title: Combination therapy with bone marrow stromal cells and FK506 enhanced amelioration of ischemic brain damage in rats.
abstract: OBJECTIVE
  Transplantation of bone marrow stromal cells (MSCs) has been shown to ameliorate ischemic brain injury in animals. In the present study, we investigated whether the transplantation of MSCs combined with FK506, a clinically used immunosuppressant, enhanced neuroprotective effects in rat experimental stroke.
  
  
  METHODS
  Male Sprague-Dawley rats underwent transient 90 min middle cerebral artery occlusion (MCAO). Two or 6h after ischemia onset, the rats were randomly assigned to receive intravenous administration of MSCs plus FK506, MSCs alone, FK506 alone, or vehicle. Infarct volume, and neurological and immunohistological assessments were performed to examine the effects of these therapies.
  
  
  RESULTS
  In 2-hour post-ischemia treatment groups, significant improvement of infarct volume and neurological scores were observed 1 day after combination therapy compared with monotherapy, and this neuroprotection continued for 7 days. Combination therapy significantly reduced the number of TUNEL-positive apoptotic cells, increased Bcl-2 expression, decreased Bax expression, and suppressed neutrophil infiltration and microglia/macrophage activation compared to monotherapy. In 6-hour post-ischemia treatment groups, a significant reduction of infarct volume, edema index, and neurological score was observed only in the combination therapy group. Moreover, the number of engrafted MSCs on day 7 with combination therapy was significantly higher than with MSCs alone.
  
  
  CONCLUSIONS
  Combination therapy using FK506 enhanced the anti-apoptotic and anti-inflammatory effects of MSCs and increased the survival of transplanted cells, leading to expansion of the therapeutic time window for MSCs.
authors.affiliation: Divisions of Neurology, Nephrology, and Rheumatology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Suda
authors.forename: Kuniko
authors.initials: K
authors.lastname: Shimazaki
authors.forename: Masayuki
authors.initials: M
authors.lastname: Ueda
authors.forename: Toshiki
authors.initials: T
authors.lastname: Inaba
authors.forename: Nobuo
authors.initials: N
authors.lastname: Kamiya
authors.forename: Ken-ichiro
authors.initials: K
authors.lastname: Katsura
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Katayama
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D016026:Bone Marrow Transplantation / Q000379:methods*; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000601:surgery*; D003131:Combined Modality Therapy / Q000379:methods*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008297:Male; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017154:Stromal Cells / Q000637:transplantation; D016559:Tacrolimus / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D016559:Tacrolimus