title: Effect of repeated allogeneic bone marrow mononuclear cell transplantation on brain injury following transient focal cerebral ischemia in rats.
abstract: OBJECTIVE
  Transplantation of bone marrow mononuclear cells (BMMCs) exerts neuroprotection against cerebral ischemia. We examined the therapeutic timepoint of allogeneic BMMC transplantation in a rat model of focal cerebral ischemia, and determined the effects of repeated transplantation outside the therapeutic window.
  
  
  METHODS
  Male Sprague-Dawley rats were subjected to 90 minute focal cerebral ischemia, followed by intravenous administration of 1 × 10(7) allogeneic BMMCs or vehicle at 0, 3 or 6 h after reperfusion or 2 × 10(7) BMMCs 6 h after reperfusion. Other rats administered 1 × 10(7) BMMCs at 6 h after reperfusion received additional BMMC transplantation or vehicle 9 h after reperfusion. Infarct volumes, neurological deficit scores and immunohistochemistry were evaluated 24 or 72 h after reperfusion.
  
  
  RESULTS
  Infarct volumes at 24 h were significantly decreased in transplantation rats at 0 and 3 h, but not at 6 h, after reperfusion, compared to vehicle-treatment. Even high dose BMMC transplantation at 6h after reperfusion was ineffective. Repeated BMMC transplantation at 6 and 9h after reperfusion reduced infarct volumes and significantly improved neurological deficit scores at 24 and 72 h. Immunohistochemistry showed repeated BMMC transplantation reduced ionized calcium-binding adapter molecule 1, 4-hydroxy-2-nonenal and 8-hydroxydeoxyguanosine expression at 24 and 72 h after reperfusion.
  
  
  CONCLUSIONS
  Intravenous allogeneic BMMCs were neuroprotective following transient focal cerebral ischemia, and the therapeutic time window of BMMC transplantation was >3 h and <6 h after reperfusion in this model. Repeated transplantation at 6 and 9 h after reperfusion suppressed inflammation and oxidative stress in ischemic brains, resulting in improved neuroprotection.
authors.affiliation: Department of Neurological Sciences, Graduate School of Medicine, Nippon Medical School, Japan. Electronic address: fu-min@nms.ac.jp.
authors.forename: Fumio
authors.initials: F
authors.lastname: Kamiya
authors.affiliation: Department of Neurological Sciences, Graduate School of Medicine, Nippon Medical School, Japan. Electronic address: ueda@nms.ac.jp.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Ueda
authors.affiliation: Department of Neurological Sciences, Graduate School of Medicine, Nippon Medical School, Japan.
authors.forename: Chikako
authors.initials: C
authors.lastname: Nito
authors.affiliation: Department of Neurological Sciences, Graduate School of Medicine, Nippon Medical School, Japan.
authors.forename: Nobuo
authors.initials: N
authors.lastname: Kamiya
authors.affiliation: Department of Neurological Sciences, Graduate School of Medicine, Nippon Medical School, Japan.
authors.forename: Toshiki
authors.initials: T
authors.lastname: Inaba
authors.affiliation: Department of Neurological Sciences, Graduate School of Medicine, Nippon Medical School, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Suda
authors.affiliation: Department of Neurological Sciences, Graduate School of Medicine, Nippon Medical School, Japan.
authors.forename: Tomonari
authors.initials: T
authors.lastname: Saito
authors.affiliation: Department of Neurological Sciences, Graduate School of Medicine, Nippon Medical School, Japan.
authors.forename: Kanako
authors.initials: K
authors.lastname: Muraga
authors.affiliation: Department of Neurological Sciences, Graduate School of Medicine, Nippon Medical School, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Katayama
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D016026:Bone Marrow Transplantation / Q000379:methods*; D001930:Brain Injuries / Q000209:etiology / Q000628:therapy*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D007249:Inflammation / Q000209:etiology / Q000628:therapy; D002546:Ischemic Attack, Transient / Q000150:complications*; D007963:Leukocytes, Mononuclear / Q000637:transplantation*; D008297:Male; D008840:Microfilament Proteins / Q000378:metabolism; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014184:Transplantation, Homologous
chemical_list: C100745:Aif1 protein, rat; D000447:Aldehydes; D002135:Calcium-Binding Proteins; D008840:Microfilament Proteins; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003849:Deoxyguanosine; C027576:4-hydroxy-2-nonenal
keywords: Allogeneic transplantation; Bone marrow; Cerebral ischemia; Neuroprotection