induced neuroapoptosis in the infant rat brain, while not inducing neuroapoptosis by itself. The present study was undertaken to evaluate the potential of xenon to induce neuroapoptosis or to protect against neuroapoptosis induced by isoflurane in the infant mouse brain.
Methods:
Seven-day-old C57BL/6 mice were exposed to one of four conditions: air (control); 0.75% isoflurane; 70% xenon; or 0.75% isoflurane + 70% xenon for four hours. For histopathological evaluation of the brains, all pups were euthanized two hours later using activated caspase-3 immunohistochemical staining to detect apoptotic neurons. Under each condition, quantitative assessment of the number of apoptotic neurons in the cerebral cortex (CC) and in the caudate/putamen (C/P) was performed by unbiased stereology.
Results:
The combination of xenon + isoflurane produced a deeper level of anesthesia than either agent alone. Both xenon alone (p < 0.003 in CC; p < 0.02 in C/P) and isoflurane alone (p < 0.001 in both CC and C/P) induced a significant increase in neuroapoptosis compared to controls. The neuroapoptotic response to isoflurane was substantially more robust than the response to xenon. When xenon was administered together with isoflurane, the apoptotic response was reduced to a level lower than that for isoflurane alone (p < 0.01 in CP; marginally non-significant in CC).
Conclusions:
We conclude that xenon, in the infant mouse brain, has paradoxical properties. It triggers neuroapoptosis, and when combined with isoflurane, it increases the depth of anesthesia, and retains its own apoptogenic activity. However, it suppresses, rather than augments, isoflurane's apoptogenic activity.
Insights
Xenon, an anesthetic gas, triggers neuroapoptosis in infant mice. While it deepens anesthesia with isoflurane, it paradoxically reduces isoflurane-induced neuroapoptosis, despite retaining its own apoptogenic activity.
Area of Science:
- Neuroscience
- Anesthesiology
- Developmental Biology
Background:
- General anesthetics, including isoflurane, induce neuroapoptosis in developing brains.
- Combinations of anesthetics can exacerbate neuroapoptosis.
- Xenon, a rare gas with anesthetic properties, has shown neuroprotective effects against isoflurane in infant rats.
Purpose of the Study:
- To investigate xenon's potential to induce neuroapoptosis in the infant mouse brain.
- To evaluate xenon's effect on isoflurane-induced neuroapoptosis in infant mice.
Main Methods:
- Seven-day-old C57BL/6 mice were exposed to air, isoflurane, xenon, or a combination of isoflurane and xenon for four hours.
- Apoptotic neurons were quantified in the cerebral cortex and caudate/putamen using activated caspase-3 immunohistochemistry and unbiased stereology.
- Anesthesia depth was assessed.
Main Results:
- Both xenon and isoflurane alone significantly increased neuroapoptosis compared to controls.
- Isoflurane induced a more robust neuroapoptotic response than xenon.
- The combination of xenon and isoflurane produced deeper anesthesia than either agent alone.
- Xenon-isoflurane combination reduced neuroapoptosis compared to isoflurane alone.
Conclusions:
- Xenon exhibits paradoxical properties in the infant mouse brain.
- Xenon induces neuroapoptosis and deepens anesthesia when combined with isoflurane.
- Xenon suppresses, rather than augments, isoflurane's neuroapoptotic activity.
