An introduction to the free radical hypothesis in Parkinson's disease

Iron‐induced oxidant stress has been implicated in the pathogenesis of Parkinson's disease. An increasing body of evidence now indicates that in Parkinson's disease the environment within the substantia nigra is conducive to the formation of cytotoxic free radicals and cell degeneration. Dopamine neurons may be particularly vulnerable because of the oxidative metabolism of dopamine and the potential of neuromelanin to promote the site‐specific accumulation and reduction of iron. This hypothesis has attracted considerable attention because it opens the way for employing antioxidant strategies as possible neuroprotective treatment for Parkinson's disease. Although the concept is appealing, free radicals have not yet been proven to play a role in Parkinson's disease, and many important issues remain to be resolved before the oxidative hypothesis can ultimately be confirmed or refuted.

[1]  K. Ohno,et al.  Increase of deleted mitochondrial DNA in the striatum in Parkinson's disease and senescence. , 1990, Biochemical and biophysical research communications.

[2]  J. Connor,et al.  Receptor‐mediated transcytosis of transferrin across the blood‐brain barrier , 1987, Journal of neuroscience research.

[3]  R. Switzer,et al.  The regional distribution and cellular localization of iron in the rat brain , 1984, Neuroscience.

[4]  J. Langston,et al.  The effect of deprenyl (selegiline) on the natural history of Parkinson's disease. , 1989, Science.

[5]  B. Halliwell.  Oxidants and the central nervous system: some fundamental questions. Is oxidant damage relevant to Parkinson's disease, Alzheimer's disease, traumatic injury or stroke? , 1989, Acta neurologica Scandinavica. Supplementum.

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

[7]  B. White,et al.  Iron chelation prevents tissue injury following ischemia , 1985 .

[8]  Y. Agid,et al.  Iron and Aluminum Increase in the Substantia Nigra of Patients with Parkinson's Disease: An X‐Ray Microanalysis , 1991, Journal of neurochemistry.

[9]  C. Marsden,et al.  A Selective Increase in Particulate Superoxide Dismutase Activity in Parkinsonian Substantia Nigra , 1989, Journal of neurochemistry.

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

[11]  J. Langston,et al.  Oxidation reactions in Parkinson's disease. Discussion , 1990 .

[12]  P. Riederer,et al.  Is Parkinson's disease a progressive siderosis of substantia nigra resulting in iron and melanin induced neurodegeneration? , 1989, Acta neurologica Scandinavica. Supplementum.

[13]  G. Cohen,et al.  Dopamine turnover and glutathione oxidation: implications for Parkinson disease. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[14]  W. Nicklas,et al.  Inhibition of NADH-linked oxidation in brain mitochondria by 1-methyl-4-phenyl-pyridine, a metabolite of the neurotoxin, 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine. , 1985, Life sciences.

[15]  R. Clavier,et al.  Nigrostriatal Dopaminergic Neurons Remain Undamaged in Rats Given High Doses of l‐DOPA and Carbidopa Chronically , 1984, Journal of neurochemistry.

[16]  J. Connor,et al.  Cellular distribution of transferrin, ferritin, and iron in normal and aged human brains , 1990, Journal of neuroscience research.

[17]  C. Olanow.  A Rationale for Dopamine Agonists as Primary Therapy for Parkinson’s Disease , 1992, Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques.

[18]  B. Hallgren,et al.  THE EFFECT OF AGE ON THE NON‐HAEMIN IRON IN THE HUMAN BRAIN , 1958, Journal of neurochemistry.

[19]  S. Linn,et al.  DNA damage and oxygen radical toxicity. , 1988, Science.

[20]  M. Stoneking,et al.  Mitochondrial DNA and human evolution , 1987, Nature.

[21]  C. Marsden,et al.  Decreased Ferritin Levels in Brain in Parkinson's Disease , 1990, Journal of neurochemistry.

[22]  K. Earle.  Studies on Parkinson's disease including x-ray fluorescent spectroscopy of formalin fixed brain tissue. , 1968, Journal of neuropathology and experimental neurology.

[23]  J. Eaton,et al.  Hemoglobin-mediated oxidant damage to the central nervous system requires endogenous ascorbate. , 1988, The Journal of clinical investigation.

[24]  Diana Brahams,et al.  Medicine and the Law , 1983, The Lancet.

[25]  F. Moroni,et al.  Excitatory Amino Acid Release from Rat Hippocampal Slices as a Consequence of Free‐Radical Formation , 1988, Journal of neurochemistry.

[26]  J. Parks,et al.  Evidence for a defect in NADH , 1990, Neurology.

[27]  Peter Riederer,et al.  Transition Metals, Ferritin, Glutathione, and Ascorbic Acid in Parkinsonian Brains , 1989, Journal of neurochemistry.

[28]  D. D. Di Monte,et al.  Glutathione in Parkinson's disease: A link between oxidative stress and mitochondrial damage? , 1992, Annals of neurology.

[29]  B. Halliwell,et al.  Protection against tissue damage in vivo by desferrioxamine: what is its mechanism of action? , 1989, Free radical biology & medicine.

[30]  David L. Felten,et al.  Chronic dietary pergolide preserves nigrostriatal neuronal integrity in aged-Fischer-344 rats , 1992, Neurobiology of Aging.

[31]  C. Marsden,et al.  Basal Lipid Peroxidation in Substantia Nigra Is Increased in Parkinson's Disease , 1989, Journal of neurochemistry.

[32]  A. Schapira,et al.  Mitochondrial DNA analysis in Parkinson's disease , 1990, Movement disorders : official journal of the Movement Disorder Society.

[33]  D. Godin,et al.  Parkinson's disease: A disorder due to nigral glutathione deficiency? , 1982, Neuroscience Letters.

[34]  A. H. V. Schapira,et al.  MITOCHONDRIAL COMPLEX I DEFICIENCY IN PARKINSON'S DISEASE , 1989, The Lancet.

[35]  K. Jellinger,et al.  Brain iron and ferritin in Parkinson's and Alzheimer's diseases , 1990, Journal of neural transmission. Parkinson's disease and dementia section.

[36]  A. Torroni,et al.  Mitochondrial oxidative phosphorylation defects in parkinson's disease , 1991, Annals of neurology.

[37]  B. Drayer,et al.  Imaging of the aging brain. Part II. Pathologic conditions. , 1988, Radiology.

[38]  T. Sarna,et al.  Modulation by neuromelanin of the availability and reactivity of metal ions , 1992, Annals of neurology.

[39]  T. Sarna,et al.  The effect of melanin on iron associated decomposition of hydrogen peroxide. , 1988, Free radical biology & medicine.

[40]  C. Marsden,et al.  Increased Nigral Iron Content and Alterations in Other Metal Ions Occurring in Brain in Parkinson's Disease , 1989, Journal of neurochemistry.

[41]  S. Kish,et al.  Glutathione peroxidase activity in Parkinson's disease brain , 1985, Neuroscience Letters.

[42]  C. Olanow,et al.  Iron induces degeneration of nigrostriatal neurons , 1992, Brain Research Bulletin.

[43]  N. Quinn,et al.  Preservation of the substanitia nigra and locus coeruleus in a patient receiving levodopa (2 kg) plus decarboxylase inhibitor over a four‐year period , 1986, Movement disorders : official journal of the Movement Disorder Society.

[44]  F. Hefti,et al.  Toxicity of 6‐hydroxydopamine and dopamine for dopaminergic neurons in culture , 1990, Journal of neuroscience research.

[45]  C. Markham,et al.  Effect of age at onset on progression and mortality in Parkinson's disease , 1989, Neurology.

[46]  R. Dean,et al.  Free radicals, lipids and protein degradation , 1986 .

[47]  C. Olanow,et al.  Does selegiline monotherapy in Parkinson's disease act by symptomatic or protective mechanisms? , 1992, Neurology.

[48]  J. Clemens,et al.  Dopamine depletion protects striatal neurons from ischemia-induced cell death. , 1988, Life sciences.

[49]  C D Marsden,et al.  Alterations in the levels of iron, ferritin and other trace metals in Parkinson's disease and other neurodegenerative diseases affecting the basal ganglia. , 1991, Brain : a journal of neurology.

[50]  M. V. Van Woert,et al.  Brain peroxidase and catalase in Parkinson disease. , 1975, Archives of neurology.

[51]  B. Ames,et al.  Oxygen radicals and human disease. , 1987, Annals of internal medicine.

[52]  T. Dormandy.  IN PRAISE OF PEROXIDATION , 1988, The Lancet.

[53]  T. Chase,et al.  Central mechanisms and levodopa response fluctuations in Parkinson's disease. , 1988, Clinical neuropharmacology.

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

[55]  U. Rinne.  Combined bromocriptine‐levodopa therapy early in Parkinson's disease , 1985, Neurology.

[56]  P. Harrison,et al.  Effect of ferritin-containing fractions with different iron loading on lipid peroxidation. , 1983, The Biochemical journal.

[57]  R. Wurtman,et al.  Long‐term administration of L‐DOPA does not damage dopaminergic neurons in the mouse , 1981, Neurology.

[58]  Anthony E. Lang,et al.  Effect of deprenyl on the progression of disability in early Parkinson's disease. , 1989, The New England journal of medicine.

[59]  J. Parks,et al.  Abnormalities of the electron transport chain in idiopathic parkinson's disease , 1989, Annals of neurology.

[60]  B. Halliwell,et al.  Oxygen toxicity, oxygen radicals, transition metals and disease. , 1984, The Biochemical journal.

[61]  S. Aust,et al.  The role of iron in the initiation of lipid peroxidation. , 1987, Chemistry and physics of lipids.

[62]  B. Halliwell,et al.  Oxygen free radicals and iron in relation to biology and medicine: some problems and concepts. , 1986, Archives of biochemistry and biophysics.

[63]  G. Cohen,et al.  Exposure of striatal [corrected] synaptosomes to L-dopa increases levels of oxidized glutathione. , 1988, The Journal of pharmacology and experimental therapeutics.