title: PET Imaging with [(18)F]FSPG Evidences the Role of System xc(-) on Brain Inflammation Following Cerebral Ischemia in Rats.
abstract: In vivo Positron Emission Tomography (PET) imaging of the cystine-glutamate antiporter (system xc(-)) activity with [(18)F]FSPG is meant to be an attractive tool for the diagnosis and therapy evaluation of brain diseases. However, the role of system xc(-) in cerebral ischemia and its involvement in inflammatory reaction has been scarcely explored. In this work, we report the longitudinal investigation of the neuroinflammatory process following transient middle cerebral artery occlusion (MCAO) in rats using PET with [(18)F]FSPG and the translocator protein (TSPO) ligand [(18)F]DPA-714. In the ischemic territory, [(18)F]FSPG showed a progressive binding increase that peaked at days 3 to 7 and was followed by a progressive decrease from days 14 to 28 after reperfusion. In contrast, [(18)F]DPA-714 evidenced maximum binding uptake values over day 7 after reperfusion. Ex vivo immnunohistochemistry confirmed the up-regulation of system xc(-) in microglial cells and marginally in astrocytes. Inhibition of system xc(-) with sulfasalazine and S-4-CPG resulted in increased arginase (anti-inflammatory M2 marker) expression at day 7 after ischemia, together with a decrease in TSPO and microglial M1 proinflammatory markers (CCL2, TNF and iNOS) expression. Taken together, these results suggest that system xc(-) plays a key role in the inflammatory reaction underlying experimental stroke.
authors: 1. Department of Neurosciences, University of the Basque Country, Barrio Sarriena s/n, 48940 Leioa, Spain, Achucarro Basque Center for Neuroscience-UPV/EHU, 48170 Zamudio, Spain and Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), 48940 Leioa, Spain.
authors: Maria
authors: M
authors: Domercq
authors: 2. Molecular Imaging Unit, CIC biomaGUNE, Pº Miramon 182, San Sebastian, Spain.
authors: Boguslaw
authors: B
authors: Szczupak
authors: 1. Department of Neurosciences, University of the Basque Country, Barrio Sarriena s/n, 48940 Leioa, Spain, Achucarro Basque Center for Neuroscience-UPV/EHU, 48170 Zamudio, Spain and Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), 48940 Leioa, Spain.
authors: Jon
authors: J
authors: Gejo
authors: 2. Molecular Imaging Unit, CIC biomaGUNE, Pº Miramon 182, San Sebastian, Spain.; 3. Radiochemistry and Nuclear Imaging, CIC biomaGUNE, Pº Miramon 182, San Sebastian, Spain.
authors: Vanessa
authors: V
authors: Gómez-Vallejo
authors: 2. Molecular Imaging Unit, CIC biomaGUNE, Pº Miramon 182, San Sebastian, Spain.; 4. Magnetic Resonance Imaging. CIC biomaGUNE, Pº Miramon 182, San Sebastian, Spain.
authors: Daniel
authors: D
authors: Padro
authors: 2. Molecular Imaging Unit, CIC biomaGUNE, Pº Miramon 182, San Sebastian, Spain.; 3. Radiochemistry and Nuclear Imaging, CIC biomaGUNE, Pº Miramon 182, San Sebastian, Spain.
authors: Kiran Babu
authors: KB
authors: Gona
authors: 5. CEA, Institut d'imagerie biomédicale, Service Hospitalier Frédéric Joliot, Orsay, France.
authors: Frédéric
authors: F
authors: Dollé
authors: 6. Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors: Makoto
authors: M
authors: Higuchi
authors: 1. Department of Neurosciences, University of the Basque Country, Barrio Sarriena s/n, 48940 Leioa, Spain, Achucarro Basque Center for Neuroscience-UPV/EHU, 48170 Zamudio, Spain and Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), 48940 Leioa, Spain.
authors: Carlos
authors: C
authors: Matute
authors: 2. Molecular Imaging Unit, CIC biomaGUNE, Pº Miramon 182, San Sebastian, Spain.; 3. Radiochemistry and Nuclear Imaging, CIC biomaGUNE, Pº Miramon 182, San Sebastian, Spain.
authors: Jordi
authors: J
authors: Llop
authors: 2. Molecular Imaging Unit, CIC biomaGUNE, Pº Miramon 182, San Sebastian, Spain.
authors: Abraham
authors: A
authors: Martín
mesh_terms: D027182:Amino Acid Transport System y+ / Q000032:analysis*; D000818:Animals; D001253:Astrocytes / Q000201:enzymology / Q000502:physiology; D002545:Brain Ischemia / Q000150:complications* / Q000000981:diagnostic imaging*; D004195:Disease Models, Animal; D004660:Encephalitis / Q000000981:diagnostic imaging* / Q000473:pathology; D005971:Glutamates / Q000008:administration & dosage*; D008137:Longitudinal Studies; D017628:Microglia / Q000201:enzymology / Q000502:physiology; D049268:Positron-Emission Tomography / Q000379:methods*; D011720:Pyrazoles / Q000008:administration & dosage*; D011743:Pyrimidines / Q000008:administration & dosage*; D051381:Rats
chemical_list: C569271:(4S)-4-(3-(18F)fluoropropyl)-L-glutamate; D027182:Amino Acid Transport System y+; D005971:Glutamates; C530129:N,N-diethyl-2-(2-(4-(2-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo(1,5-a)pyrimidin-3-yl)acetamide; D011720:Pyrazoles; D011743:Pyrimidines; C118895:SLC7A11 protein, human
keywords: PET; T2W-MRI; [18F]DPA-714; [18F]FSPG; cerebral ischemia.