Caspase inhibition reduces apoptosis and increases survival of nigral transplants

GS Schierle, O Hansson, M Leist, P Nicotera… - Nature medicine, 1999 - nature.com
Nature medicine, 1999nature.com
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 …
Abstract
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 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.
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