Parkinson’s Disease—Apoptosis and Dopamine Oxidation
James David Adams Jr.*
University of Southern California.
DOI: 10.4236/ojapo.2012.11001   PDF    HTML   XML   8,107 Downloads   21,559 Views   Citations


Tyrosine hydroxylase, monoamine oxidase and aldehyde dehydrogenase all form oxygen radicals as part of their mechanisms of action. These oxygen radicals damage dopaminergic neurons in the substantianigra of the midbrain and cause them to die by a process of necrosis or apoptosis. Oxygen radicals quickly abstract hydrogen from DNA forming DNA radicals and causing DNA fragmentation, activation of DNA protective mechanisms, NAD depletion and cell death. Tyrosine hydroxylase is present in all dopaminergic neurons, is involved in the synthesis of dopamine and forms oxygen radicals in a redox mechanism involving its cofactor, tetrahydrobiopterin. Levodopa is used therapeutically in Parkinson’s disease patients since it is a precursor for dopamine, an inhibitor of tyrosine hydroxylase, and prolongs pa-tient’s lives. Monoamine oxidase converts dopamine into 3,4-dihydroxyphenylacetaldehyde and forms oxygen radi-cals.Aldehyde dehydrogenase oxidizes the aldehyde and forms oxygen radicals and 3,4-dihydroxyphenylacetic acid. The treatment of Parkinson’s disease should involveinhibitors of oxygen radical formation in dopaminergic neurons and neuroprotective agents that stimulate DNA repair and prevent cell death.

Share and Cite:

Adams Jr., J. (2012) Parkinson’s Disease—Apoptosis and Dopamine Oxidation. Open Journal of Apoptosis, 1, 1-8. doi: 10.4236/ojapo.2012.11001.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] J. D. Adams, “Agents Used in Neurodegenerative Disor- ders,” In: M. E. Wolff, Ed., Burger’s Medicinal Chemis- try and Drug Discovery, John Wiley and Sons, New York, 1996, pp. 261-319.
[2] J. D. Adams, “Antiparkinsonian Drug Therapy,” Ameri- can Journal of Pharmacy Education, Vol. 55, 1991, pp. 173-176.
[3] J. D. Adams, L. K. Klaidman, I. N. Odunze, H. C. Shen and C. A. Miller, “Alzheimer’s and Parkinson’s Disease: Brain Levels of Glutathione, Glutathione Disulfide and Vitamin E,” Molecular and Chemical Neuropathology, Vol. 14, No. 3, 1991, pp. 213-226. doi:10.1007/BF03159937
[4] R. Heikkila and G. Cohen, “Inhibition of Biogenic Amine Uptake by Hydrogen Peroxide: A Mechanism for Toxic Effects of 6-Hydroxydopamine,” Science, Vol. 172, No. 3989, 1971, pp. 1257-1258. doi:10.1126/science.172.3989.1257
[5] R. Heikkila and G. Cohen, “In Vivo Generation of Hy- drogen Peroxide from 6-Hydroxyl-dopamine,” Experien- tia, Vol. 28, No. 10, 1972, pp. 1197-1198. doi:10.1007/BF01946168
[6] R. Heikkila and G. Cohen, “6-Hydroxydopamine: Evidence for Superoxide Radical as an Oxidative Intermediate,” Science, Vol. 81, No. 4098, 1973, pp. 456-457. doi:10.1126/science.181.4098.456
[7] A. Slivka and G. Cohen, “Hydroxyl Radical Attack on Dopamine,” Journal of Biological Chemistry, Vol. 260, No. 29, 1985, pp. 15466-15472.
[8] M. Elstner S. Muller, L. Leidolt, C. Laub, L. Krieg, F. Schlaudraff, B. Liss, C. Morris, D. Turnbull, E. Masliah, H. Prokisch, T. Klopstock and A. Bender, “Neuromelanin, Neurotransmitter Status and Brainstem Location Deter- mine the Differential Vulnerability of Catecholaminergic Neurons to Mitochondrial DNA Deletions,” Molecular Brain, Vol. 4, No. 1, 2011, p. 43. doi:10.1186/1756-6606-4-43
[9] J. D. Adams, S. K. Mukherjee, L. K. Klaidman, M. L. Chang and R. Yasharel, “Apoptosis and Oxidative Stress in the Aging Brain,” Annals of the New York Academy of Sci- ence, Vol. 786, 1996, pp. 135-151. doi:10.1111/j.1749-6632.1996.tb39058.x
[10] D. G. Graham, “On the Origin and Significance of Neuro- melanin,” Archives of Pathology and Laboratory Medi- cine, Vol. 103, No. 7, 1979, pp. 359-362.
[11] D. G. Anderson, S. V. Santhana Mariappan, G. R. Buettner and J. A. Doorn, “Oxidation of 3,4-Dihydroxyphenylace- taldehyde, a Toxic Dopaminergic Metabolite, to a Semi- quinone Radical and an Ortho-Quinone,” Journal of Bio- logical Chemistry, Vol. 286, No. 30, 2011, pp. 26978-26986. doi:10.1074/jbc.M111.249532
[12] D. G. Graham, S. M. Tiffany, W. R. Bell and W. F. Gut- knecht, “Autoxidation versus Covalent Binding of Qui- nones as the Mechanism of Toxicity of Dopamine, 6-Hy- droxydopamine, and Related Compounds toward C1300 Neuroblastoma Cells in Vitro,” Molecular Pharmacology, Vol. 14, No. 4, 1978, pp. 644-653.
[13] D. M. A. Mann and P. O. Yates, “Pathogenesis of Park- inson’s Disease,” Archives of Neurology, Vol. 39, No. 9, 1982, pp. 545-549. doi:10.1001/archneur.1982.00510210015004
[14] M. M. Hoehn and M. D. Yahr, “Parkinsonism: Onset, Pro- gression and Mortality,” Neurology, Vol. 17, No. 5, 1967, pp. 427-442.
[15] H. Zumstein and J. Siegfried, “Mortality among Parkin- son Patients Treated with L-Dopa Combined with a De- carboxylase Inhibitor,” European Neurology, Vol. 14, No. 5, 1976, pp. 321-328. doi:10.1159/000114756
[16] R. J. Uitti, J. E. Ahlskog, D. M.Maraganore, M. D. Muen- ter, E. J. Atkinson, R. H. Cha and P. C. O’Brien, “Levo- dopa Therapy and Survival in Idiopathic Parkinson’s Dis- ease: Olmstead County Project,” Neurology, Vol. 43, No. 10, 1993, pp. 1918-1926.
[17] Parkinson Study Group, “Safety and Efficacy of Prami- pexole in Early Parkinson’s Disease. A Randomized Dose Ranging Study,” Journal of the American Medical Asso- ciation, Vol. 278, No. 2, 1997, pp. 125-130. doi:10.1001/jama.1997.03550020057038
[18] C. E. Clarke and M. Guttman, “Dopamine agonist mono-therapy in Parkinson’s Disease,” Lancet, Vol. 360, No. 9347, 2002, pp. 1767-1769. doi:10.1016/S0140-6736(02)11668-0
[19] M. Gerlach, K. Double, H. Reichmann and P. Riederer, “Arguments for the Use of Dopamine Receptor Agonists in Clinical and Preclinical Parkinson’s Disease,” Journal of Neural Transmission, Vol. 65, 2003, pp. 167-183.
[20] Parkinson Study Group, (2002) “Dopamine Transporter Brain Imaging to Assess the Effects of Pramipexolevs Le- vodopa on Parkinson Disease Progression,” Journal of the American Medical Association, Vol. 287, No. 13, 1999, pp. 1653-1661. doi:10.1001/jama.287.13.1653
[21] J. S. Rakshi, N. Pavese, T. Uema, K. Ito, P. K. Morrish, D. L. Bailey and D. J. Brooks, “A Comparison of the Pro- gression Of Early Parkinson’s Disease in Patients Started on Ropinirole or L-Dopa: An 18F-Dopa PET Study,” Jour- nal of Neural Transmission, Vol. 109, No. 12, 2002, pp. 1433-1443. doi:10.1007/s00702-002-0753-0
[22] A. L. Whone, R. L. Watts, A. J. Stoessl, M. Davis, S. Re- ske, C. Nahmias, A. E. Lang, O. Rascol, M. J. Ribeiro, P. Remy, W. H. Poewe, R. A. Hauser and D. J. Brooks, “Slower Progression of Parkinson’s Disease with Ropini- role versus Levodopa: The REAL-PET Study,” Annals of Neurology, Vol. 54, No. 1, 2003, pp. 93-101. doi:10.1002/ana.10609
[23] J. E. Ahlskog, “Slowing Parkinson’s Disease Progression,” Neurology, Vol. 60, No. 3, 2003, pp. 381-389.
[24] Drug Facts and Comparisons, “Facts and Comparisons,” Drug Facts and Comparisons, St. Louis, 2012.
[25] J. E. Ahlskog, “Parkinson’s Disease: Is the Initial Treat- ment Established?” Current Neurology and Neuroscience Report, Vol. 3, No. 4, 2003, pp. 289-295.
[26] K. W. Lange, “Clinical Pharmacology of Dopamine Ago- nists in Parkinson’s Disease,” Drugs of Aging, Vol. 13, No. 5, 1998, pp. 381-389. doi:10.2165/00002512-199813050-00004
[27] S. Perez-Lloret and O. Rascol, “Dopamine Receptor Ago- nists for the Treatment of Early or Advanced Parkinson’s Disease,” CNS Drugs, Vol. 24, No. 11, 2010, pp. 941-968. doi:10.2165/11537810-000000000-00000
[28] A. Antonini and W. Poewe, “Fibrotic Heart Valve Reac- tions to Dopamine Agonist Treatment in Parkinson’s Dis- ease,” Lancet Neurology, Vol. 6, No. 9, 2007, pp. 826-829. doi:10.1016/S1474-4422(07)70218-1
[29] J. D. Adams P. Kalivas and C. Miller, “The Acute Histo- pathology of MPTP in the Mouse CNS,” Brain Research Bulletin, Vol. 23, No. 1-2, 1989, pp. 1-17. doi:10.1016/0361-9230(89)90157-3
[30] S. K. Mukherjee, L. K. Klaidman, R. Yasharel and J. D. Adams, “Increased Brain NAD Prevents Apoptosis in Vivo,” European Journal of Pharmacology, Vol. 330, No. 1, 1997, pp. 27-34. doi:10.1016/S0014-2999(97)00171-4
[31] J. D. Adams, L. K. Klaidman, M. Morales, K. Moran, B. Schiavoni, J. R. Hsu and S. K. Mukherjee, “Nicotinamide and Neuroprotection,” In: S. Bondy, Ed., Chemicals and Neurodegenerative Diseases, Prominent Press, Scottsdale, 1999, pp. 231-262.
[32] L. K. Klaidman, S. K. Mukherjee and J. D. Adams, “Oxi- dative Changes in Brain Pyridine Nucleotides and Neuro- protection Using Nicotinamide,” Biochimica et Biophy- sica Acta, Vol. 1525, No. 1-2, 2001, pp. 136-148. doi:10.1016/S0304-4165(00)00181-1
[33] J. D. Adams, B. Wang, L. K. Klaidman, C. P. LeBel, I. N. Odunze and D. Shah, “New Aspects of Brain Oxidative Stress Induced by Tert-Butylhydroperoxide,” Free Radi- cals in Biology and Medicine, Vol. 15, No. 2, 1993, pp. 195-202. doi:10.1016/0891-5849(93)90059-4
[34] M. L. Chang, L. Klaidman and J. D. Adams Jr., “Age Dependent Effects of t-BuOOH on Glutathione Disulfide Reductase Glutathione Peroxidase and Malondialdehyde in the Brain,” Molecular and Chemical Neuropathology, Vol. 26, No. 2, 1995, pp. 95-106. doi:10.1007/BF02815008
[35] M. L. Chang and J. D. Adams, “The Effects of Oxidative Stress on in Vivo Brain GSH Turnover in Young and Mature Mice,” Molecular and Chemical Neuropathology, Vol. 30, No. 3, 1997, pp. 187-198. doi:10.1007/BF02815097
[36] M. Sanchez and F. Cardozo-Pelaez, “Intracellular Signal- ing Pathways in Parkinson’s Disease,” In: J. D. Adams and K. Parker, Eds., Extracellular and Intracellular Sig- naling, Royal Society of Chemistry, Cambridge, 2011.
[37] J. D. Adams, L. K. Klaidman and A. C. Leung, “MPP+ and MPDP+ Induced Oxygen Radical Formation with Mitochondrial Enzymes,” Free Radicals in Biology and Medicine, Vol. 15, No. 2, 1993, pp. 181-186. doi:10.1016/0891-5849(93)90057-2
[38] G. Cohen, R. Farooqui and N. Kesler, “Parkinson’s Dis- ease: A New Link between Monoamine Oxidase and Mi- tochondrial Electron Flow,” Proceedings of the National Academy of Science of USA, Vol. 94, No. 10, 1997, pp. 4890-4894. doi:10.1073/pnas.94.10.4890
[39] C. Kay, H. El Mkami, G.Molla, L. Pollegioni and R. Ram- say, “Characterization of the Covalently Bound Anionic Flavin Radical in Monoamine Oxidase A by Electron Paramagnetic Resonance,” Journal of the American Chemi- cal Society, Vol. 129, No. 51, 2007, pp. 16091-16097. doi:10.1021/ja076090q
[40] J. D. Adams, “Parkinson’s Disease and Oxygen Free Radi- cals,” Neurology Forum, Vol. 4, 1993, pp. 2-14.
[41] J. P. Larsen, J. Boas and J. E. Erdal, “Doesselegiline Mod- ify the Progression of Early Parkinson’s Disease? Results from a Five Year Study,” European Journal of Neurology, Vol. 6, No. 5, 1999, pp. 539-547. doi:10.1046/j.1468-1331.1999.650539.x
[42] Parkinson Study Group, “Effects of Tocopherol and De- prenyl on the Progression of Disability in Early Parkin- son’s Disease,” New England Journal of Medicine, Vol. 328, 1993, pp. 176-183. doi:10.1056/NEJM199301213280305
[43] S. Palhagen, E. H. Heinonen, J. Hagglund, T. Kaugesaar, H. Kontants, O. Maki-Ikola, R. Palm and J. Turunen, “Se- legiline Delays the Onset of Disability in De Novo Park- insonian Patients,” Neurology, Vol. 51, No. 2, 1998, pp. 520-525.
[44] Anonymous, “Selegiline: A Second Look. Six Years Later: Too Risky in Parkinson’s Disease,” Prescrire Interna-tional, Vol. 11, No. 60, 2002, pp. 108-111.
[45] J. S. Fowler, N. D.Volkow, J. Logan, G. J.Wang, R. R. Mac- Gregor, D. Schyler, A. P. Wolf, N. Pappas, D. Alexoff and C. Shea, “Slow Recovery of Human Brain MAO B after L-Deprenyl (Selegiline) Withdrawal,” Synapse, Vol. 28, No. 2, 1994, pp. 86-93. doi:10.1002/syn.890180203
[46] J. D. Adams, J. Yang and L. Klaidman, “Parkinson’s Dis- ease, Using Drug Therapy to Slow Down Disease Pro- gression,” In: M. J. Willow, Ed., Focus on Parkinson’s Disease Research, Nova Science Publishers Inc., New York, 2006, pp. 79-96.
[47] J. D. Adams and L. K. Klaidman, “Acrolein Induced Ox- ygen Radical Formation,” Free Radicals in Biology and Medicine, Vol. 15, No. 2, 1993, pp. 187-193. doi:10.1016/0891-5849(93)90058-3
[48] C. J. Mann and H. Weiner, “Differences in the Roles of Conserved Glutamic Acid Residues in the Active Site of Human Class 3 and Class 2 Aldehyde Dehydrogenase,” Protein Science, Vol. 8, No. 10, 1999, pp. 1922-1929. doi:10.1110/ps.8.10.1922
[49] J. D. Adams, L. K. Klaidman and P. Ribeiro, “Tyrosine Hydroxylase: Mechanisms of Oxygen Radical Formation,” Redox Report, Vol. 3, No. 5-6, 1997, pp. 273-279.
[50] C. P. De La Cruz, E. Revilla, J. L. Venero, A. Ayala, J. Cano and A. Machado, “Oxidative Inactivation of Tyro- sine Hydroxylase in Substantianigra of Aged Rat,” Free Radicals in Biology and Medicine, Vol. 20, No. 1, 1996, pp. 53-61. doi:10.1016/0891-5849(95)02025-X
[51] T. Nagatsu, “Genes for Human Catecholamine Synthesiz- ing Enzymes,” Neuroscience Research, Vol. 12, No. 2, 1991, pp. 315-345. doi:10.1016/0168-0102(91)90001-F
[52] A. Nakashima, K. Mori, T. Suzuki, H. Kurita, M. Otani, T. Nagatsu and A. Ota, “Dopamine Inhibition of Human Tyrosine Hydroxylase Type 1 Is Controlled by the Spe- cific Portion in the N-Terminus of the Enzyme,” Journal of Neurochemistry, Vol. 72, No. 5, 1999, pp. 2145-2153. doi:10.1046/j.1471-4159.1999.0722145.x
[53] G. Eberlein, T. C. Bruice, R. A. Lazarus, R. Henrie and S. J. Benkovic, “The interconversion of the 5,6,7,8-Tetrahy- dro, 7,8-Dihydro and Radical Forms of 6,6,7,7-Tetrame- thyldihydropterin. A Model for the Biopterin Center of Aromatic Amino Acid Mixed Function Oxidases,” Jour- nal of the American Chemical Society, Vol. 106, No. 25, 1984, pp. 7916-7924. doi:10.1021/ja00337a047
[54] J. Haavik, B. Almas and T. Flatmark, “Generation of Re- active Oxygen Species by Tyrosine Hydroxylase: Possi- ble Contribution to the Degeneration of Dopaminergic Neurons,” Journal of Neurochemistry, Vol. 68, No. 1, 1997, pp. 328-332. doi:10.1046/j.1471-4159.1997.68010328.x
[55] D. M. Kuhn, R. E. Arthur, D. M. Thomas and L. A. Elfer- ink, “Tyrosine Hydroxylase Is Inactivated by Catechol- Quinones and Converted to a Redox-Cycling Quinopro- tein: Possible Relevance to Parkinson’s Disease,” Journal of Neurochemistry, Vol. 73, No. 3, 1999, pp. 1309-1317. doi:10.1046/j.1471-4159.1999.0731309.x
[56] P. F. VonVoigtlander, G. J. Fici and J. S. Althaus, “Phar- macological Approaches to Counter the Toxicity of Dopa,” Amino Acids, Vol. 14, No. 1-3, 1998, pp. 189-196. doi:10.1007/BF01345261
[57] J. Yang, L. K. Klaidman, A. Nalbandian, J. Oliver, M. L. Chang, P. H. Chan and J. D. Adams, “The Effects of Nico- tinamide on Energy Metabolism Following Transient Fo- cal Cerebral Ischemia in Wistar Rats,” Neuroscience Let- ters, Vol. 333, No. 2, 2002, pp. 91-94. doi:10.1016/S0304-3940(02)01005-4
[58] L. K. Klaidman, S. Mukherjee, T. Hutchin and J. D. Adams, “Nicotinamide as a Precursor for NAD prevents Apop- tosis in the Mouse Brain Induced by t-Butylhydropero- xide,” Neuroscience Letters, Vol. 206, No. 1, 1996, pp. 5-8. doi:10.1016/0304-3940(96)12446-0
[59] J. Yang, L. K. Klaidman, M. L. Chang, S. Kem, T. Suga- wara, P. Chan and J. D. Adams, “Nicotinamide Therapy Protects against Both Necrosis and Apoptosis in a Stroke Model,” Pharmacology Biochemistry and Behavior, Vol. 73, No. 4, 2002, pp. 901-910. doi:10.1016/S0091-3057(02)00939-5
[60] M. L. Chang, J. Yang, S. Kem, L. Klaidman, T. Sugawara, P. Chan and J. D. Adams, “Nicotinamide and Ketamine Reduce Infarct Volume and DNA Fragmentation in Rats after Brain Ischemia and Reperfusion,” Neuroscience Let- ters, Vol. 322, No. 3, 2002, pp. 137-140. doi:10.1016/S0304-3940(01)02520-4
[61] A. Bianchetti, R. Rozzini, C. Carabellese, O. Zanetti and M. Trabucchi, “Nutritional Intake, Socioeconomic Condi- tions, and Health Status in a Large Elderly Population,” Journal of the American Geriatric Society, Vol. 38, No. 5, 1990, pp. 521-526.
[62] J. G. D. Birkmayer, “Coenzyme Nicotinamide Adenine Dinucleotide New Therapeutic Approach for Improving Dementia of the Alzheimer Type,” Annals of Clinical and Laboratory Science, Vol. 26, No. 1, 1996, pp. 1-9.
[63] J. G. D. Birkmayer, C. Vrecko, D. Volc and W. Birkmayer, “Nicotinamide Adenine Dinucleotide: A New Therapeu- tic Approach to Parkinson’s Disease,” Acta Neurologica Scandinavica, Vol. 87, No. 146, 1993, pp. 32-35.
[64] T. Fukushima, A. Kaetsu, H. Lim and M. Moriyama, “Pos- sible Role of 1-Methylnicotinamide in the Pathogenesis of Parkinson’s Disease,” Experimental Toxicology and Pathology, Vol. 53, No. 6, 2002, pp. 469-473. doi:10.1078/0940-2993-00214
[65] J. Yang, L. K. Klaidman and J. D. Adams, “Update to Medicinal Chemistry of Nicotinamide in the Treatment of Ischemia and Reperfusion,” Medical and Chemical Re- views Online, Vol. 1, No. 1, 2004, pp. 1-5. doi:10.2174/1567203043480403

Copyright © 2024 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.