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ANESTHETIC PHARMACOLOGY

The Effects of Dexmedetomidine on Perinatal Excitotoxic Brain Injury are Mediated by the _2A-Adrenoceptor Subtype

Andrea Paris, MD^*, Jean Mantz, MD, PhD, Peter H. Tonner, MD^*, Lutz Hein, MD, Marc Brede, MD, and Pierre Gressens, MD, PhD^||

*Department of Anaesthesiology and Intensive Care Medicine, University Hospital Schleswig-Holstein, Campus Kiel; Institute of Experimental and Clinical Pharmacology and Toxicology, University of Freiburg; Department of Anaesthesia and Critical Care, University of Wuerzburg Hospitals, Germany; Hôpital Beaujon, Assistance Publique des Hôpitaux de Paris; and ||INSERM U 676 & Service de Neuropédiatrie, Hôpital Robert Debré, Paris, France

Address correspondence to Andrea Paris, MD, Department of Anaesthesiology and Intensive Care Medicine, University Hospital Schleswig-Holstein, Campus Kiel, Schwanenweg 21, D-24105 Kiel, Germany. Address e-mail to paris{at}anaesthesie.uni-kiel.de.

We performed the current study in mice lacking individual ₂-adrenoceptor subtypes to elucidate the contribution of ₂-adrenoceptor subtypes to the neuroprotective properties of dexmedetomidine in a model of perinatal excitotoxic brain injury. On postnatal Day 5, wild-type mice and mice lacking _2A-adrenoceptor (_2A-KO) or _2C-adrenoceptor subtypes (_2C-KO) were randomly assigned to receive dexmedetomidine (3 µg/kg) or phosphate-buffered saline intraperitoneally. Thirty minutes after the intraperitoneal injection, the glutamatergic agonist ibotenate (10 µg) was intracerebrally injected, producing transcortical necrosis and white matter lesions that mimic perinatal human hypoxic-like lesions. Quantification of the lesions was performed on postnatal Day 10 by histopathologic examination. Dexmedetomidine reduced mean lesion size in the cortex of wild-type mice and _2C-KO mice by 44% and 49%, respectively. Ibotenate-induced white matter lesions were reduced by 71% (wild-type mice) and 75% (_2C-KO mice) after pretreatment with dexmedetomidine. In contrast, in _2A-KO mice, dexmedetomidine did not protect against the cortical excitotoxic insult, and white matter lesions were even more pronounced (82% increase of mean lesion size). Dexmedetomidine provides potent neuroprotection in a model of perinatal excitotoxic brain damage. This effect was completely abolished in _2A-KO mice, suggesting that the neuroprotective effect is mediated via the _2A-adrenoceptor subtype.

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