title: In vivo PET imaging of the neuroinflammatory response in rat spinal cord injury using the TSPO tracer [(18)F]GE-180 and effect of docosahexaenoic acid.
abstract: OBJECTIVE
  Traumatic spinal cord injury (SCI) is a devastating condition which affects millions of people worldwide causing major disability and substantial socioeconomic burden. There are currently no effective treatments. Modulating the neuroinflammatory (NI) response after SCI has evolved as a major therapeutic strategy. PET can be used to detect the upregulation of the 18-kDa translocator protein (TSPO), a hallmark of activated microglia in the CNS. We investigated whether PET imaging using the novel TSPO tracer [(18)F]GE-180 can be used as a clinically relevant biomarker for NI in a contusion SCI rat model, and we present data on the modulation of NI by the lipid docosahexaenoic acid (DHA).
  
  
  METHODS
  A total of 22 adult male Wistar rats were subjected to controlled spinal cord contusion at the T10 spinal cord level. Six non-injured and ten T10 laminectomy only (LAM) animals were used as controls. A subset of six SCI animals were treated with a single intravenous dose of 250 nmol/kg DHA (SCI-DHA group) 30 min after injury; a saline-injected group of six animals was used as an injection control. PET and CT imaging was carried out 7 days after injury using the [(18)F]GE-180 radiotracer. After imaging, the animals were killed and the spinal cord dissected out for biodistribution and autoradiography studies. In vivo data were correlated with ex vivo immunohistochemistry for TSPO.
  
  
  RESULTS
  In vivo dynamic PET imaging revealed an increase in tracer uptake in the spinal cord of the SCI animals compared with the non-injured and LAM animals from 35 min after injection (P < 0.0001; SCI vs. LAM vs. non-injured). Biodistribution and autoradiography studies confirmed the high affinity and specific [(18)F]GE-180 binding in the injured spinal cord compared with the binding in the control groups. Furthermore, they also showed decreased tracer uptake in the T10 SCI area in relation to the non-injured remainder of the spinal cord in the SCI-DHA group compared with the SCI-saline group (P < 0.05), supporting a NI modulatory effect of DHA. Immunohistochemistry showed a high level of TSPO expression (38 %) at the T10 injury site in SCI animals compared with that in the non-injured animals (6 %).
  
  
  CONCLUSIONS
  [(18)F]GE-180 PET imaging can reveal areas of increased TSPO expression that can be visualized and quantified in vivo after SCI, offering a minimally invasive approach to the monitoring of NI in SCI models and providing a translatable clinical readout for the testing of new therapies.
authors.affiliation: Centre for Trauma Sciences, The Blizard Institute, London, UK. j.lopez-tremoleda@qmul.ac.uk.
authors.forename: J L
authors.initials: JL
authors.lastname: Tremoleda
authors.affiliation: Centre for Trauma Sciences, The Blizard Institute, London, UK.
authors.forename: O
authors.initials: O
authors.lastname: Thau-Zuchman
authors.affiliation: Centre for Trauma Sciences, The Blizard Institute, London, UK.
authors.forename: M
authors.initials: M
authors.lastname: Davies
authors.affiliation: Barts Cancer Institute, Queen Mary University London, London, UK.
authors.forename: J
authors.initials: J
authors.lastname: Foster
authors.affiliation: GE Healthcare Ltd, Amersham, UK.
authors.forename: I
authors.initials: I
authors.lastname: Khan
authors.affiliation: Centre for Trauma Sciences, The Blizard Institute, London, UK.
authors.forename: K C
authors.initials: KC
authors.lastname: Vadivelu
authors.affiliation: Centre for Trauma Sciences, The Blizard Institute, London, UK.
authors.forename: P K
authors.initials: PK
authors.lastname: Yip
authors.affiliation: Barts Cancer Institute, Queen Mary University London, London, UK.
authors.forename: J
authors.initials: J
authors.lastname: Sosabowski
authors.affiliation: GE Healthcare Ltd, Amersham, UK.
authors.forename: W
authors.initials: W
authors.lastname: Trigg
authors.affiliation: Centre for Trauma Sciences, The Blizard Institute, London, UK.
authors.forename: A T
authors.initials: AT
authors.lastname: Michael-Titus
mesh_terms: D000818:Animals; D002227:Carbazoles / Q000378:metabolism* / Q000493:pharmacokinetics; D002352:Carrier Proteins / Q000378:metabolism*; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D005462:Fluorine Radioisotopes; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology*; D049268:Positron-Emission Tomography; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000378:metabolism*; D013119:Spinal Cord Injuries / Q000000981:diagnostic imaging* / Q000378:metabolism* / Q000503:physiopathology; D014018:Tissue Distribution
chemical_list: D002227:Carbazoles; D002352:Carrier Proteins; D005462:Fluorine Radioisotopes; C571664:GE-180; D018696:Neuroprotective Agents; D011963:Receptors, GABA-A; C069997:Tspo protein, rat; D004281:Docosahexaenoic Acids
keywords: Docosahexaenoic acid; Neuroinflammatory respone; Rat model; Spinal cord injury; [18F]GE-180