title: In vivo expression of cyclooxygenase-1 in activated microglia and macrophages during neuroinflammation visualized by PET with 11C-ketoprofen methyl ester.
abstract: Cyclooxygenase (COX)-1 and -2 are prostanoid-synthesizing enzymes that play important roles in the regulation of neuroinflammation and in the development of neurodegenerative disorders. However, the specific functions of these isoforms are still unclear. We recently developed (11)C-labeled ketoprofen methyl ester as a PET probe that targets the COXs for imaging neuroinflammation, though its responsible isoform is yet to be determined. In the present study, we performed ex vivo and in vivo imaging studies with (11)C-ketoprofen methyl ester and determined the contributions of the COX isoforms during the neuroinflammatory process.
  
  
  METHODS
  To identify the COX isoform responsible for (11)C-ketoprofen methyl ester in the brain, we examined the ex vivo autoradiography of (11)C-ketoprofen methyl ester using COX-deficient mice. Time-dependent changes in accumulation of (11)C-ketoprofen methyl ester during the neuroinflammatory process were evaluated by PET in rats with hemispheric neuroinflammation induced by intrastriatal injection of lipopolysaccharide or quinolinic acid. In both rat models, cell-type specificity of COX isoform expression during neuroinflammation was identified immunohistochemically.
  
  
  RESULTS
  Ex vivo autoradiographic analysis of COX-deficient mice revealed a significant reduction of (11)C-ketoprofen methyl ester accumulation only in COX-1-deficient mice, not COX-2-deficient mice. PET of rats after intrastriatal injection of lipopolysaccharide showed a significant increase in accumulation of (11)C-ketoprofen methyl ester in the inflamed area. This increase was evident at the early phase of 6 h, peaked at day 1, and then returned to basal levels by day 7. In addition, immunohistochemical analysis revealed that the population of activated microglia and macrophages was elevated at the early phase with COX-1 expression but not COX-2. A significant increase in (11)C-ketoprofen methyl ester accumulation was also observed at day 1 after intrastriatal injection of quinolinic acid, with increased COX-1-expressing activated microglia and macrophages.
  
  
  CONCLUSIONS
  We have identified (11)C-ketoprofen methyl ester as a COX-1-selective PET probe, and using this, we have also demonstrated a time-dependent expression of COX-1 in activated microglia and macrophages during the neuroinflammatory process in the living brain. Thus, COX-1 may play a crucial role in the pathology of neuroinflammation and might be a critical target for the diagnosis and therapy of neurodegenerative disorders.
authors.affiliation: RIKEN Center for Molecular Imaging Science, Hyogo, Japan.
authors.forename: Miho
authors.initials: M
authors.lastname: Shukuri
authors.forename: Misato
authors.initials: M
authors.lastname: Takashima-Hirano
authors.forename: Keiko
authors.initials: K
authors.lastname: Tokuda
authors.forename: Tadayuki
authors.initials: T
authors.lastname: Takashima
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Matsumura
authors.forename: Osamu
authors.initials: O
authors.lastname: Inoue
authors.forename: Hisashi
authors.initials: H
authors.lastname: Doi
authors.forename: Masaaki
authors.initials: M
authors.lastname: Suzuki
authors.forename: Yasuyoshi
authors.initials: Y
authors.lastname: Watanabe
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Onoe
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051545:Cyclooxygenase 1 / Q000172:deficiency / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000172:deficiency; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D007249:Inflammation / Q000139:chemically induced / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D007660:Ketoprofen / Q000031:analogs & derivatives*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D017628:Microglia / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009498:Neurotoxins / Q000633:toxicity; D049268:Positron-Emission Tomography; D017378:Quinolinic Acid / Q000633:toxicity; D051381:Rats; D013997:Time Factors
chemical_list: D008070:Lipopolysaccharides; D009498:Neurotoxins; C560799:ketoprofen methyl ester; D007660:Ketoprofen; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D017378:Quinolinic Acid