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NEUROSURGICAL ANESTHESIA

The Effect of the ₂-Agonist Dexmedetomidine and the N-Methyl-D-Aspartate Antagonist S(+)-Ketamine on the Expression of Apoptosis-Regulating Proteins After Incomplete Cerebral Ischemia and Reperfusion in Rats

Kristin Engelhard, MD^*, Christian Werner, MD^*, Eva Eberspächer, DVM^*, Monika Bachl, MD^*, Manfred Blobner, MD^*, Eberhard Hildt, PhD, Peter Hutzler, PhD, and Eberhard Kochs, MD^*

*Klinik für Anaesthesiologie and Experimentelle Onkologie und Therapieforschung, Technische Universität München, Klinikum Rechts der Isar; and Institut für Pathologie der GSF-Forschungszentrum für Umwelt und Gesundheit, Munich, Germany

Address correspondence and reprint requests to Kristin Engelhard, MD, Klinik für Anaesthesiologie der Technischen Universität München, Klinikum Rechts der Isar, Ismaninger Straße 22, 81675 München, Germany. Address e-mail to k.engelhard{at}lrz.tum.de

In this study, we investigated whether the neuroprotection previously seen with dexmedetomidine or S(+)-ketamine involves regulation of proapoptotic (Bax and p53) and antiapoptotic (Bcl-2 and Mdm-2) proteins. Rats were anesthetized with isoflurane. After surgical preparation of isoflurane was discontinued, animals were randomly assigned to receive fentanyl and nitrous oxide (N₂O)/oxygen plus 100 µg/kg of dexmedetomidine intraperitoneally 30 min before ischemia (n = 8), 1 mg · kg^-1 · min^-1 of S(+)-ketamine and oxygen/air (n = 8), or fentanyl and N₂O/oxygen (n = 8; control group). In all three treatment groups, incomplete cerebral ischemia (30 min) was induced by unilateral carotid artery occlusion and hemorrhagic hypotension to a mean arterial blood pressure of 30–35 mm Hg. Four hours after the start of reperfusion, the brains were removed, and the expression of apoptosis-regulating proteins was determined by using immunofluorescence and Western blot analysis. The results were compared with sham-operated animals (n = 8). After cerebral ischemia/reperfusion, the relative protein concentration of Bax was increased by 110% in control animals compared with the dexmedetomidine- and S(+)-ketamine-treated rats and by 140% compared with the sham-operated animals. In animals treated with dexmedetomidine, the expression of Bcl-2 and Mdm-2 was larger compared with control (68% and 210%, respectively) or sham-operated (110% and 180%, respectively) animals. Therefore, it is possible that the neuroprotective properties of dexmedetomidine and S(+)-ketamine seen in previous studies involve ultra-early modulation of the balance between pro- and antiapoptotic proteins.

IMPLICATIONS: This study shows that dexmedetomidine and S(+)-ketamine influence the expression of apoptosis-regulating proteins in rat brains 4 h after cerebral ischemia/reperfusion. Therefore, it is possible that the neuroprotection seen with dexmedetomidine and S(+)-ketamine might also involve antiapoptotic mechanisms in addition to reducing necrotic cell death.

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