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Energy Stress‐Induced Dopamine Loss in Glutathione Peroxidase‐Overexpressing Transgenic Mice and in Glutathione‐Depleted Mesencephalic Cultures
Author(s) -
Zeevalk Gail D.,
Bernard Laura P.,
Albers David S.,
Mirochnitchenko Oleg,
Nicklas William J.,
Sonsalla Patricia K.
Publication year - 1997
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1997.68010426.x
Subject(s) - glutathione , dopamine , glutathione peroxidase , medicine , buthionine sulfoximine , oxidative stress , endocrinology , malonate , chemistry , dopamine transporter , biology , dopaminergic , biochemistry , enzyme
The role of the glutathione system in protecting dopamine neurons from a mild impairment of energy metabolism imposed by the competitive succinate dehydrogenase inhibitor, malonate, was investigated in vitro and in vivo. Treatment of mesencephalic cultures with 10 µ M buthionine sulfoxamine for 24 h reduced total glutathione levels in the cultures by 68%. Reduction of cellular glutathione per se was not toxic to the dopamine population, but potentiated toxicity when the cultures were exposed to malonate. In contrast, transgenic mice overexpressing glutathione peroxidase (hGPE) that received an intrastriatal infusion of malonate (3 µmol) into the left side had significantly less loss of striatal dopamine than their hGPE‐negative littermates when assayed 1 week following infusion. These studies demonstrate that manipulation of the glutathione system influences susceptibility of dopamine neurons to damage due to energy impairment. The findings may provide insight into the loss of dopamine neurons in Parkinson's disease in which defects in both energy metabolism and the glutathione system have been identified.