title: A non-brain penetrant PDE5A inhibitor improves functional recovery after stroke in rats.
abstract: OBJECTIVE
  Phosphodiesterase 5A (PDE5A) inhibitors improve functional recovery in experimental models of stroke in rats when treatment is delayed and without effect on infarct volume. PDE5A is expressed to only a very limited extent in forebrain tissues, raising the possibility that the locus of effect for the inhibitors is outside the brain. To start to address this question, we determined whether PDE5A inhibitors must have the ability to cross the blood brain barrier to improve recovery.
  
  
  METHODS
  After permanent middle cerebral artery occlusion in rats, PF-5 and UK-489,791, PDE5A inhibitors that do or do not pass the blood brain barrier, were administered starting 24 h after occlusion and continued for 1 week. Motor function was assessed at intervals to 28 days using body swing and limb placement measures.
  
  
  RESULTS
  Both PF-5 and UK-489,791 produced improvement in motor scores over 28 days that were significantly greater than in vehicle treated animals. There was no difference in efficacy between the two PDE5A inhibitors.
  
  
  CONCLUSIONS
  Brain penetrability appears not to be critical to the ability of a PDE5A inhibitor to improve functional recovery after experimental stroke in rats. This finding is discussed with regard to the cellular target(s) for PDE5A inhibitors mediating this effect.
authors.affiliation: Neuroscience Biology, Pfizer Global Research and Development, Groton, CT, USA. mennitifs@gmail.com
authors.forename: Frank S
authors.initials: FS
authors.lastname: Menniti
authors.forename: Jingmei
authors.initials: J
authors.lastname: Ren
authors.forename: Dana K
authors.initials: DK
authors.lastname: Sietsma
authors.forename: Angel
authors.initials: A
authors.lastname: Som
authors.forename: Fredrick R
authors.initials: FR
authors.lastname: Nelson
authors.forename: Diane T
authors.initials: DT
authors.lastname: Stephenson
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Tate
authors.forename: Seth P
authors.initials: SP
authors.lastname: Finklestein
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000098:blood supply / Q000187:drug effects; D004195:Disease Models, Animal; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects*; D020521:Stroke / Q000188:drug therapy* / Q000503:physiopathology; D013997:Time Factors
chemical_list: D018696:Neuroprotective Agents; D058986:Phosphodiesterase 5 Inhibitors