Article

In vivo expression of cyclooxygenase-1 in activated microglia and macrophages during neuroinflammation visualized by PET with 11C-ketoprofen methyl ester.

RIKEN Center for Molecular Imaging Science, Hyogo, Japan.
Journal of Nuclear Medicine (Impact Factor: 5.56). 06/2011; 52(7):1094-101. DOI: 10.2967/jnumed.110.084046
Source: PubMed

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.
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.
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.
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.

0 Bookmarks
 · 
133 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Neuroinflammation plays a central role in a variety of neurological diseases, including stroke, multiple sclerosis, Alzheimer's disease, and malignant CNS neoplasms, among many other. Different cell types and molecular mediators participate in a cascade of events in the brain that is ultimately aimed at control, regeneration and repair, but leads to damage of brain tissue under pathological conditions. Non-invasive molecular imaging of key players in the inflammation cascade holds promise for identification and quantification of the disease process before it is too late for effective therapeutic intervention. In this review, we focus on molecular imaging techniques that target inflammatory cells and molecules that are of interest in neuroinflammation, especially those with high translational potential. Over the past decade, a plethora of molecular imaging agents have been developed and tested in animal models of (neuro)inflammation, and a few have been translated from bench to bedside. The most promising imaging techniques to visualize neuroinflammation include MRI, positron emission tomography (PET), single photon emission computed tomography (SPECT), and optical imaging methods. These techniques enable us to image adhesion molecules to visualize endothelial cell activation, assess leukocyte functions such as oxidative stress, granule release, and phagocytosis, and label a variety of inflammatory cells for cell tracking experiments. In addition, several cell types and their activation can be specifically targeted in vivo, and consequences of neuroinflammation such as neuronal death and demyelination can be quantified. As we continue to make progress in utilizing molecular imaging technology to study and understand neuroinflammation, increasing efforts and investment should be made to bring more of these novel imaging agents from the "bench to bedside."
    Journal of clinical & cellular immunology. 01/2014; 5.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Étudier la biodistribution physiologique en TEP/TDM du N,N-diéthyl-2-(2-(4-(2-fluoroethoxy)phényl)-5,7-diméthylpyrazolo[1,5-α]pyrimidin-3-yl) acétamide marqué au fluor 18 (18F-DPA-714) chez l’homme, au niveau du cerveau et du corps entier. Le DPA-714 est un ligand de la protéine translocatrice de 18 kDa (TSPO), protéine surexprimée par la microglie en cas de neuroinflammation.Matériel et méthodesDes acquisitions dynamiques TEP/TDM cérébrales ont été réalisées chez six sujets sains, pendant 90 minutes, après injection intraveineuse de 18F-DPA-714. La biodistribution cérébrale du 18F-DPA-714 a été évaluée visuellement et à l’aide de régions d’intérêts (ROI), selon le référentiel de la MNI-AAL afin d’obtenir les courbes d’activité/temps pour chaque région cérébrale prédéfinie. Un des sujets inclus a eu également des acquisitions TEP/TDM corps entier une heure après injection du 18F-DPA-714, permettant une analyse visuelle et semi-quantitative de la distribution du traceur, par définition de ROI et calcul des SUVs max.RésultatsLa captation cérébrale maximale du 18F-DPA-714 a été visualisée vers 3,5 minutes après injection, au niveau de la substance grise surtout thalamique. Elle a été suivie de deux phases d’élimination : une première phase rapide (3,5–35 minutes), puis une phase plus lente jusqu’en fin d’enregistrement. La captation du 18F-DPA-714 a été globalement homogène au sein des structures cérébrales analysées. Les images corps entier ont montré une activité importante au niveau de la vésicule biliaire, du rachis et des glandes salivaires sous-maxillaires, conformément aux précédentes études publiées utilisant d’autres radioligands de la TSPO.Conclusion Cette étude, très préliminaire, confirme que la biodistribution cérébrale du 18F-DPA-714 fait de lui un marqueur intéressant de la neuroinflammation. Elle permet de proposer un protocole d’acquisition des images TEP. Cependant, il semble maintenant nécessaire de mettre en application ces résultats chez des sujets malades.
    Medecine Nucleaire 02/2013; 37(2):44-51. · 0.16 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Alzheimer's disease (AD), dementia with Lewy bodies, frontotemporal dementia (FTD), and Huntington's disease (HD) are the main neurodegenerative causes of dementia. Causes and mechanisms of these diseases remain elusive. Neuroinflammation is increasingly emerging as an important pathological factor in their development. Positron emission tomography (PET) using [11C]PK11195 represents a method of visualizing the microglial component of neuroinflammation via the translocator protein (TSPO) and we discuss the valuable insights this has yielded in neurodegenerative diseases. We discuss the limitations of this method and the development of second generation TSPO PET ligands which hope to overcome these limitations. We also discuss other methods of visualizing neuroinflammation and review the state of current dementia treatments targeted at neuroinflammation. It is our view that a multimodal investigation into neuroinflammation in AD, Parkinson's disease dementia, FTD and HD will yield valuable pathological insights which will usefully inform development of therapeutic targets and biomarkers.
    Alzheimer's and Dementia 11/2014; · 17.47 Impact Factor