title: A dose-response study of thymosin β4 for the treatment of acute stroke.
abstract: BACKGROUND
  Thymosin β4 (Tβ4) is a 5K actin binding peptide. Tβ4 improves neurological outcome in a rat model of embolic stroke and research is now focused on optimizing its dose for clinical trials. The purpose of this study was to perform a dose-response study of Tβ4 to determine the optimal dose of neurological improvement in a rat model of embolic stroke.
  
  
  METHODS
  Male Wistar rats were subjected to embolic middle cerebral artery occlusion (MCAo). Rats were divided into 4 groups of 10 animals/group: control, 2, 12 and 18 mg/kg. Tβ4 was administered intraperitoneally 24h after MCAo and then every 3 days for 4 additional doses in a randomized controlled fashion. Neurological tests were performed after MCAo and before treatment and up to 8 weeks after treatment. The rats were sacrificed 56 days after MCAo and lesion volumes measured. Generalized estimating equation was used to compare the treatment effect on long term functional recovery at day 56. A quartic regression model was used for an optimal dose determination.
  
  
  RESULTS
  Tβ4 significantly improved neurological outcome at dose of 2 and 12 mg/kg at day 14 and extended to day 56 (p-values <0.05). The higher dose of 18 mg/kg did not show significant improvement. The estimated optimal dose of 3.75 mg/kg would provide optimal neurological improvement.
  
  
  CONCLUSIONS
  This study shown that Tβ4 significantly improved the long term neurological functional recovery at day 56 after MCAo with an optimal dose of 3.75 mg/kg. These results provide preclinical data for human clinical trials.
authors: Department of Emergency Medicine, Henry Ford Health Systems, Detroit, MI 48202, USA. Electronic address: morris@neuro.hfh.edu.
authors: D C
authors: DC
authors: Morris
authors: Department of Neurology, Henry Ford Health Systems, Detroit, MI 48202, USA. Electronic address: yisheng@neuro.hfh.edu.
authors: Y
authors: Y
authors: Cui
authors: Department of Emergency Medicine, Henry Ford Health Systems, Detroit, MI 48202, USA. Electronic address: wcheung1@hfhs.org.
authors: W L
authors: WL
authors: Cheung
authors: Department of Public Health Sciences, Henry Ford Health Systems, Detroit, MI 48202, USA. Electronic address: mlu1@hfhs.org.
authors: M
authors: M
authors: Lu
authors: Department of Neurology, Henry Ford Health Systems, Detroit, MI 48202, USA. Electronic address: lzhang@neuro.hfh.edu.
authors: L
authors: L
authors: Zhang
authors: Department of Neurology, Henry Ford Health Systems, Detroit, MI 48202, USA. Electronic address: zhazh@neuro.hfh.edu.
authors: Z G
authors: ZG
authors: Zhang
authors: Department of Neurology, Henry Ford Health Systems, Detroit, MI 48202, USA; Department of Physics, Oakland University, Rochester, MI 48309, USA. Electronic address: michael.chopp@gmail.com.
authors: M
authors: M
authors: Chopp
mesh_terms: D000208:Acute Disease; D011125:Adenomatous Polyposis Coli / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001973:Bromodeoxyuridine / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D020244:Infarction, Middle Cerebral Artery / Q000150:complications; D008297:Male; D004676:Myelin Basic Protein / Q000378:metabolism; D059906:Neuroimaging; D009460:Neurologic Examination; D051381:Rats; D020521:Stroke / Q000188:drug therapy* / Q000209:etiology; D013947:Thymosin / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome; D053675:Versicans / Q000378:metabolism; D000099201:Thymosin beta(4)
chemical_list: D001973:Bromodeoxyuridine; D004676:Myelin Basic Protein; D013947:Thymosin; D053675:Versicans; D000099201:Thymosin beta(4); C508324:Vcan protein, rat
keywords: Actin-binding protein; Embolic stroke; Neurorestorative therapy; Oligodendrocyte; Rat model; Thymosin