title: Systematic review and stratified meta-analysis of the efficacy of RhoA and Rho kinase inhibitors in animal models of ischaemic stroke.
abstract: BACKGROUND
  There is currently only one clinically approved drug, tissue plasminogen activator (tPA), for the treatment of acute ischaemic stroke. The RhoA pathway, including RhoA and its downstream effector Rho kinase (ROCK), has been identified as a possible therapeutic target. Our aim was to assess the impact of study design characteristics and study quality on reported measures of efficacy and to assess for the presence and impact of publication bias.
  
  
  METHODS
  We conducted a systematic review and meta-analysis on publications describing the efficacy of RhoA and ROCK inhibitors in animal models of focal cerebral ischaemia where outcome was assessed as a change in lesion size or neurobehavioural score, or both.
  
  
  RESULTS
  We identified 25 published papers which met our inclusion criteria. RhoA and ROCK inhibitors reduced lesion size by 37.3% in models of focal cerebral ischaemia (95% CI, 28.6% to 46.0%, 41 comparisons), and reduced neurobehavioural data by 40.5% (33.4% to 47.7%, 30 comparisons). Overall study quality was low (median=4, interquartile range 3-5) and measures to reduce bias were seldom reported. Publication bias was prevalent and associated with a substantial overstatement of efficacy for lesion size.
  
  
  CONCLUSIONS
  RhoA and ROCK inhibitors appear to be effective in animal models of stroke. However the low quality score, publication bias and limited number of studies are areas which need attention prior to conducting clinical trials.
authors.affiliation: The Department of Clinical Neurosciences, Chancellors Building, University of Edinburgh, 49 Little France Crescent, Edinburgh, EH16 4SB, UK.
authors.forename: Hanna M
authors.initials: HM
authors.lastname: Vesterinen
authors.forename: Gillian L
authors.initials: GL
authors.lastname: Currie
authors.forename: Samantha
authors.initials: S
authors.lastname: Carter
authors.forename: Sarah
authors.initials: S
authors.lastname: Mee
authors.forename: Ralf
authors.initials: R
authors.lastname: Watzlawick
authors.forename: Kieren J
authors.initials: KJ
authors.lastname: Egan
authors.forename: Malcolm R
authors.initials: MR
authors.lastname: Macleod
authors.forename: Emily S
authors.initials: ES
authors.lastname: Sena
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy*; D004195:Disease Models, Animal; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D020521:Stroke / Q000188:drug therapy*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors*
chemical_list: D047428:Protein Kinase Inhibitors; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein