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Caspase inhibition reduces apoptosis and increases survival of nigral transplants

Schierle, Gabriele LU ; Hansson, Oskar LU ; Leist, M; Nicotera, P; Widner, Håkan LU and Brundin, Patrik LU (1999) In Nature Medicine 5(1). p.97-100
Abstract
Transplantation of embryonic nigral tissue ameliorates functional deficiencies in Parkinson disease. 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, and that most of this cell death is apoptotic. Modified peptides, such as acetyl-tyrosinyl-valyl-alanyl-aspartyl-chloro-methylketone (Ac-YVAD-cmk), that specifically inhibit proteases of the caspase family effectively block apoptosis in a... (More)
Transplantation of embryonic nigral tissue ameliorates functional deficiencies in Parkinson disease. 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, and that most of this cell death is apoptotic. Modified peptides, such as acetyl-tyrosinyl-valyl-alanyl-aspartyl-chloro-methylketone (Ac-YVAD-cmk), that specifically inhibit proteases of the caspase family effectively block apoptosis in a plethora of experimental paradigms, such as growth factor withdrawal, excitotoxicity, axotomy, cerebral ischemia and brain trauma. 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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Medicine
volume
5
issue
1
pages
97 - 100
publisher
Nature Publishing Group
external identifiers
  • pmid:9883846
  • scopus:0033008216
ISSN
1546-170X
DOI
10.1038/4785
language
English
LU publication?
yes
id
14fb8e03-a38f-4991-8464-bc5b21b8abc9 (old id 1114606)
date added to LUP
2008-07-04 14:14:27
date last changed
2017-05-07 04:12:45
@article{14fb8e03-a38f-4991-8464-bc5b21b8abc9,
  abstract     = {Transplantation of embryonic nigral tissue ameliorates functional deficiencies in Parkinson disease. 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, and that most of this cell death is apoptotic. Modified peptides, such as acetyl-tyrosinyl-valyl-alanyl-aspartyl-chloro-methylketone (Ac-YVAD-cmk), that specifically inhibit proteases of the caspase family effectively block apoptosis in a plethora of experimental paradigms, such as growth factor withdrawal, excitotoxicity, axotomy, cerebral ischemia and brain trauma. 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.},
  author       = {Schierle, Gabriele and Hansson, Oskar and Leist, M and Nicotera, P and Widner, Håkan and Brundin, Patrik},
  issn         = {1546-170X},
  language     = {eng},
  number       = {1},
  pages        = {97--100},
  publisher    = {Nature Publishing Group},
  series       = {Nature Medicine},
  title        = {Caspase inhibition reduces apoptosis and increases survival of nigral transplants},
  url          = {http://dx.doi.org/10.1038/4785},
  volume       = {5},
  year         = {1999},
}