Mechanism of 6-hydroxydopamine neurotoxicity.

The catecholaminergic neurotoxin 6-hydroxydopamine (6-OHDA) has recently been found to be formed endogenously in patients suffering from Parkinson's disease. In this article, we highlight the latest findings on the biochemical mechanism of 6-OHDA toxicity. 6-OHDA has two ways of action: it easily forms free radicals and it is a potent inhibitor of the mitochondrial respiratory chain complexes I and IV. The inhibition of respiratory enzymes by 6-OHDA is reversible and insensitive towards radical scavengers and iron chelators with the exception of desferrioxamine. We conclude that free radicals are not involved in the interaction between 6-OHDA and the respiratory chain and that the two mechanisms are biochemically independent, although they may act synergistically in vivo.

[1]  Y. Glinka,et al.  Dopamine Neurotoxicity: Inhibition of Mitochondrial Respiration , 1995, Journal of neurochemistry.

[2]  J. Cadet,et al.  Vitamin E attenuates the toxic effects of 6-hydroxydopamine on free radical scavenging systems in rat brain , 1992, Brain Research Bulletin.

[3]  E. Stadtman,et al.  Oxidation of free amino acids and amino acid residues in proteins by radiolysis and by metal-catalyzed reactions. , 1993, Annual review of biochemistry.

[4]  K. Jellinger,et al.  The role of transition metals in the pathogenesis of Parkinson's disease , 1995, Journal of the Neurological Sciences.

[5]  L. King,et al.  Effects of pargyline and pyrogallol on the methamphetamine-induced dopamine depletion. , 1995, Molecular and chemical neuropathology.

[6]  C. Winterbourn,et al.  6-Hydroxydopamine releases iron from ferritin and promotes ferritin-dependent lipid peroxidation. , 1989, Biochemical pharmacology.

[7]  G. Lescoat,et al.  Antioxidant and free radical scavenging activities of the iron chelators pyoverdin and hydroxypyrid-4-ones in iron-loaded hepatocyte cultures: comparison of their mechanism of protection with that of desferrioxamine. , 1992, Free radical biology & medicine.

[8]  K. Fuxe,et al.  Temporal and spatial increase of astroglial basic fibroblast growth factor synthesis after 6-hydroxydopamine-induced degeneration of the nigrostriatal dopamine neurons , 1994, Neuroscience.

[9]  B. Hyman,et al.  Do defecs in mitochondrial energy metabolism underlie the pathology of neurodegenerative diseases? , 1993, Trends in Neurosciences.

[10]  M. Erecińska,et al.  Relationships between the neuronal sodium/potassium pump and energy metabolism. Effects of K+, Na+, and adenosine triphosphate in isolated brain synaptosomes , 1990, The Journal of general physiology.

[11]  A. Vinogradov,et al.  Effect of Ca2+ ions on the slow active/inactive transition of the mitochondrial NADH-ubiquinone reductase. , 1992, Biochimica et biophysica acta.

[12]  J. Townsend,et al.  Pre- and Postsynaptic Neurotoxic Effects of Dopamine Demonstrated by Intrastriatal Injection , 1993, Experimental Neurology.

[13]  C. Marsden,et al.  Alterations in levels of iron, ferritin, and other trace metals in neurodegenerative diseases affecting the basal ganglia , 1992 .

[14]  P. Riederer,et al.  The role of iron in senescence of dopaminergic neurons in Parkinson's disease. , 1993, Journal of neural transmission. Supplementum.

[15]  Y. Kagawa,et al.  Deficiencies in complex I subunits of the respiratory chain in Parkinson's disease. , 1989, Biochemical and biophysical research communications.

[16]  A. Barzilai,et al.  Dopamine-induced programmed cell death in mouse thymocytes. , 1995, Biochimica et biophysica acta.

[17]  P. Brachet,et al.  Reactive Oxygen Species Influence Nerve Growth Factor Synthesis in Primary Rat Astrocytes , 1994, Journal of neurochemistry.

[18]  L. Wooldridge,et al.  Effect of 6-hydroxydopamine on murine hematopoietic stem cells: enhanced cytotoxicity on megakaryocyte colony forming units. , 1991, Life sciences.

[19]  C. Yokoyama,et al.  Resistance of hypothalamic dopaminergic neurons to neonatal 6-hydroxydopamine toxicity , 1993, Brain Research Bulletin.

[20]  S. Vroegop,et al.  Localization of damage induced by reactive oxygen species in cultured cells. , 1995, Free radical biology & medicine.

[21]  D. Ben-shachar,et al.  Intranigral Iron Injection Induces Behavioral and Biochemical “Parkinsonism” in Rats , 1991, Journal of neurochemistry.

[22]  M. Youdim,et al.  Inhibition of mitochondrial complexes I and IV by 6-hydroxydopamine. , 1995, European journal of pharmacology.

[23]  H. Ueda,et al.  Supersensitization of neurochemical responses by L-DOPA and dopamine receptor agonists in the striatum of experimental Parkinson's disease model rats. , 1995, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[24]  H. Ueda,et al.  Supersensitivity of quinpirole-evoked GTPase activation without changes in gene expression of D2 and Gi protein in the striatum of hemi-dopaminergic lesioned rats , 1994, Neuroscience Letters.

[25]  S. Wiegand,et al.  Efficacy of Brain‐Derived Neurotrophic Factor and Neurotrophin‐3 on Neurochemical and Behavioral Deficits Associated with Partial Nigrostriatal Dopamine Lesions , 1994, Journal of neurochemistry.

[26]  H. Stich,et al.  Clastogenic and mutagenic actions of active species generated in the 6-hydroxydopamine/oxygen reaction: effects of scavengers of active oxygen, iron, and metal chelating agents. , 1992, Free radical research communications.

[27]  K. Tipton,et al.  Nature of Inhibition of Mitochondrial Respiratory Complex I by 6‐Hydroxydopamine , 1996, Journal of neurochemistry.

[28]  N. Nishiyama,et al.  Neurotrophic factor gene expression in astrocytes during development and following injury , 1994, Brain Research Bulletin.

[29]  D. Ben-shachar,et al.  Selectivity of melaninized nigra-striatal dopamine neurons to degeneration in Parkinson's disease may depend on iron-melanin interaction. , 1990, Journal of neural transmission. Supplementum.

[30]  J. Connor.  Metals and Oxidative Damage in Neurological Disorders , 1997, Springer US.

[31]  M. Egan,et al.  Absence of 6‐Hydroxydopamine in the Rat Brain After Treatment with Stimulants and Other Dopaminergic Agents: A Mass Fragmentographic Study , 1993, Journal of neurochemistry.

[32]  D. Ben-shachar,et al.  The Iron Chelator Desferrioxamine (Desferal) Retards 6‐Hydroxydopamine‐Induced Degeneration of Nigrostriatal Dopamine Neurons , 1991, Journal of neurochemistry.

[33]  S. Orrenius,et al.  The calcium ion and cell death. , 1994, Journal of neural transmission. Supplementum.

[34]  R. Lindsay,et al.  Brain‐Derived Neurotrophic Factor Protects Dopamine Neurons Against 6‐Hydroxydopamine and N‐Methyl‐4‐Phenylpyridinium Ion Toxicity: Involvement of the Glutathione System , 1992, Journal of neurochemistry.

[35]  J. Perez-polo,et al.  Effects of Nerve Growth Factor on Glutathione Peroxidase and Catalase in PC 12 Cells , 1994, Journal of neurochemistry.

[36]  P. Ruppel,et al.  Competitive irreversible inhibition of dopamine uptake by 6-hydroxydopamine. , 1993, Research communications in chemical pathology and pharmacology.