Caspase inhibition reduces apoptosis and increases survival of nigral transplants

Publisher Website
Google Scholar
Abstract
Transplantation of embryonic nigral tissue ameliorates functional deficiencies in Parkinson disease1,2. The main practical constraints of neural grafting are the shortage of human donor tissue and the poor survival of dopaminergic neurons grafted into patients, which is estimated at 5–10% (refs. 3,4). The required amount of human tissue could be considerably reduced if the neuronal survival was augmented. Studies in rats indicate that most implanted embryonic neurons die within 1 week of transplantation5,6, and that most of this cell death is apoptotic6. Modified peptides, such as acetyl–tyrosinyl–valyl–alanyl–aspartyl–chloro– methylketone (Ac–YVAD–cmk), that specifically inhibit proteases of the caspase family7 effectively block apoptosis in a plethora of experimental paradigms, such as growth factor withdrawal8, excitotoxicity9, axotomy10, cerebral ischemia11 and brain trauma12. Here we examined the effects of caspase inhibition by Ac–YVAD–cmk on cell death immediately after donor tissue preparation and on long–term graft survival. Treatment of the embryonic nigral cell suspension with Ac–YVAD–cmk mitigated DNA fragmentation and reduced apoptosis in transplants. It also increased survival of dopaminergic neurons grafted to hemiparkinsonian rats, and thereby substantially improved functional recovery.