Four main therapeutic keys for Parkinson’s disease: A mini review

Document Type: Mini Review


1 CONACYT-Instituto de Neuroetologia, Universidad Veracruzana, Xalapa, Veracruz, Mexico

2 IIIT Srikakulam, Rajiv Gandhi University of Knowledge Technologies (RGUKT); International collaboration ID:1840; India

3 Centro de Investigacion Biomedica del Noreste. IMSS. Monterrey, Nuevo Leon. Mexico

4 Instituto de Neuroetologia, Universidad Veracruzana. Xalapa, Veracruz, Mexico

5 Facultad de Medicina. Universidad Autonoma de Nuevo Leon. Monterrey, Nuevo Leon, Mexico


Objective(s): Parkinson’s disease (PD) is characterized by motor and cognitive dysfunctions. The progressive degeneration of dopamine-producing neurons that are present in the substantia nigra pars compacta (SNpc) has been the main focus of study and PD therapies since ages.
Materials and Methods: In this manuscript, a systematic revision of experimental and clinical evidence of PD-associated cell process was conducted.
Results: Classically, the damage in the dopaminergic neuronal circuits of SNpc is favored by reactive oxidative/nitrosative stress, leading to cell death. Interestingly, the therapy for PD has only focused on avoiding the symptom progression but not in finding a complete reversion of the disease. Recent evidence suggests that the renin-angiotensin system imbalance and neuroinflammation are the main keys in the progression of experimental PD.
Conclusion: The progression of neurodegeneration in SNpc is due to the complex interaction of multiple processes. In this review, we analyzed the main contribution of four cellular processes and discussed in the perspective of novel experimental approaches. 


Main Subjects

1. Ascherio A, Schwarzschild MA. The epidemiology of Parkinson’s disease: risk factors and prevention. Lancet Neurol 2016; 15:1257-1272.
2. Moustafa AA, Chakravarthy S, Phillips JR, Gupta A, Keri S, Polner B, et al. Motor symptoms in Parkinson’s disease: A unified framework. Neurosci Biobehav Rev 2016; 68:727-740.
3. DeMaagd G, Philip A. Parkinson’s Disease and Its Management: Part 5: Treatment of Nonmotor Complications. P T 2015; 40:838-846.
4. Sulzer D, Surmeier DJ. Neuronal vulnerability, pathogenesis, and Parkinson’s disease. Mov Disord 2013; 28:715-724.
5. Hernandez-Baltazar D, Zavala-Flores LM, Villanueva-Olivo A. The 6-hydroxydopamine model and parkinsonian pathophysiology: Novel findings in an older model. Neurologia 2017; 32:533-539.
6. Villar-Cheda B, Valenzuela R, Rodriguez-Perez AI, Guerra MJ, Labandeira-Garcia JL. Aging-related changes in the nigral angiotensin system enhances proinflammatory and pro-oxidative markers and 6-OHDA-induced dopaminergic degeneration. Neurobiol Aging 2012; 33:204 e201-211.
7. Vogt Weisenhorn DM, Giesert F, Wurst W. Diversity matters - heterogeneity of dopaminergic neurons in the ventral mesencephalon and its relation to Parkinson’s Disease. J Neurochem 2016; 139 Suppl 1:8-26.
8. Mazzone P, Lozano A, Stanzione P, Galati S, Scarnati E, Peppe A, et al. Implantation of human pedunculopontine nucleus: a safe and clinically relevant target in Parkinson’s disease. Neuroreport 2005; 16:1877-1881.
9. Okun MS. Deep-brain stimulation for Parkinson’s disease. N Engl J Med 2012; 367:1529-1538.
10. Okun MS, Gallo BV, Mandybur G, Jagid J, Foote KD, Revilla FJ, et al. Subthalamic deep brain stimulation with a constant-current device in Parkinson’s disease: an open-label randomised controlled trial. Lancet Neurol 2012; 11:140-149.
11. Aquilonius SM, Nyholm D. Development of new levodopa treatment strategies in Parkinson’s disease-from bedside to bench to bedside. Ups J Med Sci 2017; 122:71-77.
12. Devos D, French DSG. Patient profile, indications, efficacy and safety of duodenal levodopa infusion in advanced Parkinson’s disease. Mov Disord 2009; 24:993-1000.
13. Hauser RA, Shulman LM, Trugman JM, Roberts JW, Mori A, Ballerini R, et al. Study of istradefylline in patients with Parkinson’s disease on levodopa with motor fluctuations. Mov Disord 2008; 23:2177-2185.
14. Hickey P, Stacy M. Adenosine A2A antagonists in Parkinson’s disease: what’s next? Curr Neurol Neurosci Rep 2012; 12:376-385.
15. Cruz MP. Xadago (Safinamide): A Monoamine oxidase B inhibitor for the adjunct treatment of motor symptoms in Parkinson’s disease. P T 2017; 42:622-637.
16. deSouza RM, Schapira A. Safinamide for the treatment of Parkinson’s disease. Expert Opin Pharmacother 2017; 18:937-943.
17. Teo KC, Ho SL. Monoamine oxidase-B (MAO-B) inhibitors: implications for disease-modification in Parkinson’s disease. Transl Neurodegener 2013; 2:19.
18. Borovac JA. Side effects of a dopamine agonist therapy for Parkinson’s disease: a mini-review of clinical pharmacology. Yale J Biol Med 2016; 89:37-47.
19. Stacy M, Galbreath A. Optimizing long-term therapy for Parkinson disease: levodopa, dopamine agonists, and treatment-associated dyskinesia. Clin Neuropharmacol 2008; 31:51-56.
20. Blesa J, Trigo-Damas I, Quiroga-Varela A, Jackson-Lewis VR. Oxidative stress and Parkinson’s disease. Front Neuroanat 2015; 9:91.
21. Dias V, Junn E, Mouradian MM. The role of oxidative stress in Parkinson’s disease. J Parkinsons Dis 2013; 3:461-491.
22. Di Meo S, Reed TT, Venditti P, Victor VM. Role of ROS and RNS sources in physiological and pathological conditions. Oxid Med Cell Longev 2016; 2016:1245049.
23. Sovolyova N, Healy S, Samali A, Logue SE. Stressed to death - mechanisms of ER stress-induced cell death. Biol Chem 2014; 395:1-13.
24. Gonzalez-Hernandez T, Cruz-Muros I, Afonso-Oramas D, Salas-Hernandez J, Castro-Hernandez J. Vulnerability of mesostriatal dopaminergic neurons in Parkinson’s disease. Front Neuroanat 2010; 4:140-153.
25. Haddad D, Nakamura K. Understanding the susceptibility of dopamine neurons to mitochondrial stressors in Parkinson’s disease. FEBS Lett 2015; 589:3702-3713.
26. Labandeira-Garcia JL, Rodriguez-Pallares J, Dominguez-Meijide A, Valenzuela R, Villar-Cheda B, Rodriguez-Perez AI. Dopamine-angiotensin interactions in the basal ganglia and their relevance for Parkinson’s disease. Mov Disord 2013; 28:1337-1342.
27. Ghavami S, Shojaei S, Yeganeh B, Ande SR, Jangamreddy JR, Mehrpour M, et al. Autophagy and apoptosis dysfunction in neurodegenerative disorders. Prog Neurobiol 2014; 112:24-49.
28. Franco-Iborra S, Perier C. Neurodegeneration: The Size Takes It All. Curr Biol 2015; 25:R797-800.
29. Giguere N, Trudeau LE. [Axon arborization size is a key factor influencing cellular bioenergetics and vulnerability of dopamine neurons in Parkinson’s disease]. Med Sci (Paris) 2016; 32:342-344.
30. Pacelli C, Giguere N, Bourque MJ, Levesque M, Slack RS, Trudeau LE. Elevated mitochondrial bioenergetics and axonal arborization size are key contributors to the vulnerability of dopamine neurons. Curr Biol 2015; 25:2349-2360.
31. Giguere N, Burke Nanni S, Trudeau LE. On cell loss and selective vulnerability of neuronal populations in Parkinson’s disease. Front Neurol 2018; 9:455.
32. Venderova K, Park DS. Programmed cell death in Parkinson’s disease. Cold Spring Harb Perspect Med 2012; 2.
33. Van Laar VS, Berman SB. The interplay of neuronal mitochondrial dynamics and bioenergetics: implications for Parkinson’s disease. Neurobiol Dis 2013; 51:43-55.
34. Hernandez DG, Reed X, Singleton AB. Genetics in Parkinson disease: Mendelian versus non-Mendelian inheritance. J Neurochem 2016; 139 Suppl 1:59-74.
35. Kalinderi K, Bostantjopoulou S, Fidani L. The genetic background of Parkinson’s disease: current progress and future prospects. Acta Neurol Scand 2016; 134:314-326.
36. Klein C, Westenberger A. Genetics of Parkinson’s disease. Cold Spring Harb Perspect Med 2012; 2:a008888.
37. Grunewald A, Kumar KR, Sue CM. New insights into the complex role of mitochondria in Parkinson’s disease. Prog Neurobiol 2018.
38. Yakhine-Diop SMS, Niso-Santano M, Rodriguez-Arribas M, Gomez-Sanchez R, Martinez-Chacon G, Uribe-Carretero E, et al. Impaired mitophagy and protein acetylation levels in fibroblasts from Parkinson’s disease patients. Mol Neurobiol 2018.
39. Campbell P, Morris H, Schapira A. Chaperone-mediated autophagy as a therapeutic target for Parkinson disease. Expert Opin Ther Targets 2018:1-10.
40. Zhang J, Cao R, Cai T, Aschner M, Zhao F, Yao T, et al. The role of autophagy dysregulation in manganese-induced dopaminergic neurodegeneration. Neurotox Res 2013; 24:478-490.
41. Hughes AJ, Daniel SE, Lees AJ. The clinical features of Parkinson’s disease in 100 histologically proven cases. Adv Neurol 1993; 60:595-599.
42. Hernandez-Baltazar D, Mendoza-Garrido ME, Martinez-Fong D. Activation of GSK-3beta and caspase-3 occurs in Nigral dopamine neurons during the development of apoptosis activated by a striatal injection of 6-hydroxydopamine. PLoS One 2013; 8:e70951.
43. Blanco-Alvarez VM, Lopez-Moreno P, Soto-Rodriguez G, Martinez-Fong D, Rubio H, Gonzalez-Barrios JA, et al. Subacute zinc administration and L-NAME caused an increase of NO, zinc, lipoperoxidation, and caspase-3 during a cerebral hypoxia-ischemia process in the rat. Oxid Med Cell Longev 2013; 2013:240560.
44. Duda P, Wisniewski J, Wojtowicz T, Wojcicka O, Jaskiewicz M, Drulis-Fajdasz D, et al. Targeting GSK3 signaling as a potential therapy of neurodegenerative diseases and aging. Expert Opin Ther Targets 2018:1-16.
45. Shin EJ, Hwang YG, Sharma N, Tran HQ, Dang DK, Jang CG, et al. Role of protein kinase Cdelta in dopaminergic neurotoxic events. Food Chem Toxicol 2018; 121:254-261.
46. Kettenmann H, Kirchhoff F, Verkhratsky A. Microglia: new roles for the synaptic stripper. Neuron 2013; 77:10-18.
47. Mittal M, Siddiqui MR, Tran K, Reddy SP, Malik AB. Reactive oxygen species in inflammation and tissue injury. Antioxid Redox Signal 2014; 20:1126-1167.
48. Tang Y, Le W. Differential Roles of M1 and M2 Microglia in neurodegenerative diseases. Mol Neurobiol 2016; 53:1181-1194.
49. Stefanis L. alpha-Synuclein in Parkinson’s disease. Cold Spring Harb Perspect Med 2012; 2:a009399.
50. Altenhofer S, Kleikers PW, Radermacher KA, Scheurer P, Rob Hermans JJ, Schiffers P, et al. The NOX toolbox: validating the role of NADPH oxidases in physiology and disease. Cell Mol Life Sci 2012; 69:2327-2343.
51. Ma MW, Wang J, Dhandapani KM, Brann DW. NADPH Oxidase 2 Regulates NLRP3 Inflammasome Activation in the Brain after Traumatic Brain Injury. Oxid Med Cell Longev 2017; 2017:6057609.
52. Flores-Martinez YM, Fernandez-Parrilla MA, Ayala-Davila J, Reyes-Corona D, Blanco-Alvarez VM, Soto-Rojas LO, et al. Acute neuroinflammatory response in the Substantia Nigra pars compacta of rats after a local injection of lipopolysaccharide. J Immunol Res 2018; 2018:1838921.
53. Buffo A, Rite I, Tripathi P, Lepier A, Colak D, Horn AP, et al. Origin and progeny of reactive gliosis: A source of multipotent cells in the injured brain. Proc Natl Acad Sci U S A 2008; 105:3581-3586.
54. Doetsch F, Caille I, Lim DA, Garcia-Verdugo JM, Alvarez-Buylla A. Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 1999; 97:703-716.
55. Seri B, Garcia-Verdugo JM, Collado-Morente L, McEwen BS, Alvarez-Buylla A. Cell types, lineage, and architecture of the germinal zone in the adult dentate gyrus. J Comp Neurol 2004; 478:359-378.
56. Kitamura Y, Inden M, Minamino H, Abe M, Takata K, Taniguchi T. The 6-hydroxydopamine-induced nigrostriatal neurodegeneration produces microglia-like NG2 glial cells in the rat substantia nigra. Glia 2010; 58:1686-1700.
57. Nadella R, Voutilainen MH, Saarma M, Gonzalez-Barrios JA, Leon-Chavez BA, Jimenez JM, et al. Transient transfection of human CDNF gene reduces the 6-hydroxydopamine-induced neuroinflammation in the rat substantia nigra. J Neuroinflammation 2014; 11:209.
58. Wright JW, Harding JW. Importance of the brain Angiotensin system in Parkinson’s disease. Parkinsons Dis 2012; 2012:860923.
59. Labandeira-Garcia JL, Garrido-Gil P, Rodriguez-Pallares J, Valenzuela R, Borrajo A, Rodriguez-Perez AI. Brain renin-angiotensin system and dopaminergic cell vulnerability. Front Neuroanat 2014; 8:67.
60. Dominguez-Meijide A, Rodriguez-Perez AI, Diaz-Ruiz C, Guerra MJ, Labandeira-Garcia JL. Dopamine modulates astroglial and microglial activity via glial renin-angiotensin system in cultures. Brain Behav Immun 2017; 62:277-290.
61. Rodriguez-Pallares J, Quiroz CR, Parga JA, Guerra MJ, Labandeira-Garcia JL. Angiotensin II increases differentiation of dopaminergic neurons from mesencephalic precursors via angiotensin type 2 receptors. Eur J Neurosci 2004; 20:1489-1498.
62. Rodriguez-Pallares J, Rey P, Parga JA, Munoz A, Guerra MJ, Labandeira-Garcia JL. Brain angiotensin enhances dopaminergic cell death via microglial activation and NADPH-derived ROS. Neurobiol Dis 2008; 31:58-73.
63. Chao J, Yang L, Buch S, Gao L. Angiotensin II increased neuronal stem cell proliferation: role of AT2R. PLoS One 2013; 8:e63488.
64. Li J, Culman J, Hortnagl H, Zhao Y, Gerova N, Timm M, et al. Angiotensin AT2 receptor protects against cerebral ischemia-induced neuronal injury. FASEB J 2005; 19:617-619.
65. Garrido-Gil P, Rodriguez-Pallares J, Dominguez-Meijide A, Guerra MJ, Labandeira-Garcia JL. Brain angiotensin regulates iron homeostasis in dopaminergic neurons and microglial cells. Exp Neurol 2013; 250:384-396.
66. Labandeira-Garcia JL, Rodriguez-Pallares J, Rodriguez-Perez AI, Garrido-Gil P, Villar-Cheda B, Valenzuela R, et al. Brain angiotensin and dopaminergic degeneration: relevance to Parkinson’s disease. Am J Neurodegener Dis 2012; 1:226-244.
67. Munoz A, Garrido-Gil P, Dominguez-Meijide A, Labandeira-Garcia JL. Angiotensin type 1 receptor blockage reduces l-dopa-induced dyskinesia in the 6-OHDA model of Parkinson’s disease. Involvement of vascular endothelial growth factor and interleukin-1beta. Exp Neurol 2014; 261:720-732.
68. Rocha NP, Scalzo PL, Barbosa IG, de Campos-Carli SM, Tavares LD, de Souza MS, et al. Peripheral levels of angiotensins are associated with depressive symptoms in Parkinson’s disease. J Neurol Sci 2016; 368:235-239.
69. Villar-Cheda B, Costa-Besada MA, Valenzuela R, Perez-Costas E, Melendez-Ferro M, Labandeira-Garcia JL. The intracellular angiotensin system buffers deleterious effects of the extracellular paracrine system. Cell Death Dis 2017; 8:e3044.
70. Jones LL, Yamaguchi Y, Stallcup WB, Tuszynski MH. NG2 is a major chondroitin sulfate proteoglycan produced after spinal cord injury and is expressed by macrophages and oligodendrocyte progenitors. J Neurosci 2002; 22:2792-2803.
71. Stallcup WB. The NG2 proteoglycan: past insights and future prospects. J Neurocytol 2002; 31:423-435.
72. Belachew S, Chittajallu R, Aguirre AA, Yuan X, Kirby M, Anderson S, et al. Postnatal NG2 proteoglycan-expressing progenitor cells are intrinsically multipotent and generate functional neurons. J Cell Biol 2003; 161:169-186.
73. Chung SH, Guo F, Jiang P, Pleasure DE, Deng W. Olig2/Plp-positive progenitor cells give rise to Bergmann glia in the cerebellum. Cell Death Dis 2013; 4:e546.
74. Tripathi RB, Rivers LE, Young KM, Jamen F, Richardson WD. NG2 glia generate new oligodendrocytes but few astrocytes in a murine experimental autoimmune encephalomyelitis model of demyelinating disease. J Neurosci 2010; 30:16383-16390.
75. Chari DM, Blakemore WF. Efficient recolonisation of progenitor-depleted areas of the CNS by adult oligodendrocyte progenitor cells. Glia 2002; 37:307-313.
76. Magnus T, Carmen J, Deleon J, Xue H, Pardo AC, Lepore AC, et al. Adult glial precursor proliferation in mutant SOD1G93A mice. Glia 2008; 56:200-208.
77. Nait-Oumesmar B, Decker L, Lachapelle F, Avellana-Adalid V, Bachelin C, Baron-Van Evercooren A. Progenitor cells of the adult mouse subventricular zone proliferate, migrate and differentiate into oligodendrocytes after demyelination. Eur J Neurosci 1999; 11:4357-4366.
78. Tamura Y, Kataoka Y, Cui Y, Takamori Y, Watanabe Y, Yamada H. Multi-directional differentiation of doublecortin- and NG2-immunopositive progenitor cells in the adult rat neocortex in vivo. Eur J Neurosci 2007; 25:3489-3498.
79. Charvin D, Medori R, Hauser RA, Rascol O. Therapeutic strategies for Parkinson disease: beyond dopaminergic drugs. Nat Rev Drug Discov 2018; 17:804-822
80. Carrascal L, Nunez-Abades P, Ayala A, Cano M. Role of melatonin in the inflammatory process and its therapeutic potential. Curr Pharm Des 2018; 24:1563-1588.
81. Sanchez-Barcelo EJ, Rueda N, Mediavilla MD, Martinez-Cue C, Reiter RJ. Clinical Uses of Melatonin in Neurological Diseases and Mental and Behavioural Disorders. Curr Med Chem 2017; 24:3851-3878.
82. Martinez B, Peplow PV. Neuroprotection by immunomodulatory agents in animal models of Parkinson’s disease. Neural Regen Res 2018; 13:1493-1506.
83. Wang YL, Ju B, Zhang YZ, Yin HL, Liu YJ, Wang SS, et al. Protective effect of curcumin against oxidative stress-induced injury in rats with Parkinson’s disease through the Wnt/ beta-catenin signaling pathway. Cell Physiol Biochem 2017; 43:2226-2241.
84. Ullah H, Khan H. Anti-Parkinson potential of silymarin: mechanistic insight and therapeutic standing. Front Pharmacol 2018; 9:422.
85. Zanforlin E, Zagotto G, Ribaudo G. The medicinal chemistry of natural and semisynthetic compounds against Parkinson’s and Huntington’s diseases. ACS Chem Neurosci 2017; 8:2356-2368.
86. Kirik D, Cederfjall E, Halliday G, Petersen A. Gene therapy for Parkinson’s disease: Disease modification by GDNF family of ligands. Neurobiol Dis 2017; 97:179-188.
87. Pignataro D, Sucunza D, Rico AJ, Dopeso-Reyes IG, Roda E, Rodriguez-Perez AI, et al. Gene therapy approaches in the non-human primate model of Parkinson’s disease. J Neural Transm (Vienna) 2018; 125:575-589.