title: Prostaglandin F2α FP receptor antagonist improves outcomes after experimental traumatic brain injury.
abstract: BACKGROUND
  Injuries to the brain promote upregulation of prostaglandins, notably the proinflammatory PGF2α, and overactivation of their cognate G-protein-coupled FP receptor, which could exacerbate neuronal damage. Our study is focused on investigation of the FP receptor as a target for novel neuroprotective drugs in a preclinical animal traumatic brain injury (TBI) model.
  
  
  METHODS
  Accordingly, the effects of acute intraperitoneal post-treatment with selective FP antagonist AL-8810 were studied in wildtype (WT) and FP receptor knockout (FP-/-) mice after controlled cortical impact (CCI). Neurological impairments were evaluated using neurological deficit scores (NDS) and the grip strength test. Cortical lesions and overall brain pathology were assessed using immunohistochemistry.
  
  
  RESULTS
  Morphological analyses of cerebral vasculature and anastomoses revealed no differences between WT and FP-/- mice. CCI produced cortical lesions characterized by cavitation, neuronal loss, and hematoma with a volume of 20.0 ± 1.0 mm(3) and significant hippocampal swelling (146.5 ± 7.4% of contralateral) compared with sham (P < 0.05). Post-treatment with AL-8810 (1 to 10 mg/kg) had no significant effect on cortical lesions, which suggests the irreversible effect of primary CCI injury, but significantly reduced hippocampal swelling to a size not significantly different from the sham group. Post-treatment with AL-8810 at a dose of 10 mg/kg significantly improved NDS at 24 and 48 hours after CCI (P < 0.001 and P < 0.01, respectively). In the AL-8810 group, CCI-induced decrease in grip strength was three-fold (2.93 ± 1.71) less and significantly different than in the saline-treated group. The FP-/- mice had significantly less hippocampal swelling, but not NDS, compared with WT mice. In addition, immunohistochemistry showed that pharmacologic blockade and genetic deletion of FP receptor led to attenuation of CCI-induced gliosis and microglial activation in selected brain regions.
  
  
  CONCLUSIONS
  This study provides, for the first time, demonstration of the unique role of the FP receptor as a potential target for disease-modifying CNS drugs for treatment of acute traumatic injury.
authors.affiliation: Department of Anesthesiology, University of Florida College of Medicine, PO Box 100159, Gainesville, FL 32610, USA. sdore@ufl.edu.
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Glushakov
authors.forename: Sean W
authors.initials: SW
authors.lastname: Robbins
authors.forename: Connor L
authors.initials: CL
authors.lastname: Bracy
authors.forename: Shuh
authors.initials: S
authors.lastname: Narumiya
authors.forename: Sylvain
authors.initials: S
authors.lastname: Doré
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001930:Brain Injuries / Q000378:metabolism* / Q000473:pathology*; D015237:Dinoprost / Q000031:analogs & derivatives* / Q000494:pharmacology; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors*
chemical_list: D018696:Neuroprotective Agents; D011982:Receptors, Prostaglandin; C034671:prostaglandin F2alpha receptor; C121227:AL 8810; D015237:Dinoprost