title: Parecoxib is neuroprotective in spontaneously hypertensive rats after transient middle cerebral artery occlusion: a divided treatment response?
abstract: BACKGROUND
  Anti-inflammatory treatment affects ischemic damage and neurogenesis in rodent models of cerebral ischemia. We investigated the potential benefit of COX-2 inhibition with parecoxib in spontaneously hypertensive rats (SHRs) subjected to transient middle cerebral artery occlusion (tMCAo).
  
  
  METHODS
  Sixty-four male SHRs were randomized to 90 min of intraluminal tMCAo or sham surgery. Parecoxib (10 mg/kg) or isotonic saline was administered intraperitoneally (IP) during the procedure, and twice daily thereafter. Nineteen animals were euthanized after 24 hours, and each hemisphere was examined for mRNA expression of pro-inflammatory cytokines and COX enzymes by quantitative RT-PCR. Twenty-three tMCAo animals were studied with diffusion and T2 weighted MRI within the first 24 hours, and ten of the SHRs underwent follow-up MRI six days later. Thirty-three SHRs were given 5-bromo-2'-deoxy-uridine (BrdU) twice daily on Day 4 to 7 after tMCAo. Animals were euthanized on Day 8 and the brains were studied with free-floating immunohistochemistry for activated microglia (ED-1), hippocampal granule cell BrdU incorporation, and neuronal nuclei (NeuN). Infarct volume estimation was done using the 2D nucleator and Cavalieri principle on NeuN-stained coronal brain sections. The total number of BrdU+ cells in the dentate gyrus (DG) of the hippocampus was estimated using the optical fractionator.
  
  
  RESULTS
  We found a significant reduction in infarct volume in parecoxib treated animals one week after tMCAo (p < 0.03). Cortical ADC values in the parecoxib group were markedly less increased on Day 8 (p < 0.01). Interestingly, the parecoxib treated rats were segregated into two subgroups, suggesting a responder vs. non-responder phenomenon. We found indications of mRNA up-regulation of IL-1beta, IL-6, TNF-alpha and COX-2, whereas COX-1 remained unaffected. Hippocampal granule cell BrdU incorporation was not affected by parecoxib treatment. Presence of ED-1+ activated microglia in the hippocampus was related to an increase in BrdU uptake in the DG.
  
  
  CONCLUSIONS
  IP parecoxib administration during tMCAo was neuroprotective, as evidenced by a large reduction in mean infarct volume and a lower cortical ADC increment. Increased pro-inflammatory cytokine mRNA levels and hippocampal granule cell BrdU incorporation remained unaffected.
authors.affiliation: The Water and Salt Research Centre, University of Aarhus, DK-8000 Aarhus C, Denmark. jesper.kelsen@ki.au.dk
authors.forename: Jesper
authors.initials: J
authors.lastname: Kelsen
authors.forename: Katrine
authors.initials: K
authors.lastname: Kjaer
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.forename: Michael
authors.initials: M
authors.lastname: Pedersen
authors.forename: Lisbeth
authors.initials: L
authors.lastname: Røhl
authors.forename: Jørgen
authors.initials: J
authors.lastname: Frøkiaer
authors.forename: Søren
authors.initials: S
authors.lastname: Nielsen
authors.forename: Jens R
authors.initials: JR
authors.lastname: Nyengaard
authors.forename: Lars Christian B
authors.initials: LC
authors.lastname: Rønn