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Novel imine antioxidants at low nanomolar concentrations protect dopaminergic cells from oxidative neurotoxicity
Author(s) -
Hajieva Parvana,
Mocko Justyna B.,
Moosmann Bernd,
Behl Christian
Publication year - 2009
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 - 10.1111/j.1471-4159.2009.06114.x
Subject(s) - glutathione , buthionine sulfoximine , rotenone , oxidative stress , antioxidant , chemistry , lipid peroxidation , cytoprotection , pharmacology , biochemistry , mitochondrion , neuroprotection , neurotoxicity , biology , toxicity , enzyme , organic chemistry
Strong evidence indicates that oxidative stress may be causally involved in the pathogenesis of Parkinson’s disease. We have employed human dopaminergic neuroblastoma cells and rat primary mesencephalic neurons to assess the protective potential of three novel bisarylimine antioxidants on dopaminergic cell death induced by complex I inhibition or glutathione depletion. We have found that exceptionally low concentrations (EC 50 values ∼20 nM) of these compounds (iminostilbene, phenothiazine, and phenoxazine) exhibited strong protective effects against the toxicities of MPP + , rotenone, and l ‐buthionine sulfoximine. Investigating intracellular glutathione levels, it was found that MPP + , l ‐buthionine sulfoximine, and rotenone disrupted different aspects of the native glutathione equilibrium, while the aromatic imines did not further influence glutathione levels or redox state on any baseline. However, the imines independently reduced protein oxidation and total oxidant flux, saved the mitochondrial membrane potential, and provided full cytoprotection under conditions of complete glutathione depletion. The unusually potent antioxidant effects of the bisarylimines could be reproduced in isolated mitochondria, which were instantly protected from lipid peroxidation and pathological swelling. Aromatic imines may be interesting lead structures for a potential antioxidant therapy of Parkinson’s disease and other disorders accompanied by glutathione dysregulation.