title: Neuronal and nonneuronal COX-2 expression confers neurotoxic and neuroprotective phenotypes in response to excitotoxin challenge.
abstract: Treating acute brain injuries with COX-2 inhibitors can produce both neuroprotective and neurotoxic effects. This study investigated the role of COX-2 in modulating acute brain injury induced by excitotoxic neural damage. Intrastriatal injection of excitotoxin (RS)-(tetrazole-5yl) glycine elicited COX-2 expression in two distinct groups of cells. cortical neurons surrounding the lesion and vascular cells in the lesion core. The vascular COX-2 was expressed in two cell types, endothelial cells and monocytes. Selective deletion of COX-2 in vascular cells in Tie2Cre Cox-2(flox/flox) mice did not affect the induction of COX-2 in neurons after the excitotoxin injection but resulted in increased lesion volume, indicating a neuroprotective role for the COX-2 expressed in the vascular cells. Selective deletion of monocyte COX-2 in LysMCre Cox-2(flox/flox) mice did not reduce COX-2-dependent neuroprotection, suggesting that endothelial COX-2 is sufficient to confer neuroprotection. Pharmacological inhibition of COX-2 activity in Tie2Cre Cox-2(flox/flox) mice reduced lesion volume, indicating a neurotoxic role for the COX-2 expressed in neurons. Furthermore, COX-2-dependent neurotoxicity was mediated, at least in part, via the activation of the EP1 receptor. These results show that Cox-2 expression induced in different cell types can confer opposite effects.
authors.affiliation: Institute for Behavior Medicine Research, The Ohio State University, Columbus, Ohio; Department of Oral Biology, College of Dentistry, The Ohio State University, Columbus, Ohio.
authors.forename: Ying
authors.initials: Y
authors.lastname: An
authors.forename: Natalya
authors.initials: N
authors.lastname: Belevych
authors.forename: Yufen
authors.initials: Y
authors.lastname: Wang
authors.forename: Hao
authors.initials: H
authors.lastname: Zhang
authors.forename: Harvey
authors.initials: H
authors.lastname: Herschman
authors.forename: Qun
authors.initials: Q
authors.lastname: Chen
authors.forename: Ning
authors.initials: N
authors.lastname: Quan
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000172:deficiency* / Q000235:genetics; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D005998:Glycine / Q000031:analogs & derivatives / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016202:N-Methylaspartate / Q000633:toxicity; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D020258:Neurotoxicity Syndromes / Q000209:etiology / Q000473:pathology* / Q000517:prevention & control*; D009498:Neurotoxins / Q000633:toxicity; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D013777:Tetrazoles / Q000633:toxicity
chemical_list: D000943:Antigens, Differentiation; D018696:Neuroprotective Agents; D009498:Neurotoxins; D013777:Tetrazoles; C036763:monocyte-macrophage differentiation antigen; C073649:(tetrazol-5-yl)glycine; D016202:N-Methylaspartate; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D010751:Phosphopyruvate Hydratase; D005998:Glycine
keywords: inflammation; injury; knockout mouse