Depletion of dopamine in Parkinson's disease and relevant therapeutic options: A review of the literature

Sairam Ramesh; Arosh S. Perera Molligoda Arachchige; Sairam Ramesh; Arosh S. Perera Molligoda Arachchige

doi:10.3934/Neuroscience.2023017

AIMS Neuroscience

2023, Volume 10, Issue 3: 200-231. doi: 10.3934/Neuroscience.2023017

Previous Article Next Article

Review

Depletion of dopamine in Parkinson's disease and relevant therapeutic options: A review of the literature

Department of Biomedical Sciences, Humanitas University, Milan, Italy

Received: 27 April 2023 Revised: 27 July 2023 Accepted: 02 August 2023 Published: 14 August 2023

Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects motor and cognition functions. The etiology of Parkinson's disease remains largely unknown, but genetic and environmental factors are believed to play a role. The neurotransmitter dopamine is implicated in regulating movement, motivation, memory, and other physiological processes. In individuals with Parkinson's disease, the loss of dopaminergic neurons leads to a reduction in dopamine levels, which causes motor impairment and may also contribute to the cognitive deficits observed in some patients. Therefore, it is important to understand the pathophysiology that leads to the loss of dopaminergic neurons, along with reliable biomarkers that may help distinguish PD from other conditions, monitor its progression, or indicate a positive response to a therapeutic intervention. Important advances in the treatment, etiology, and pathogenesis of Parkinson's disease have been made in the past 50 years. Therefore, this review tries to explain the different possible mechanisms behind the depletion of dopamine in PD patients such as alpha-synuclein abnormalities, mitochondrial dysfunction, and 3,4-dihydroxyphenylacetaldehyde (DOPAL) toxicity, along with the current therapies we have and the ones that are in development. The clinical aspect of Parkinson's disease such as the manifestation of both motor and non-motor symptoms, and the differential diagnosis with similar neurodegenerative disease are also discussed.
- Parkinson's disease,
- alpha-synuclein,
- dopamine,
- therapies,
- DOPAL neurotoxicity,
- Braak,
- deep brain stimulation,
- MAO inhibitors,
- COMT inhibitors,
- L-DOPA
Citation: Sairam Ramesh, Arosh S. Perera Molligoda Arachchige. Depletion of dopamine in Parkinson's disease and relevant therapeutic options: A review of the literature[J]. AIMS Neuroscience, 2023, 10(3): 200-231. doi: 10.3934/Neuroscience.2023017

Related Papers:

Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects motor and cognition functions. The etiology of Parkinson's disease remains largely unknown, but genetic and environmental factors are believed to play a role. The neurotransmitter dopamine is implicated in regulating movement, motivation, memory, and other physiological processes. In individuals with Parkinson's disease, the loss of dopaminergic neurons leads to a reduction in dopamine levels, which causes motor impairment and may also contribute to the cognitive deficits observed in some patients. Therefore, it is important to understand the pathophysiology that leads to the loss of dopaminergic neurons, along with reliable biomarkers that may help distinguish PD from other conditions, monitor its progression, or indicate a positive response to a therapeutic intervention. Important advances in the treatment, etiology, and pathogenesis of Parkinson's disease have been made in the past 50 years. Therefore, this review tries to explain the different possible mechanisms behind the depletion of dopamine in PD patients such as alpha-synuclein abnormalities, mitochondrial dysfunction, and 3,4-dihydroxyphenylacetaldehyde (DOPAL) toxicity, along with the current therapies we have and the ones that are in development. The clinical aspect of Parkinson's disease such as the manifestation of both motor and non-motor symptoms, and the differential diagnosis with similar neurodegenerative disease are also discussed.

Conflicts of interest

The authors have no conflicts of interest to declare.

References

[1]	Parkinson J (2002) An Essay on the Shaking Palsy. J Neuropsych Clin N 14: 223-236. https://neuro.psychiatryonline.org/doi/full/10.1176/jnp.14.2.223
[2]	de Lau LML, Breteler MMB (2006) Epidemiology of Parkinson's disease. Lancet Neurol 5: 525-535. https://doi.org/10.1016/S1474-4422(06)70471-9
[3]	Poewe W, Seppi K, Tanner CM, et al. (2017) Parkinson disease. Nat Rev Dis Primers 3: 17013. https://doi.org/10.1038/nrdp.2017.13
[4]	Kalia LV, Lang AE (2015) Parkinson's disease. Lancet 386: 896-912. https://doi.org/10.1016/S0140-6736(14)61393-3
[5]	Hernandez DG, Reed X, Singleton AB (2016) Genetics in Parkinson disease: Mendelian versus non-Mendelian inheritance. J Neurochem 139: 59-74. https://doi.org/10.1111/jnc.13593
[6]	Jankovic J (2008) Parkinson's disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry 79: 368-76. https://doi.org/10.1136/jnnp.2007.131045
[7]	Jankovic J, McDermott M, Carter J, et al. (1990) Variable expression of Parkinson's disease: a base-line analysis of the DATATOP cohort. The Parkinson Study Group. Neurology 40: 1529-34. https://doi.org/10.1212/WNL.40.10.1529
[8]	Aarsland D, Zaccai J, Brayne C (2005) A systematic review of prevalence studies of dementia in Parkinson's disease. Movement Disord 20: 1255-1263. https://doi.org/10.1002/mds.20527
[9]	Chaudhuri K R, Odin P, Antonini A, et al. (2011) Parkinson's disease: the non-motor issues. Parkinsonism Relat Disord 17: 717-723. https://doi.org/10.1016/j.parkreldis.2011.02.018
[10]	Postuma RB, Aarsland D, Barone P, et al. (2012) Identifying prodromal Parkinson's disease: pre-motor disorders in Parkinson's disease. Mov Disord 27: 617-626. https://doi.org/10.1002/mds.24996
[11]	Siderowf A, Lang AE (2012) Premotor Parkinson's disease: concepts and definitions. Mov Disord 27: 608-16. https://doi.org/10.1002/mds.24954
[12]	Hornykiewicz O (1966) Dopamine (3-hydroxytyramine) and brain function. Pharmacol Rev 18: 925-964.
[13]	Albin RL, Young AB, Penney JB (1989) The functional anatomy of basal ganglia disorders. Trends Neurosci 12: 366-375. https://doi.org/10.1016/0166-2236(89)90074-X
[14]	Kouli A, Torsney KM, Kuan WL (2018) Parkinson's Disease: Etiology, Neuropathology, and Pathogenesis. Parkinson's Disease: Pathogenesis and Clinical Aspects [Internet]. Brisbane (AU): Codon Publications. https://www.ncbi.nlm.nih.gov/books/NBK536722/
[15]	Goedert M (2001) Alpha-synuclein and neurodegenerative diseases. Nat Rev Neurosci 2: 492-501. https://doi.org/10.1038/35081564
[16]	Xilouri M, Vogiatzi T, Vekrellis K, et al. (2009) Abberant alpha-synuclein confers toxicity to neurons in part through inhibition of chaperone-mediated autophagy. PLoS One 4: e5515. https://doi.org/10.1371/journal.pone.0005515
[17]	Dickson DW, Braak H, Duda JE, et al. (2009) Neuropathological assessment of Parkinson's disease: refining the diagnostic criteria. Lancet Neurol 8: 1150-1157. https://doi.org/10.1016/S1474-4422(09)70238-8
[18]	Petersen MV (2017) Tractography and Neurosurgical Targeting in Deep Brain Stimulation for Parkinson's Disease. Researchgate . http://dx.doi.org/10.13140/RG.2.2.16230.93769
[19]	Braak H, del Tredici K, Rüb U, et al. (2003) Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging 24: 197-211. https://doi.org/10.1016/S0197-4580(02)00065-9
[20]	Brundin P, Melki R, Kopito R (2010) Prion-like transmission of protein aggregates in neurodegenerative diseases. Nat Rev Mol Cell Biol 11: 301-307. https://doi.org/10.1038/nrm2873
[21]	Farrer MJ (2006) Genetics of Parkinson disease: paradigm shifts and future prospects. Nat Rev Genet 7: 306-318. https://doi.org/10.1038/nrg1831
[22]	Sidhu A, Wersinger C, C. Moussa E-H, et al. (2004) The role of alpha-synuclein in both neuroprotection and neurodegeneration. Ann N Y Acad Sci 1035: 250-70. https://doi.org/10.1196/annals.1332.016
[23]	Noyce AJ, Bestwick JP, Silveira-Moriyama L, et al. (2012) Meta-analysis of early nonmotor features and risk factors for Parkinson disease. Ann Neurol 72: 893-901. https://doi.org/10.1002/ana.23687
[24]	Michel PP, Hirsch EC, Hunot S (2016) Understanding Dopaminergic Cell Death Pathways in Parkinson Disease. Neuron 90: 675-691. https://doi.org/10.1016/j.neuron.2016.03.038
[25]	Surmeier DJ (2018) Determinants of dopaminergic neuron loss in Parkinson's disease. FEBS J 285: 3657-3668. https://doi.org/10.1111/febs.14607
[26]	Sulzer D, Surmeier DJ (2013) Neuronal Vulnerability, Pathogenesis, and Parkinson's Disease. Movement Disord 28: 715-724. https://doi.org/10.1002/mds.25187
[27]	Li JY, Englund E, Holton JL, et al. (2008) Lewy bodies in grafted neurons in subjects with Parkinson's disease suggest host-to-graft disease propagation. Nat Med 14: 501-503. https://doi.org/10.1038/nm1746
[28]	Mao X, Ou MT, Karuppagounder SS, et al. (2016) Pathological alpha-synuclein transmission initiated by binding lymphocyte-activation gene 3. Science 353: aah3374.
[29]	Cabin DE, Shimazu K, Murphy D, et al. (2002) Synaptic vesicle depletion correlates with attenuated synaptic responses to prolonged repetitive stimulation in mice lacking alpha-synuclein. J Neurosci 22: 8797-807. https://doi.org/10.1523/JNEUROSCI.22-20-08797.2002
[30]	Yavich L, Tanila H, Vepsäläinen S, et al. (2004) Role of alpha-synuclein in presynaptic dopamine recruitment. J Neurosci 24: 11165-70. https://doi.org/10.1523/JNEUROSCI.2559-04.2004
[31]	Nemani VM, Lu W, Berge V, et al. (2010) Increased expression of alpha-synuclein reduces neurotransmitter release by inhibiting synaptic vesicle reclustering after endocytosis. Neuron 65: 66-79. https://doi.org/10.1016/j.neuron.2009.12.023
[32]	Venda LL, Cragg SJ, Buchman VL, et al. (2010) α-Synuclein and dopamine at the crossroads of Parkinson's disease. Trends Neurosci 33: 559-568. https://doi.org/10.1016/j.tins.2010.09.004
[33]	Heo JY, Park JH, Kim SJ, et al. (2012) DJ-1 null dopaminergic neuronal cells exhibit defects in mitochondrial function and structure: involvement of mitochondrial complex I assembly. PLoS One 7: e32629. https://doi.org/10.1371/journal.pone.0032629
[34]	Schapira AHV, Cooper JM, Dexter D, et al. (1990) Mitochondrial complex I deficiency in Parkinson's disease. Lancet 54: 823-827. https://doi.org/10.1111/j.1471-4159.1990.tb02325.x
[35]	Liang CL, Wang TT, Luby-Phelps K, et al. (2007) Mitochondria mass is low in mouse substantia nigra dopamine neurons. Exp Neurol 203: 370-380. https://doi.org/10.1016/j.expneurol.2006.08.015
[36]	Khaliq ZM, Bean BP (2010) Pacemaking in dopaminergic ventral tegmental area neurons: depolarizing drive from background and voltage-dependent sodium conductances. J Neurosci 30: 7401-7413. https://doi.org/10.1523/JNEUROSCI.0143-10.2010
[37]	Votyakova TV, Reynolds I (2001) DeltaPsi(m)-Dependent and -independent production of reactive oxygen species by rat brain mitochondria. J Neurochem 79: 266-277. https://doi.org/10.1046/j.1471-4159.2001.00548.x
[38]	Mattammal MB, Haring JH, Chung HD, et al. (1995) An endogenous dopaminergic neurotoxin: implication for Parkinson's disease. Neurodegeneration 4: 271-281. https://doi.org/10.1016/1055-8330(95)90016-0
[39]	Masato A, Plotegher N, Boassa D, et al. (2019) Impaired dopamine metabolism in Parkinson's disease pathogenesis. Mol Neurodegener 14: 35. https://doi.org/10.1186/s13024-019-0332-6
[40]	Goldstein DS, Jinsmaa Y, Sullivan P, et al. (2016) Comparison of Monoamine Oxidase Inhibitors in Decreasing Production of the Autotoxic Dopamine Metabolite 3,4-Dihydroxyphenylacetaldehyde in PC12 Cells. J Pharmacol Exp Ther 356: 483-92. https://doi.org/10.1124/jpet.115.230201
[41]	Fearnley JM, Lees AJ (1991) Ageing and Parkinson's disease: substantia nigra regional selectivity. Brain 114: 2283-301. https://doi.org/10.1093/brain/114.5.2283
[42]	Monje MHG, Sánchez-Ferro Á, Pineda-Pardo JA, et al. (2021) Motor Onset Topography and Progression in Parkinson's Disease: the Upper Limb Is First. Mov Disord 36: 905-915. https://doi.org/10.1002/mds.28462
[43]	Alcalay RN, Caccappolo E, Mejia-Santana H, et al. (2010) Frequency of known mutations in early-onset Parkinson disease: implication for genetic counseling: the consortium on risk for early onset Parkinson disease study. Arch Neurol 67: 1116-1122. https://doi.org/10.1001/archneurol.2010.194
[44]	Rizzo G, Copetti M, Arcuti S, et al. (2016) Accuracy of clinical diagnosis of Parkinson disease: a systematic review and meta-analysis. Neurology 86. https://doi.org/10.1212/WNL.0000000000002350
[45]	Postuma RB, Aarsland D, Barone P, et al. (2012) Identifying prodromal Parkinson's disease: pre-motor disorders in Parkinson's disease. Mov Disord 27: 617-26. https://doi.org/10.1002/mds.24996
[46]	Garnett ES, Firnau G, Nahmias C (1983) Dopamine visualized in the basal ganglia of living man. Nature 305: 137-138. https://doi.org/10.1038/305137a0
[47]	Brooks DJ (2010) Imaging approaches to Parkinson disease. J Nucl Med 51: 596-609. https://doi.org/10.2967/jnumed.108.059998
[48]	Pagano G, Niccolini F, Politis M (2016) Imaging in Parkinson's disease. Clin Med 16: 371-375. https://doi.org/10.7861/clinmedicine.16-4-371
[49]	McKeith IG, Boeve BF, Dickson DW, et al. (2017) Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB Consortium. Neurology 89: 88-100. https://doi.org/10.1212/WNL.0000000000004058
[50]	Höglinger GU, Respondek G, Stamelou M, et al. (2017) Clinical diagnosis of progressive supranuclear palsy: The movement disorder society criteria. Mov Disord 32: 853-864. https://doi.org/10.1002/mds.26987
[51]	Rehman HU (2001) Multiple system atrophy. Postgrad Med J 77: 379-82. https://doi.org/10.1136/pmj.77.908.379
[52]	Armstrong MJ, Litvan I, Lang AE, et al. (2013) Criteria for the diagnosis of corticobasal degeneration. Neurology 80: 496-503. https://doi.org/10.1212/WNL.0b013e31827f0fd1
[53]	Olanow CW, Obeso JA, Stocchi F (2006) Continuous dopamine-receptor treatment of Parkinson's disease: scientific rationale and clinical implications. Lancet Neurol 5: 677-687. https://doi.org/10.1016/S1474-4422(06)70521-X
[54]	Poewe W, Antonini A (2015) Novel formulations and modes of delivery of levodopa. Mov Disord 30: 114-120. https://doi.org/10.1002/mds.26078
[55]	Stocchi F, Olanow CW (2016) Obstacles to the development of a neuroprotective therapy for Parkinson's disease. Parkinsonism Relat Disord 28: 3-7. https://doi.org/10.1002/mds.25337
[56]	Schapira AH (2011) Monoamine oxidase B inhibitors for the treatment of Parkinson's disease: a review of symptomatic and potential disease-modifying effects. CNS Drugs 25: 1061-1071. https://doi.org/10.2165/11596310-000000000-00000
[57]	Connolly BS, Lang AE (2014) Pharmacological treatment of Parkinson disease: a review. JAMA 311: 1670-1683. https://doi.org/10.1001/jama.2014.3654
[58]	GlaxoSmithKlineClinical Evaluation of Ropinirole Prolonged Release/Extended Release (PR/XR) Tablet for Adjunctive Therapy to L-dopa in Subjects With Advanced Parkinson's Disease (2009). https://classic.clinicaltrials.gov/ct2/show/results/NCT00823836
[59]	Bronstein JM, Tagliati M, Alterman RL, et al. (2011) Deep brain stimulation for Parkinson disease: an expert consensus and review of key issues. Arch Neurol 68: 165. https://doi.org/10.1001/archneurol.2010.260
[60]	Barker RA, Drouin-Ouellet J, Parmar M (2015) Cell-based therapies for Parkinson disease-past insights and future potential. Nat Rev Neurosci 11: 492-503. https://doi.org/10.1038/nrneurol.2015.123
[61]	Barker RA, Barrett J, Mason SL, et al. (2013) Fetal dopaminergic transplantation trials and the future of neural grafting in Parkinson's disease. Lancet Neurol 12: 84-91. https://doi.org/10.1016/S1474-4422(12)70295-8
[62]	Barker RA, Studer L, Cattaneo E, et al. (2015) G-Force PD: a global initiative in coordinating stem cell-based dopamine treatments for Parkinson's disease. NPJ Parkinsons Dis 1: 1-5. https://doi.org/10.1038/npjparkd.2015.17
[63]	Mandler M, Valera E, Rockenstein E, et al. (2014) Next-generation active immunization approach for synucleinopathies: implications for Parkinson's disease clinical trials. Acta Neuropathol 127: 861-879. https://doi.org/10.1007/s00401-014-1256-4
[64]	Barker RA, Björklund A, Gash DM, et al. (2020) GDNF and Parkinson's Disease: Where Next? A Summary from a Recent Workshop. J Parkinsons Dis 10: 875-891. https://doi.org/10.3233/JPD-202004
[65]	Balash Y, Bar-Lev Schleider L, Korczyn A, et al. (2017) Medical Cannabis in Parkinson Disease: Real-Life Patients' Experience. Clin Neuropharmacol 40: 268-272. https://doi.org/10.1097/WNF.0000000000000246
[66]	Chagas MHN, Zuardi AW, Tumas V, et al. (2014) Effects of cannabidiol in the treatment of patients with Parkinson's disease: an exploratory double-blind trial. J Psychopharmacol 28: 1088-98. https://doi.org/10.1177/0269881114550355
[67]	Seppi K, Peball M (2021) Nabilone for non-motor symptoms in Parkinson's disease: An openlabel study to evaluate long-term safety and efficacy. Clinicaltrials.gov . https://www.clinicaltrialsregister.eu/ctr-search/rest/download/result/attachment/2017-004253-16/1/35293
[68]	Freed CR, Greene PE, Breeze RE, et al. (2001) Transplantation of embryonic dopamine neurons for severe Parkinson's disease. N Engl J Med 344: 710-9. https://doi.org/10.1056/NEJM200103083441002
[69]	Olanow CW, Goetz CG, Kordower JH, et al. (2003) A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson's disease. Ann Neurol 54: 403-14. https://doi.org/10.1002/ana.10720
[70]	Stover NP, Bakay RAE, Subramanian T, et al. (2005) Intrastriatal implantation of human retinal pigment epithelial cells attached to microcarriers in advanced Parkinson disease. Arch Neurol 62: 1833-7. https://doi.org/10.1001/archneur.62.12.1833
[71]	Concha-Marambio L, Pritzkow S, Shahnawaz M, et al. (2023) Seed amplification assay for the detection of pathologic alpha-synuclein aggregates in cerebrospinal fluid. Nat Protoc 18: 1179-1196. https://doi.org/10.1038/s41596-022-00787-3
[72]	Stefanis L (2012) α-Synuclein in Parkinson's disease. CSH Perspect Med 2: a009399. https://doi.org/10.1101/cshperspect.a009399
[73]	Arachchige ASPM (2023) Marijuana's potential in neurodegenerative diseases: an editorial. AIMS Neurosci 10: 175-177. https://doi.org/10.3934/Neuroscience.2023014
[74]	Scorza FA, Guimarães-Marques M, Nejm M, et al. (2022) Sudden unexpected death in Parkinson's disease: Insights from clinical practice. Clinics (Sao Paulo, Brazil) 77: 100001. https://doi.org/10.1016/j.clinsp.2021.100001

Reader Comments

Your name:*

Email:*
© 2023 the Author(s), licensee AIMS Press. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0)