Nature Medicine
5, 97 - 100 (1999)
doi:10.1038/4785
Caspase inhibition reduces apoptosis and increases survival of nigral
transplantsGabriele S. Schierle1, Oskar Hansson1, Marcel Leist2, Pierluigi Nicotera2, Håkan Widner1
& Patrik Brundin11
Section for Neuronal Survival, Wallenberg Neuroscience
Center, Lund University, Sölvegatan 17,
S−223 62 Lund, Sweden
2
Chair of Molecular Toxicology, Faculty of Biology,
Konstanz University, Box X911, D−78457
Konstanz, Germany
Correspondence should be addressed to Gabriele S. Schierle Gabriele.Schierle@mphy.lu.se
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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