This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (37) Citing Articles via Google Scholar Google Scholar Articles by Kawaguchi, M. Articles by Patel, P. M. Search for Related Content PubMed PubMed Citation Articles by Kawaguchi, M. Articles by Patel, P. M. Related Collections Critical Care Resuscitation Neuroanesthesia Pharmacology

---

NEUROSURGICAL ANESTHESIA

Effect of Isoflurane on Neuronal Apoptosis in Rats Subjected to Focal Cerebral Ischemia

Masahiko Kawaguchi, MD^*, John C. Drummond, MD FRCPC, Daniel J. Cole, MD, Paul J. Kelly, BS^*, Mark P. Spurlock, BS^*, and Piyush M. Patel, MD FRCPC^* Section Editor

*Department of Anesthesiology, VA Medical Center and University of California, San Diego, San Diego, California, the Department of Anesthesiology, University of California, San Diego, San Diego, California, and the Department of Anesthesiology, Mayo Clinic, Scottsdale, Arizona

Address correspondence to Piyush M. Patel, MD, Anesthesia Service 125, VA Medical Center, 3350 La Jolla Village Drive, San Diego, CA 92161. Address email to ppatel{at}ucsd.edu

Although isoflurane can reduce ischemic neuronal injury after short postischemic recovery intervals, this neuroprotective efficacy is not sustained. Neuronal apoptosis can contribute to the gradual increase in infarct size after ischemia. This suggests that isoflurane, although capable of reducing early neuronal death, may not inhibit ischemia-induced apoptosis. We investigated the effects of isoflurane on markers of apoptosis in rats subjected to focal ischemia. Fasted Wistar-Kyoto rats were anesthetized with isoflurane and randomly allocated to awake (n = 40) or isoflurane (n = 40) groups. Animals in both groups were subjected to focal ischemia by filament occlusion of the middle cerebral artery for 70 min. Pericranial temperature was servo-controlled at 37°C ± 0.2°C throughout the experiment. In the awake group, isoflurane was discontinued and the animals were allowed to awaken. In the isoflurane group, isoflurane anesthesia was maintained at 1.5 MAC (minimum alveolar anesthetic concentration). Animals were killed 7 h, 1 day, 4 days, or 7 days after reperfusion (n = 10/group/time point). The area of cerebral infarction was measured by image analysis in a hematoxylin and eosin stained section. In three adjacent sections, apoptotic neurons were identified by TUNEL staining and immunostaining for active caspase-9 and caspase-3. Infarct size was smaller in the isoflurane group than the awake group 7 h, 1 day, and 4 days after reperfusion (P < 0.05). However, this difference was absent 7 days after reperfusion. The number of apoptotic (TUNEL, caspase-3, and caspase-9 positive) cells 1 day after ischemia was significantly more in the awake versus isoflurane group. After a recovery period of 4 or 7 days, the number of apoptotic cells in the isoflurane group was more than in the awake group. After 7 days, the number of caspase-3 and -9 positive neurons was more in the isoflurane group (P < 0.05). The data indicate that isoflurane delays but does not prevent the development of cerebral infarction caused by ischemia. Isoflurane reduced the development of apoptosis early after ischemia but did not prevent it at later stages of postischemic recovery.

IMPLICATIONS: The effect of isoflurane on neuronal apoptosis was investigated in rats subjected to focal cerebral ischemia. In isoflurane-anesthetized animals, ischemia-induced apoptosis occurred during the later stages of postischemic recovery. Isoflurane did not inhibit postischemic neuronal apoptosis.

This article has been cited by other articles:

				G. Zhang, Y. Dong, B. Zhang, F. Ichinose, X. Wu, D. J. Culley, G. Crosby, R. E. Tanzi, and Z. Xie Isoflurane-Induced Caspase-3 Activation Is Dependent on Cytosolic Calcium and Can Be Attenuated by Memantine J. Neurosci., April 23, 2008; 28(17): 4551 - 4560. [Abstract] [Full Text] [PDF]

				Z. Xie, Y. Dong, U. Maeda, R. Moir, S. K. Inouye, D. J. Culley, G. Crosby, and R. E. Tanzi Isoflurane-Induced Apoptosis: A Potential Pathogenic Link Between Delirium and Dementia J. Gerontol. A Biol. Sci. Med. Sci., December 1, 2006; 61(12): 1300 - 1306. [Abstract] [Full Text] [PDF]

				J. Raphael, S. Abedat, J. Rivo, K. Meir, R. Beeri, T. Pugatsch, Z. Zuo, and Y. Gozal Volatile Anesthetic Preconditioning Attenuates Myocardial Apoptosis in Rabbits after Regional Ischemia and Reperfusion via Akt Signaling and Modulation of Bcl-2 Family Proteins J. Pharmacol. Exp. Ther., July 1, 2006; 318(1): 186 - 194. [Abstract] [Full Text] [PDF]

				M. Pape, K. Engelhard, E. Eberspacher, R. Hollweck, K. Kellermann, S. Zintner, P. Hutzler, and C. Werner The Long-Term Effect of Sevoflurane on Neuronal Cell Damage and Expression of Apoptotic Factors After Cerebral Ischemia and Reperfusion in Rats. Anesth. Analg., July 1, 2006; 103(1): 173 - 179. [Abstract] [Full Text] [PDF]

				S. Inoue, D. P. Davis, J. C. Drummond, D. J. Cole, and P. M. Patel The combination of isoflurane and caspase 8 inhibition results in sustained neuroprotection in rats subject to focal cerebral ischemia. Anesth. Analg., May 1, 2006; 102(5): 1548 - 1555. [Abstract] [Full Text] [PDF]

				H. Cao, I. S. Kass, J. E. Cottrell, and P. J. Bergold Pre- or Postinsult Administration of Lidocaine or Thiopental Attenuates Cell Death in Rat Hippocampal Slice Cultures Caused by Oxygen-Glucose Deprivation Anesth. Analg., October 1, 2005; 101(4): 1163 - 1169. [Abstract] [Full Text] [PDF]

				L. Wise-Faberowski, M. Aono, R. D. Pearlstein, and D. S. Warner Apoptosis Is Not Enhanced in Primary Mixed Neuronal/Glial Cultures Protected by Isoflurane AgainstN-Methyl-D-Aspartate Excitotoxicity Anesth. Analg., December 1, 2004; 99(6): 1708 - 1714. [Abstract] [Full Text] [PDF]

				D. S. Warner Perioperative Neuroprotection: Are We Asking the Right Questions? Anesth. Analg., March 1, 2004; 98(3): 563 - 565. [Full Text] [PDF]