A therapeutic window for intravenous administration of autologous bone marrow after cerebral ischemia in adult rats.
The primary objective of this study was to test the hypothesis that intravenous administration of autologous bone marrow cells could improve functional recovery after middle cerebral artery occlusion (MCAO) for 45 min in the rat and to determine specific time windows for efficacy. Mononuclear cells from autologous bone marrow were transfected with the LacZ reporter gene, and injected intravenously into rats at 3-72 h after induction of MCAO. Histological analysis of the ischemic lesion at 14 days after transplantation revealed reduced ischemic lesion volume. Lesion volume was 250+/-45 mm(3) (n=6) after MCAO without cell transplantation. Lesions were minimally detected by absence of 2,3,5-triphenyltetrazolium chloride (TTC) staining when bone marrow cells were infused 3 h after lesion induction. Lesions were clearly detected beginning with the 6-h postlesion group and became progressively larger at 12, 24 and 72 h (80+/-25, 140+/-18, and 180+/-22 mm(3), respectively; n=6 for each group). Transplanted LacZ(+) bone marrow cells accumulated extensively in and around the ischemic lesions, and immunohistochemistry suggests some neuronal and glial lineage differentiation. Behavioral testing (Morris water maze and Treadmill stress test) indicated greater functional recovery in the treated group. These findings suggest that early intervention with intravenous administration of autologous mononuclear cells from bone marrow can reduce lesion size in the MCAO model in the rat, and improve functional outcome.
Iihoshi
Satoshi
S
Department of Neurosurgery, Sapporo Medical University School of Medicine, Sapporo, South-1st, West-16th, Chuo, Sapporo, Hokkaido 060-8543, Japan.
Honmou
Osamu
O
Houkin
Kiyohiro
K
Hashi
Kazuo
K
Kocsis
Jeffery D
JD
D000818:Animals; D001522:Behavior, Animal; D001854:Bone Marrow Cells / Q000502:physiology*; D016026:Bone Marrow Transplantation; D020520:Brain Infarction / Q000175:diagnosis / Q000209:etiology / Q000473:pathology; D002545:Brain Ischemia / Q000209:etiology / Q000628:therapy*; D002452:Cell Count; D004195:Disease Models, Animal; D005080:Exercise Test / Q000379:methods; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000628:therapy; D007275:Injections, Intravenous; D008297:Male; D018782:Maze Learning / Q000502:physiology; D009043:Motor Activity / Q000502:physiology; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function; D013194:Staining and Labeling / Q000379:methods; D013778:Tetrazolium Salts; D013997:Time Factors; D014182:Transplantation, Autologous
D005904:Glial Fibrillary Acidic Protein; D013778:Tetrazolium Salts; C009591:triphenyltetrazolium; D010751:Phosphopyruvate Hydratase