Lazaroids improve the survival of grafted rat embryonic dopamine neurons

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Lazaroids improve the survival of grafted rat embryonic dopamine neurons. / Nakao, Naoyuki; Grasbon-Frodl, Eva Maria; Duan, W M; Widner, H; Brundin, P.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 91, No. 26, 20.12.1994, p. 12408-12.

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Nakao, Naoyuki ; Grasbon-Frodl, Eva Maria ; Duan, W M ; Widner, H ; Brundin, P. / Lazaroids improve the survival of grafted rat embryonic dopamine neurons. In: Proceedings of the National Academy of Sciences of the United States of America. 1994 ; Vol. 91, No. 26. pp. 12408-12.

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TY - JOUR

T1 - Lazaroids improve the survival of grafted rat embryonic dopamine neurons

AU - Nakao, Naoyuki

AU - Grasbon-Frodl, Eva Maria

AU - Duan, W M

AU - Widner, H

AU - Brundin, P

PY - 1994/12/20

Y1 - 1994/12/20

N2 - 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.

AB - 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.

KW - Animals

KW - Cell Survival

KW - Chromans

KW - Female

KW - Mesencephalon

KW - Neurons

KW - Parkinson Disease

KW - Piperazines

KW - Pregnatrienes

KW - Rats

KW - Rats, Sprague-Dawley

KW - Stereotyped Behavior

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

M3 - Article

VL - 91

SP - 12408

EP - 12412

JO - Proceedings of the National Academy of Sciences

T2 - Proceedings of the National Academy of Sciences

JF - Proceedings of the National Academy of Sciences

SN - 1091-6490

IS - 26

ER -