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Caspase inhibition reduces apoptosis and increases survival of nigral transplants

Nature Medicine volume 5, pages 97–100 (1999)Cite this article

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.

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Figure 1: Inhibition of serum deprivation–induced neuronal death in mesencephalic cultures by Ac–YVAD–cmk.
Figure 2: Prevention of apoptosis in ventral mesencephalic cell suspensions and grafts by Ac–YVAD–cmk.
Figure 3: Reversal of amphetamine–induced motor asymmetry by neural grafting, and histological evidence for increased survival of dopaminergic neurons in nigral grafts treated with Ac–YVAD–cmk.

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Acknowledgements

We acknowledge the technical assistance of T. Björklund, B. Haraldsson, H. Naumann, B. Lindberg and M. Pettersson. This study was supported by grants from the Medical Faculty at Lund University, the Swedish Medical Research Council, the Thorsten and Elsa Segerfalk Foundation, and Deutsche Forschungsgemeinschaft. G.S.S. was supported by a Marie Curie Fellowship within the 4th framework program of the European Commission.

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  1. Section for Neuronal Survival, Wallenberg Neuroscience Center, Lund University, Sölvegatan 17, Lund, S–223 62, Sweden

    Gabriele S. Schierle, Oskar Hansson, Håkan Widner & Patrik Brundin

  2. Chair of Molecular Toxicology, Faculty of Biology, Konstanz University, Box X911, Konstanz, D–78457, Germany

    Marcel Leist & Pierluigi Nicotera

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  1. Gabriele S. Schierle
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Correspondence to Gabriele S. Schierle.

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Schierle, G., Hansson, O., Leist, M. et al. Caspase inhibition reduces apoptosis and increases survival of nigral transplants. Nat Med 5, 97–100 (1999). https://doi.org/10.1038/4785

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