Neuroprotective effects of Wharton’s jelly-derived mesenchymal stem cells on motor deficits due to Parkinson’s disease

Document Type : Original Article


1 Persian Gulf Physiology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

2 Department of Physiology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

3 Department of Anatomical Sciences, Cellular and Molecular Research Center, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

4 Department of Immunology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran


Objective(s): Human Wharton’s jelly-derived mesenchymal stem cells (hWJ-MSCs) have been recognized as a potential tool to replace damaged cells by improving the survival of the dopaminergic cells in Parkinson’s disease (PD). In this study, we examined the effects of hWJ-MSCs and associated with L-dopa/carbidopa on motor disturbances in the PD model.
Materials and Methods: PD was induced by injection of 6-hydroxydopamine (6-OHDA) (16 μg/2 μl into medial forebrain bundle (MFB)). Sham group received a vehicle instead of 6-OHDA. PD+C group received hWJ-MSCs twice on the 14th and 28th days post PD induction. PD+C+D group received hWJ-MSCs and also L-dopa/carbidopa (10/30 mg/kg). PD+D group received L-dopa/carbidopa alone. Four months later, motor activities (the parameters of  locomotor and muscle stiffness) were evaluated, dopaminergic neurons were counted in substantia nigra pars compacta (SNc), the level of dopamine (DA), and tyrosine hydroxylase (TH) were measured in the striatum.  
Results: Data indicated that motor activities, the number of dopaminergic neurons, and levels of DA and TH activities were significantly reduced in PD rats as compared to the sham group (p <0.001). However, the same parameters were improved in the treated groups when compared with the PD group (p Conclusion: The chronic treatment of PD rats with hWJ-MSCs and L-dopa/carbidopa, improved motor activity, which may be the result of increased TH activity and due to released DA from dopaminergic neurons.


1. Af Bjerkén S, Boger HA, Nelson M, Hoffer BJ, Granholm A-C, Strömberg I. Effects of glial cell line-derived neurotrophic factor deletion on ventral mesencephalic organotypic tissue cultures. Brain Res 2007;1133:10-19.
2.    Akerud P, Canals JM, Snyder EY, Arenas E. Neuroprotection through delivery of glial cell line-derived neurotrophic factor by neural stem cells in a mouse model of Parkinson’s disease. J Neurosci 2001;21: 8108-8118.
3.    Björklund A, Dunnett SB. Dopamine neuron systems in the brain: an update. Trends Neurosci 2007; 30: 194-202.
4.    Blanchard-Fillion B, Souza JM, Friel T, Jiang GC, Vrana K, Sharov V, et al. Nitration and inactivation of tyrosine hydroxylase by peroxynitrite. JBC 2001;276:46017-46023.
5.    Blandini F, Cova L, Armentero M-T, Zennaro E, Levandis G, Bossolasco P, et al. Transplantation of undifferentiated human mesenchymal stem cells protects against 6-hydroxydopamine neurotoxicity in the rat. Cell Transplant 2010;19:203-217.
6.    Borgal L, Hong M, Sadi D, Mendez I. Differential effects of glial cell line-derived neurotrophic factor on A9 and A10 dopamine neuron survival in vitro. Neuroscience 2007;147:712-719.
7.    Brederlau A, Correia AS, Anisimov SV, Elmi M, Paul G, Roybon L, et al. Transplantation of human embryonic stem cell‐derived cells to a rat model of Parkinson’s disease: Effect of in vitro differentiation on graft survival and teratoma formation. Stem Cells 2006;24:1433-1440.
8.    Chang K-A, Kim HJ, Joo Y, Ha S, Suh Y-H. The therapeutic effects of human adipose-derived stem cells in Alzheimer’s disease mouse models. Neurodegener Dis 2014;13:99-102.
9.    Choi HS, Kim HJ, Oh J-H, Park H-G, Ra JC, Chang K-A, et al. Therapeutic potentials of human adipose-derived stem cells on the mouse model of Parkinson’s disease. Neurobiol Aging 2015;36:2885-2892
10.    Costall B, Domeney A, Gerrard P, Kelly M, Naylor R. Zacopride: anxiolytic profile in rodent and primate models of anxiety. J Pharm Pharmacol 1988;40:302-305.
11.    Cunha JM, Masur J. Evaluation of psychotropic drugs with a modified open field test. Pharmacology 1978;16:259-267.
12.    Dai W, Hale SL, Martin BJ, Kuang J-Q, Dow JS, Wold LE, et al. Allogeneic mesenchymal stem cell transplantation in postinfarcted rat myocardium. Circulation 2005;112:214-223.
13.    Dexter D, Wells F, Lee A, Agid F, Agid Y, Jenner P, et al. Increased nigral iron content and alterations in other metal ions occurring in brain in Parkinson’s disease. J Neurochem 1989;52:1830-1836.
14.    Farbood Y, Sarkaki A, Dolatshahi M, Mansouri SMT, Khodadadi A. Ellagic acid protects the brain against 6-hydroxydopamine induced neuroinflammation in a rat model of Parkinson’s disease. Basic Clin Neurosci 2015;6:83-89.
15.    Fink JS, Smith GP. Mesolimbicocortical dopamine terminal fields are necessary for normal locomotor and investigatory exploration in rats. Brain Res 1980;199:359-384.
16.    Fu YS, Cheng YC, Lin MYA, Cheng H, Chu PM, Chou SC, et al. Conversion of human umbilical cord mesenchymal stem cells in Wharton’s jelly to dopaminergic neurons in vitro: potential therapeutic application for Parkinsonism. Stem Cells 2006;24:115-124.
17.    Gutiérrez-Fernández M, Rodríguez-Frutos B, Ramos-Cejudo J, Vallejo-Cremades MT, Fuentes B, Cerdán S, et al. Effects of intravenous administration of allogenic bone marrow-and adipose tissue-derived mesenchymal stem cells on functional recovery and brain repair markers in experimental ischemic stroke. Stem Cell Res Ther 2013;4:1-12.
18.    Huang Y, Chang C, Zhang J, Gao X. Bone marrow-derived mesenchymal stem cells increase dopamine synthesis in the injured striatum. Neural Regen Res 2012;7:2653-2662
19.    Jalali MS, Sarkaki A, Farbood Y, saeed Azandeh S, Mansouri E, Dehcheshmeh MG, et al. Transplanted Wharton’s jelly mesenchymal stem cells improve memory and brain hippocampal electrophysiology in rat model of Parkinson’s disease. J Chem Neuroanat 2020;110:101865.(in press)
20.    Jones G, Robbins T. Differential effects of mesocortical, mesolimbic, and mesostriatal dopamine depletion on spontaneous, conditioned, and drug-induced locomotor activity. Pharmacol Biochem Behav 1992;43:887-895.
21.    Joyce N, Annett G, Wirthlin L, Olson S, Bauer G, Nolta JA. Mesenchymal stem cells for the treatment of neurodegenerative disease. Regen Med 2010;5:933-946.
22.    Kääriäinen TM, Käenmäki M, Forsberg MM, Oinas N, Tammimäki A, Männistö PT. Unpredictable rotational responses to l‐dopa in the rat model of parkinson’s disease: the role of l‐dopa pharmacokinetics and striatal dopamine depletion. Basic Clin Pharmacol Toxicol 2012;110:162-170.
23.    Kim S, Chang K-A, Park H-G, Ra JC, Kim H-S, Suh Y-H. The preventive and therapeutic effects of intravenous human adipose-derived stem cells in Alzheimer’s disease mice. PloS one. 2012: e-45757.
24.    Lazarini C, Florio J, Lemonica I, Bernardi MM. Effects of prenatal exposure to deltamethrin on forced swimming behavior, motor activity, and striatal dopamine levels in male and female rats. Neurotoxicol Teratol 2001;23:665-673.
25.    Leow S, Luu CD, Nizam MH, Mok P, Ruhaslizan R, Wong H, et al. Safety and efficacy of human Wharton’s Jelly-derived mesenchymal stem cells therapy for retinal degeneration. PLoS One 2015;10:e-0128973.
26.    Levy R, Dubois B. Apathy and the functional anatomy of the prefrontal cortex–basal ganglia circuits. Cereb Cortex 2005;16:916-928.
27.    McLeod M, Hong M, Mukhida K, Sadi D, Ulalia R, Mendez I. Erythropoietin and GDNF enhance ventral mesencephalic fiber outgrowth and capillary proliferation following neural transplantation in a rodent model of Parkinson’s disease. Eur J Neurosci 2006;24:361-370.
28.    Metz GA, Tse A, Ballermann M, Smith LK, Fouad K. The unilateral 6‐OHDA rat model of Parkinson’s disease revisited: an electromyographic and behavioural analysis. Eur J Neurosci 2005;22:735-744.
29.    Moon HE, Yoon SH, Hur YS, Park HW, Ha JY, Kim K-H, et al. Mitochondrial dysfunction of immortalized human adipose tissue-derived mesenchymal stromal cells from patients with Parkinson’s disease. Exp Neurobiol 2013;22:283-300.
30.    Morpurgo C. Effects of antiparkinson drugs on a phenothiazine-induced catatonic reaction. Arch Ints Pharmacodyn Ther 1962;137:84-90.
31.    Muñoz-Manchado AB, Villadiego J, Suárez-Luna N, Bermejo-Navas A, Garrido-Gil P, Labandeira-García JL, et al. Neuroprotective and reparative effects of carotid body grafts in a chronic MPTP model of Parkinson’s disease. Neurobiol Aging 2013;34:902-915.
32.    Nagatsu T. Change of tyrosine hydroxylase in the parkinsonian brain and in the brain of MPTP-treated mice as revealed by homospecific activity. Neurochem Res1990; 15:425-429.
33.    Oiwa Y, Nakai K, Itakura T. Histological effects of intraputaminal infusion of glial cell line-derived neurotrophic factor in Parkinson disease model macaque monkeys. Neurol Med Chir 2006; 46:267-276.
34.    Park HJ, Shin JY, Kim HN, Oh SH, Lee PH. Neuroprotective effects of mesenchymal stem cells through autophagy modulation in a parkinsonian model. Neurobiol Aging 2014;35:1920-1928.
35.    Pawitan JA. Prospect of cell therapy for Parkinson’s disease. Anat Cell Biol 2011; 44:256-264.
36.    Poewe W, Antonini A, Zijlmans JC, Burkhard PR, Vingerhoets F. Levodopa in the treatment of Parkinson’s disease: an old drug still going strong. Clin Interv Aging 2010;5:229-238.
37.    Prinssen EP, Colpaert FC, Koek W. 5-HT1A receptor activation and anti-cataleptic effects: high-efficacy agonists maximally inhibit haloperidol-induced catalepsy. Eur J Pharmacol 2002;453:217-221.
38.    Roof RL, Schielke GP, Ren X, Hall ED. A comparison of long-term functional outcome after 2 middle cerebral artery occlusion models in rats. Stroke 2001;32:2648-2657.
39.    Sameri MJ, Sarkaki A, Farbood Y, Mansouri SMT. Motor disorders and impaired electrical power of pallidal EEG improved by gallic acid in animal model of Parkinsons disease. Pak J Biol Sci 2011;14:1109-1116.
40.    Sarkaki A, Farbood Y, Dolatshahi M, Mansouri SMT, Khodadadi A. Neuroprotective effects of ellagic acid in a rat model of Parkinson’s disease. Acta Med Iran 2016;54:494-502.
41.    Schwerk A, Altschüler J, Roch M, Gossen M, Winter C, Berg J, et al. Human adipose-derived mesenchymal stromal cells increase endogenous neurogenesis in the rat subventricular zone acutely after 6-hydroxydopamine lesioning. Cytotherapy 2015; 17:199-214.
42.    Shim JH, Yoon SH, Kim K-H, Han JY, Ha J-Y, Hyun DH, et al. The antioxidant Trolox helps recovery from the familial Parkinson’s disease-specific mitochondrial deficits caused by PINK1-and DJ-1-deficiency in dopaminergic neuronal cells. Mitochondrion 2011;11:707-715.
43.    Sriram K, Pai KS, Boyd MR, Ravindranath V. Evidence for generation of oxidative stress in brain by MPTP: in vitro and in vivo studies in mice. Brain Res 1997;749:44-52.
44.    Stoddard-Bennett T, Reijo Pera R. Treatment of Parkinson’s disease through personalized medicine and induced pluripotent stem cells. Cells 2019;8:26-41.
45.    Su P, Loane C, Politis M. The Use of Stem Cells in the Treatment of Parkinsons Disease. Insciences J 2011; 1:136-156.
46.    Tameh AA, Clarner T, Beyer C, Atlasi MA, Hassanzadeh G, Naderian H. Regional regulation of glutamate signaling during cuprizone-induced demyelination in the brain. Ann Anat 2013;195:415-423.
47.    Van den Buuse M, de Jong W. Differential effects of dopaminergic drugs on open-field behavior of spontaneously hypertensive rats and normotensive Wistar-Kyoto rats. J Pharmacol Exp Ther 1989;248:1189-1196.
48.    Vidal S, Villegas P, Bray G, Aguayo A. Persistent retrograde labeling of adult rat retinal ganglion cells with the carbocyanine dye dil. Exp Neurol 1988;102:92-101.
49.    Volosin M, Cancela L, Molina V. Influence of adrenocorticotrophic hormone on the behaviour in the swim test of rats treated chronically with desipramine. J Pharm Pharmacol. 1988;40:74-76.
50.    Vorhees CV. Some behavioral effects of maternal hypervitaminosis A in rats. Teratology 1974;10:269-273.
51.    Wang F, Yasuhara T, Shingo T, Kameda M, Tajiri N, Yuan WJ, et al. Intravenous administration of mesenchymal stem cells exerts therapeutic effects on parkinsonian model of rats: focusing on neuroprotective effects of stromal cell-derived factor-1α. BMC Neurosci 2010; 11:52-61.
52.    Wang Z, Ji Y, Shan W, Zeng B, Raksadawan N, Pastores G, et al. Therapeutic effects of astrocytes expressing both tyrosine hydroxylase and brain-derived neurotrophic factor on a rat model of Parkinson’s disease. Neuroscience 2002;113: 629-640.
53.    Wangde D, Sharon L, Kuang J, Dow J, Wold L. Allogeneic mesenchymal stem cell transplantation in postinfarcted rat myocardium: Shortand long-term effects. Circulation 2005; 112:214-223.
54.    Yamada K TM, Kamei H, Nagai T, Dohniwa M, Kobayashi K. Effects of memantine and donepezil on amyloid beta-induced memory impairment in a delayed-matching to position task in rats. Behav Brain Res 2005;162:191-199.
55.    Yun J-W, Ahn J-B, Kang B-C. Modeling Parkinson’s disease in the common marmoset (Callithrix jacchus): Overview of models, methods, and animal care. Lab Anim Res 2015; 31:155-165.
56.    Zhao Q, Ren H, Li X, Chen Z, Zhang X, Gong W, et al. Differentiation of human umbilical cord mesenchymal stromal cells into low immunogenic hepatocyte-like cells. Cytotherapy 2009; 11:414-426.