Novel imine antioxidants at low nanomolar concentrations protect dopaminergic cells from oxidative neurotoxicity
Open Access
- 15 June 2009
- journal article
- Published by Wiley in Journal of Neurochemistry
- Vol. 110 (1), 118-132
- https://doi.org/10.1111/j.1471-4159.2009.06114.x
Abstract
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 approximately 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.Keywords
This publication has 54 references indexed in Scilit:
- Free radical damage to cerebral cortex in Alzheimer's disease, microvascular brain injury, and smokingAnnals of Neurology, 2009
- Activation of c-Jun N-Terminal Protein Kinase Is a Common Mechanism Underlying Paraquat- and Rotenone-Induced Dopaminergic Cell ApoptosisToxicological Sciences, 2007
- Oxidative stress and neurodegeneration: where are we now?Journal of Neurochemistry, 2006
- Mitochondrial membrane depolarization and the selective death of dopaminergic neurons by rotenone: protective effect of coenzyme Q10Journal of Neurochemistry, 2005
- Antioxidants as treatment for neurodegenerative disordersExpert Opinion on Investigational Drugs, 2002
- Role of Free Radicals in the Neurodegenerative DiseasesDrugs & Aging, 2001
- Full length articleBrain Research, 1997
- Manipulation of glutathione contents fails to alter dopaminergic nigrostriatal neurotoxicity of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the mouseNeuroscience Letters, 1986
- Idiopathic Parkinson's disease, progressive supranuclear palsy and glutathione metabolism in the substantia nigra of patientsNeuroscience Letters, 1986
- A comparison between dopamine-stimulated adenylate cyclase and 3H-SCH 23390 binding in rat striatumLife Sciences, 1985