Caspase inhibition reduces apoptosis and increases survival of nigral transplants

Transplantation of embryonic nigral tissue ameliorates functional deficienc ies in Parkinson disease(1,2). The main practical constraints of neural gra fting are the shortage of human donor tissue and the poor survival of dopam inergic neurons grafted into patients, which is estimated at 5-10% (refs. 3 ,4). The required amount of human tissue could be considerably reduced if t he neuronal survival was augmented. Studies in rats indicate that most impl anted embryonic neurons die within 1 week of transplantation(5,6), and that most of this cell death is apoptotic(6). Modified peptides, such as acetyl -tyrosinyl-valyl-alanyl-aspartyl-chloro-methylketone (Ac-YVAD-cmk), that sp ecifically inhibit proteases of the caspase family(7) effectively block apo ptosis in a plethora of experimental paradigms, such as growth factor withd rawal(8), excitotoxicity(9), axotomy(10), cerebral ischemia(11) and brain t rauma(12). Here we examined the effects of caspase inhibition by Ac-YVAD-cm k on cell death immediately after donor tissue preparation and on long-term graft survival. Treatment of the embryonic nigral cell suspension with AcY VAD-cmk mitigated DNA fragmentation and reduced apoptosis in transplants. I t also increased survival of dopaminergic neurons grafted to hemiparkinsoni an rats, and thereby substantially improved functional recovery.