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Additive effects of caspase inhibitor and lazaroid on the survival of transplanted rat and human embryonic dopamine neurons

Hansson, Oskar LU ; Castilho, Roger F; Schierle, Gabriele LU ; Karlsson, Jenny LU ; Nicotera, P; Leist, M and Brundin, Patrik LU (2000) In Experimental Neurology 164(1). p.102-111
Abstract
Major practical constraints on neural grafting in Parkinson's disease are the shortage of human donor tissue and the great loss of dopamine neurons during the grafting procedure. The vast majority of implanted embryonic dopamine neurons are believed to die within a few days of transplantation surgery, at least in part through apoptosis. We have previously found that survival of nigral grafts in rodents can be significantly augmented by pretreatment with the caspase inhibitor Ac-YVAD-cmk or by lazaroids (lipid peroxidation inhibitors). We now report that pretreatment with the caspase inhibitor Ac-DEVD-cmk, but not z-VAD-fmk, results in a significantly improved survival of transplanted dopamine neurons of similar magnitude to that achieved... (More)
Major practical constraints on neural grafting in Parkinson's disease are the shortage of human donor tissue and the great loss of dopamine neurons during the grafting procedure. The vast majority of implanted embryonic dopamine neurons are believed to die within a few days of transplantation surgery, at least in part through apoptosis. We have previously found that survival of nigral grafts in rodents can be significantly augmented by pretreatment with the caspase inhibitor Ac-YVAD-cmk or by lazaroids (lipid peroxidation inhibitors). We now report that pretreatment with the caspase inhibitor Ac-DEVD-cmk, but not z-VAD-fmk, results in a significantly improved survival of transplanted dopamine neurons of similar magnitude to that achieved in this study using Ac-YVAD-cmk (both 220-230% of control). In addition, we found that treatment of the graft tissue with tirilazad mesylate (a lazaroid allowed for clinical use) almost doubled the survival of grafted dopamine neurons. When Ac-YVAD-cmk and tirilazad mesylate treatments were combined, the number of surviving dopamine neurons increased significantly further to 280% of control. Importantly, the same combination of neuroprotectants enhanced the survival of human dopamine neurons xenotransplanted to immunosuppressed rats (to 240% of control). In conclusion, these results suggest that combining treatments that counteract oxidative stress and caspase activation is a valuable strategy to enhance nigral graft survival that should be considered for clinical application. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
neural transplantation, apoptosis, caspase, dopamine, lazaroid, Parkinson's disease
in
Experimental Neurology
volume
164
issue
1
pages
102 - 111
publisher
Academic Press
external identifiers
  • pmid:10877920
  • scopus:0033940543
ISSN
0014-4886
DOI
10.1006/exnr.2000.7406
language
English
LU publication?
yes
id
2c1a33e0-f843-4af2-a8a0-597ac0d44dc2 (old id 1117106)
date added to LUP
2008-07-02 16:33:12
date last changed
2017-02-26 03:39:59
@article{2c1a33e0-f843-4af2-a8a0-597ac0d44dc2,
  abstract     = {Major practical constraints on neural grafting in Parkinson's disease are the shortage of human donor tissue and the great loss of dopamine neurons during the grafting procedure. The vast majority of implanted embryonic dopamine neurons are believed to die within a few days of transplantation surgery, at least in part through apoptosis. We have previously found that survival of nigral grafts in rodents can be significantly augmented by pretreatment with the caspase inhibitor Ac-YVAD-cmk or by lazaroids (lipid peroxidation inhibitors). We now report that pretreatment with the caspase inhibitor Ac-DEVD-cmk, but not z-VAD-fmk, results in a significantly improved survival of transplanted dopamine neurons of similar magnitude to that achieved in this study using Ac-YVAD-cmk (both 220-230% of control). In addition, we found that treatment of the graft tissue with tirilazad mesylate (a lazaroid allowed for clinical use) almost doubled the survival of grafted dopamine neurons. When Ac-YVAD-cmk and tirilazad mesylate treatments were combined, the number of surviving dopamine neurons increased significantly further to 280% of control. Importantly, the same combination of neuroprotectants enhanced the survival of human dopamine neurons xenotransplanted to immunosuppressed rats (to 240% of control). In conclusion, these results suggest that combining treatments that counteract oxidative stress and caspase activation is a valuable strategy to enhance nigral graft survival that should be considered for clinical application.},
  author       = {Hansson, Oskar and Castilho, Roger F and Schierle, Gabriele and Karlsson, Jenny and Nicotera, P and Leist, M and Brundin, Patrik},
  issn         = {0014-4886},
  keyword      = {neural transplantation,apoptosis,caspase,dopamine,lazaroid,Parkinson's disease},
  language     = {eng},
  number       = {1},
  pages        = {102--111},
  publisher    = {Academic Press},
  series       = {Experimental Neurology},
  title        = {Additive effects of caspase inhibitor and lazaroid on the survival of transplanted rat and human embryonic dopamine neurons},
  url          = {http://dx.doi.org/10.1006/exnr.2000.7406},
  volume       = {164},
  year         = {2000},
}