The effects of dexmedetomidine on perinatal excitotoxic brain injury are mediated by the alpha2A-adrenoceptor subtype.
We performed the current study in mice lacking individual alpha2-adrenoceptor subtypes to elucidate the contribution of alpha(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 alpha2A-adrenoceptor (alpha2A-KO) or alpha2C-adrenoceptor subtypes (alpha2C-KO) were randomly assigned to receive dexmedetomidine (3 microg/kg) or phosphate-buffered saline intraperitoneally. Thirty minutes after the intraperitoneal injection, the glutamatergic agonist ibotenate (10 microg) 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 alpha2C-KO mice by 44% and 49%, respectively. Ibotenate-induced white matter lesions were reduced by 71% (wild-type mice) and 75% (alpha2C-KO mice) after pretreatment with dexmedetomidine. In contrast, in alpha2A-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 alpha2A-KO mice, suggesting that the neuroprotective effect is mediated via the alpha2A-adrenoceptor subtype.
Paris
Andrea
A
Department of Anaesthesiology and Intensive Care Medicine, University Hospital Schleswig-Holstein, Campus Kiel, Germany. paris@anaesthesie.uni-kiel.de
Mantz
Jean
J
Tonner
Peter H
PH
Hein
Lutz
L
Brede
Marc
M
Gressens
Pierre
P
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D020927:Dexmedetomidine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D007051:Ibotenic Acid / Q000633:toxicity*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018696:Neuroprotective Agents / Q000494:pharmacology; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*
D000316:Adrenergic alpha-Agonists; D018690:Excitatory Amino Acid Agonists; D018696:Neuroprotective Agents; D018341:Receptors, Adrenergic, alpha-2; D007051:Ibotenic Acid; D020927:Dexmedetomidine