Advanced

Lazaroids improve the survival of grafted rat embryonic dopamine neurons

Nakao, Naoyuki; Grasbon-Frodl, Eva Maria; Duan, W M LU ; Widner, H LU and Brundin, P LU (1994) In Proceedings of the National Academy of Sciences of the United States of America 91(26). p.12-12408
Abstract

In rodent models of Parkinson disease in which transplants of dissociated rodent and human embryonic mesencephalic tissue, rich in dopamine neurons, have been studied, only 5-20% of the dopamine neurons survive the implantation procedure. We have investigated the effects of inhibiting free radical generation with two lazaroids, U-74389G and U-83836E, on the survival of embryonic rat dopamine neurons. U-74389G is a 21-aminosteroid, and U-83836E combines the piperazinyl pyrimidine portion of 21-aminosteroids with the antioxidant ring of alpha-tocopherol. In an initial study, we found that the lazaroids markedly prolonged the period after tissue dissociation that an embryonic mesencephalic cell suspension exhibits high cell viability in... (More)

In rodent models of Parkinson disease in which transplants of dissociated rodent and human embryonic mesencephalic tissue, rich in dopamine neurons, have been studied, only 5-20% of the dopamine neurons survive the implantation procedure. We have investigated the effects of inhibiting free radical generation with two lazaroids, U-74389G and U-83836E, on the survival of embryonic rat dopamine neurons. U-74389G is a 21-aminosteroid, and U-83836E combines the piperazinyl pyrimidine portion of 21-aminosteroids with the antioxidant ring of alpha-tocopherol. In an initial study, we found that the lazaroids markedly prolonged the period after tissue dissociation that an embryonic mesencephalic cell suspension exhibits high cell viability in vitro, as assessed by using a dye exclusion method. In a second series of experiments, addition of lazaroids to dissociated mesencephalic graft tissue increased the yield of surviving rat dopamine neurons 2.6-fold after implantation in the dopamine-denervated rat striatum. The improved survival correlated with an earlier onset of graft-induced functional effects in the amphetamine-induced rotation test. Thus, inhibition of free radical generation can significantly increase the yield of grafted embryonic dopamine neurons. Addition of lazaroids to the graft preparation is a relatively simple modification of the transplantation protocol and could readily be applied in a clinical setting. Moreover, since iron-dependent lipid peroxidation has been suggested to play a role in the death of nigral dopamine neurons in Parkinson disease and lazaroids are particularly potent inhibitors of such processes, the findings may have implications for the pathogenesis of this disease.

(Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Animals, Cell Survival, Chromans, Female, Mesencephalon, Neurons, Parkinson Disease, Piperazines, Pregnatrienes, Rats, Rats, Sprague-Dawley, Stereotyped Behavior, Journal Article, Research Support, Non-U.S. Gov't
in
Proceedings of the National Academy of Sciences of the United States of America
volume
91
issue
26
pages
12 - 12408
publisher
National Acad Sciences
external identifiers
  • scopus:0028574168
ISSN
0027-8424
language
English
LU publication?
yes
id
60b32f29-840c-4ad9-897a-bef02b16f9f2
date added to LUP
2017-04-19 18:27:34
date last changed
2017-06-20 15:41:51
@article{60b32f29-840c-4ad9-897a-bef02b16f9f2,
  abstract     = {<p>In rodent models of Parkinson disease in which transplants of dissociated rodent and human embryonic mesencephalic tissue, rich in dopamine neurons, have been studied, only 5-20% of the dopamine neurons survive the implantation procedure. We have investigated the effects of inhibiting free radical generation with two lazaroids, U-74389G and U-83836E, on the survival of embryonic rat dopamine neurons. U-74389G is a 21-aminosteroid, and U-83836E combines the piperazinyl pyrimidine portion of 21-aminosteroids with the antioxidant ring of alpha-tocopherol. In an initial study, we found that the lazaroids markedly prolonged the period after tissue dissociation that an embryonic mesencephalic cell suspension exhibits high cell viability in vitro, as assessed by using a dye exclusion method. In a second series of experiments, addition of lazaroids to dissociated mesencephalic graft tissue increased the yield of surviving rat dopamine neurons 2.6-fold after implantation in the dopamine-denervated rat striatum. The improved survival correlated with an earlier onset of graft-induced functional effects in the amphetamine-induced rotation test. Thus, inhibition of free radical generation can significantly increase the yield of grafted embryonic dopamine neurons. Addition of lazaroids to the graft preparation is a relatively simple modification of the transplantation protocol and could readily be applied in a clinical setting. Moreover, since iron-dependent lipid peroxidation has been suggested to play a role in the death of nigral dopamine neurons in Parkinson disease and lazaroids are particularly potent inhibitors of such processes, the findings may have implications for the pathogenesis of this disease.</p>},
  author       = {Nakao, Naoyuki and Grasbon-Frodl, Eva Maria and Duan, W M and Widner, H and Brundin, P},
  issn         = {0027-8424},
  keyword      = {Animals,Cell Survival,Chromans,Female,Mesencephalon,Neurons,Parkinson Disease,Piperazines,Pregnatrienes,Rats,Rats, Sprague-Dawley,Stereotyped Behavior,Journal Article,Research Support, Non-U.S. Gov't},
  language     = {eng},
  month        = {12},
  number       = {26},
  pages        = {12--12408},
  publisher    = {National Acad Sciences},
  series       = {Proceedings of the National Academy of Sciences of the United States of America},
  title        = {Lazaroids improve the survival of grafted rat embryonic dopamine neurons},
  volume       = {91},
  year         = {1994},
}