Caspase inhibition by Z-VAD increases the survival of grafted bone marrow cells and improves functional outcome after MCAo in rats.
Marrow stromal cells (MSCs) transplantation into brain has been employed to treat experimental ischemia. However, MSCs undergo apoptosis and few survive in the ischemic brain. We test the hypotheses that coadministration of bone marrow cells (BMCs) with a cell-permeable inhibitor of caspases, Z-Val-Ala-DL-Asp-fluoromethylketone (Z-VAD), into the ischemic boundary zone (IBZ) of brain promotes BMCs survival and improve outcome. Experimental groups consist of: 24 h after MCAo, either phosphate-buffered saline (PBS, n=4), dead BMC (n=4), fresh BMC (n=10), Z-VAD only (n=4), or BMC with Z-VAD (n=6) were intracerebrally injected. BMCs were harvested from donor adult rats labeled with bromodeoxyuridine (BrdU). Rats were subjected to an adhesive-removal somatosensory and motor-rotarod functional tests before MCAo and at 1 and 7 days after MCAo. Rats treated with a combination of Z-VAD and BMCs exhibited significant improvement in the adhesive-removal test at 7 days compared with the control group (combined MCAo+PBS and MCAo+dead BMC) (p<0.01), and the numbers of BrdU-BMC increased (p<0.05) and apoptotic cells decreased (p<0.05) compared with BMC alone transplantation. Our data suggest that intracerebral coadministration of BMC with Z-VAD enhances the survival of grafted BMC and improves neurological functional recovery after MCAo.
Chen
Jieli
J
Department of Neurology, Henry Ford Health Sciences Center, 2799 West Grand Boulevard, Detroit, MI 48202, USA.
Li
Yi
Y
Wang
Lei
L
Lu
Mei
M
Chopp
Michael
M
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D016026:Bone Marrow Transplantation; D061945:Caspase Inhibitors; D002452:Cell Count; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004195:Disease Models, Animal; D004333:Drug Administration Routes; D006085:Graft Survival / Q000187:drug effects*; D020244:Infarction, Middle Cerebral Artery / Q000628:therapy*; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D020127:Recovery of Function; D017154:Stromal Cells / Q000637:transplantation; D016896:Treatment Outcome
D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D018696:Neuroprotective Agents; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone