The effect of the alpha 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.
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 (N(2)O)/oxygen plus 100 microg/kg of dexmedetomidine intraperitoneally 30 min before ischemia (n = 8), 1 mg x kg(-1) x min(-1) of S(+)-ketamine and oxygen/air (n = 8), or fentanyl and N(2)O/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.
Engelhard
Kristin
K
Klinik für Anaesthesiologie, Technische Universität München, Klinikum Rechts der Isar, Munich, Germany. k.engelhard@lrz.tum.de
Werner
Christian
C
Eberspächer
Eva
E
Bachl
Monika
M
Blobner
Manfred
M
Hildt
Eberhard
E
Hutzler
Peter
P
Kochs
Eberhard
E
D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics*; D001784:Blood Gas Analysis; D015153:Blotting, Western; D001923:Brain Chemistry / Q000187:drug effects; D002545:Brain Ischemia / Q000235:genetics* / Q000473:pathology; D002560:Cerebrovascular Circulation / Q000187:drug effects; D020927:Dexmedetomidine / Q000494:pharmacology*; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D015427:Reperfusion Injury / Q000235:genetics* / Q000473:pathology
D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists; D011480:Protease Inhibitors; D016194:Receptors, N-Methyl-D-Aspartate; D020927:Dexmedetomidine; D007649:Ketamine