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Antioxidant treatment protects striatal neurons against excitotoxic insults

Nakao, Naoyuki; Grasbon-Frodl, Eva Maria; Widner, H LU and Brundin, P LU (1996) In Neuroscience 73(1). p.185-200
Abstract

It has been suggested that oxidative stress plays an important role in mediating excitotoxic neuronal death. We have therefore investigated the protective effects of antioxidants against excitotoxic injury in the rat on striatal neurons both in vitro and in vivo. In the first part of the study, we determined whether two different types of antioxidants, the spin trapping agent, alpha-phenyl-tert-butyl nitrone and an inhibitor of lipid peroxidation, U-83836E, could protect cultured striatal neurons against either hypoglycemic injury or N-methyl-D-aspartate-induced excitotoxicity. Dopamine- and cyclic AMP-regulated phosphoprotein, which is enriched in medium-sized spiny neurons, was chosen as a marker for striatal neurons.... (More)

It has been suggested that oxidative stress plays an important role in mediating excitotoxic neuronal death. We have therefore investigated the protective effects of antioxidants against excitotoxic injury in the rat on striatal neurons both in vitro and in vivo. In the first part of the study, we determined whether two different types of antioxidants, the spin trapping agent, alpha-phenyl-tert-butyl nitrone and an inhibitor of lipid peroxidation, U-83836E, could protect cultured striatal neurons against either hypoglycemic injury or N-methyl-D-aspartate-induced excitotoxicity. Dopamine- and cyclic AMP-regulated phosphoprotein, which is enriched in medium-sized spiny neurons, was chosen as a marker for striatal neurons. alpha-Phenyl-t-butyl nitrone and U-83836E both significantly reduced cell death induced by these insults as indicated by an increased number of surviving dopamine- and cyclic AMP-regulated phospho-protein-positive neurons. The two antioxidants also promoted the survival of cultured striatal neurons grown at low cell density under serum-free culture conditions. In an in vivo experiment systemically administered alpha-phenyl-t-butyl nitrone exerted neuroprotective effects in the rat striatum following injection of the excitotoxin quinolinic acid. Apomorphine-induced rotation tests revealed that alpha-phenyl-t-butyl nitrone-treated animals were significantly less asymmetric in their motor behavior than control rats. Treatment with alpha-phenyl-t-butyl nitrone significantly reduced the size of the quinolinic acid-induced striatal lesions, as assessed by the degree of sparing of dopamine- and cyclic AMP-regulated phospho-protein-positive and nicotinamide adenine dinucleotide phosphate-diaphorase-positive neurons, and of microtubule-associated protein-2-immunorective areas. Furthermore, lesion-induced morphological changes in the substantia nigra pars reticulate, i.e. loss of dopamine- and cyclic AMP-regulated phosphoprotein-positive afferent fibers and atrophic changes due to transsynaptic degeneration, were also less extensive in the alpha-phenyl-t-butyl nitrone-treated animals. The results support the hypothesis that oxygen-free radicals contribute to excitotoxic neuronal injury. The in vivo cytoprotective effects of alpha-phenyl-t-butyl nitrone against striatal excitotoxic lesions suggest that antioxidants could be used as potential neuroprotective agents in Huntington's disease, which has been suggested to involve excitotoxicity.

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Animals, Antioxidants, Cell Death, Cell Survival, Cells, Cultured, Cyclic N-Oxides, Dopamine and cAMP-Regulated Phosphoprotein 32, Female, Hypoglycemia, Immunohistochemistry, NADPH Dehydrogenase, Neostriatum, Nerve Degeneration, Nerve Tissue Proteins, Neurons, Neurotoxins, Nitrogen Oxides, Phosphoproteins, Quinolinic Acid, Rats, Rats, Sprague-Dawley, Spin Labels, Stereotyped Behavior, Substantia Nigra
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Neuroscience
volume
73
issue
1
pages
16 pages
publisher
Elsevier
external identifiers
  • scopus:0029995487
ISSN
0306-4522
DOI
10.1016/0306-4522(96)00034-6
language
English
LU publication?
yes
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9e3647e5-8549-4971-9c86-ab23aaf8c172
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2017-04-19 18:26:28
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2017-11-05 05:16:25
@article{9e3647e5-8549-4971-9c86-ab23aaf8c172,
  abstract     = {<p>It has been suggested that oxidative stress plays an important role in mediating excitotoxic neuronal death. We have therefore investigated the protective effects of antioxidants against excitotoxic injury in the rat on striatal neurons both in vitro and in vivo. In the first part of the study, we determined whether two different types of antioxidants, the spin trapping agent, alpha-phenyl-tert-butyl nitrone and an inhibitor of lipid peroxidation, U-83836E, could protect cultured striatal neurons against either hypoglycemic injury or N-methyl-D-aspartate-induced excitotoxicity. Dopamine- and cyclic AMP-regulated phosphoprotein, which is enriched in medium-sized spiny neurons, was chosen as a marker for striatal neurons. alpha-Phenyl-t-butyl nitrone and U-83836E both significantly reduced cell death induced by these insults as indicated by an increased number of surviving dopamine- and cyclic AMP-regulated phospho-protein-positive neurons. The two antioxidants also promoted the survival of cultured striatal neurons grown at low cell density under serum-free culture conditions. In an in vivo experiment systemically administered alpha-phenyl-t-butyl nitrone exerted neuroprotective effects in the rat striatum following injection of the excitotoxin quinolinic acid. Apomorphine-induced rotation tests revealed that alpha-phenyl-t-butyl nitrone-treated animals were significantly less asymmetric in their motor behavior than control rats. Treatment with alpha-phenyl-t-butyl nitrone significantly reduced the size of the quinolinic acid-induced striatal lesions, as assessed by the degree of sparing of dopamine- and cyclic AMP-regulated phospho-protein-positive and nicotinamide adenine dinucleotide phosphate-diaphorase-positive neurons, and of microtubule-associated protein-2-immunorective areas. Furthermore, lesion-induced morphological changes in the substantia nigra pars reticulate, i.e. loss of dopamine- and cyclic AMP-regulated phosphoprotein-positive afferent fibers and atrophic changes due to transsynaptic degeneration, were also less extensive in the alpha-phenyl-t-butyl nitrone-treated animals. The results support the hypothesis that oxygen-free radicals contribute to excitotoxic neuronal injury. The in vivo cytoprotective effects of alpha-phenyl-t-butyl nitrone against striatal excitotoxic lesions suggest that antioxidants could be used as potential neuroprotective agents in Huntington's disease, which has been suggested to involve excitotoxicity.</p>},
  author       = {Nakao, Naoyuki and Grasbon-Frodl, Eva Maria and Widner, H and Brundin, P},
  issn         = {0306-4522},
  keyword      = {Animals,Antioxidants,Cell Death,Cell Survival,Cells, Cultured,Cyclic N-Oxides,Dopamine and cAMP-Regulated Phosphoprotein 32,Female,Hypoglycemia,Immunohistochemistry,NADPH Dehydrogenase,Neostriatum,Nerve Degeneration,Nerve Tissue Proteins,Neurons,Neurotoxins,Nitrogen Oxides,Phosphoproteins,Quinolinic Acid,Rats,Rats, Sprague-Dawley,Spin Labels,Stereotyped Behavior,Substantia Nigra},
  language     = {eng},
  number       = {1},
  pages        = {185--200},
  publisher    = {Elsevier},
  series       = {Neuroscience},
  title        = {Antioxidant treatment protects striatal neurons against excitotoxic insults},
  url          = {http://dx.doi.org/10.1016/0306-4522(96)00034-6},
  volume       = {73},
  year         = {1996},
}