Anesthetics isoflurane and desflurane differently affect mitochondrial function, learning, and memory
Version of Record online: 24 FEB 2012
Copyright © 2012 American Neurological Association
Annals of Neurology
Volume 71, Issue 5, pages 687–698, May 2012
How to Cite
Zhang, Y., Xu, Z., Wang, H., Dong, Y., Shi, H. N., Culley, D. J., Crosby, G., Marcantonio, E. R., Tanzi, R. E. and Xie, Z. (2012), Anesthetics isoflurane and desflurane differently affect mitochondrial function, learning, and memory. Ann Neurol., 71: 687–698. doi: 10.1002/ana.23536
- Issue online: 20 APR 2012
- Version of Record online: 24 FEB 2012
- Accepted manuscript online: 19 JAN 2012 06:50AM EST
- Manuscript Accepted: 6 JAN 2012
- Manuscript Revised: 28 NOV 2011
- Manuscript Received: 8 AUG 2011
- NIH grants. Grant Numbers: K08 NS048140, (NINDS), R21 AG029856 (NIA), R01 GM088801 (NINDS) (Z. Xie)
- American Geriatrics Society Jahnigen Award (Z. Xie)
- Alzheimer's Association (Z. Xie)
- Cure Alzheimer's Fund (Z. Xie)
- NIH. Grant Number: DK082427 (NIDDK) (H.S.)
There are approximately 8.5 million Alzheimer disease (AD) patients who need anesthesia and surgery care every year. The inhalation anesthetic isoflurane, but not desflurane, has been shown to induce caspase activation and apoptosis, which are part of AD neuropathogenesis, through the mitochondria-dependent apoptosis pathway. However, the in vivo relevance, underlying mechanisms, and functional consequences of these findings remain largely to be determined.
We therefore set out to assess the effects of isoflurane and desflurane on mitochondrial function, cytotoxicity, learning, and memory using flow cytometry, confocal microscopy, Western blot analysis, immunocytochemistry, and the fear conditioning test.
Here we show that isoflurane, but not desflurane, induces opening of mitochondrial permeability transition pore (mPTP), increase in levels of reactive oxygen species, reduction in levels of mitochondrial membrane potential and adenosine-5′-triphosphate, activation of caspase 3, and impairment of learning and memory in cultured cells, mouse hippocampus neurons, mouse hippocampus, and mice. Moreover, cyclosporine A, a blocker of mPTP opening, attenuates isoflurane-induced mPTP opening, caspase 3 activation, and impairment of learning and memory. Finally, isoflurane may induce the opening of mPTP via increasing levels of reactive oxygen species.
These findings suggest that desflurane could be a safer anesthetic for AD patients as compared to isoflurane, and elucidate the potential mitochondria-associated underlying mechanisms, and therefore have implications for use of anesthetics in AD patients, pending human study confirmation. ANN NEUROL 2012;