Caspase inhibition reduces apoptosis and increases survival of nigral transplants

Transplantation of embryonic nigral tissue ameliorates functional deficiencies in Parkinson disease(1,2). 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 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 specifically inhibit proteases of the caspase family(7) effectively block apoptosis in a plethora of experimental paradigms, such as growth factor withdrawal(8), excitotoxicity(9), axotomy(10), cerebral ischemia(11) and brain trauma(12). 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 AcYVAD-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.