Intravenous Transplantation of Adipose-Derived Mesenchymal Stem Cells Promoted The Production of Dopaminergic Neurons and Improved Spatial Memory in A Rat Model of Parkinson’s Disease

Document Type : Original Article


1 Department of Cellular and Molecular Biology, School of Biology, Damghan University, Damghan, Iran

2 Dental School, Semnan University of Medical Science, Semnan, Iran

3 Department of Embryology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran


Objective: Parkinson’s disease (PD) is a neurodegenerative disorder described by the dynamic decline of dopaminergic
neurons in the substantia nigra pars compacta (SNpc). Stem cell transplantation is a new therapeutic strategy in the
treatment of PD. The objective of the study was to assess the impact of intravenous infusion of adipose-derived
mesenchymal stem cells (AD-MSCs) on memory disorder in Parkinsonian rats.
Materials and Methods: In this experimental study, male Wistar rats were randomly divided to four groups containing
sham, cell treatment, control, and lesion. The cell treatment group received intravenous injection of AD-MSCs 12 days
after PD induction by bilateral injection of 6-hydroxydopamine. Four weeks after lesion formation, spatial memory
was examined using the Morris water maze (MWM) assessment. The rats’ brains were removed and assessed by
bromodeoxyuridine (BrdU), tyrosine hydroxylase (TH), and glial fibrillary acidic protein (Gfap) immunostaining.
Results: Statistical analyses revealed a significant addition and reduction in time spent and escape latency in the target
quadrant, respectively, in the cell group as compared to the lesion group. Also, BrdU-labeled cells were present in the
substantia nigra (SN). The density of TH-positive cells was significantly increased in the AD-MSCs transplantation group
as compared to the lesion group, and the density of astrocytes significantly diminished in the AD-MSCs transplantation
group as compared to the lesion group.
Conclusion: It appears that AD-MSCs treatment for Parkinson’s could decrease the density of astrocytes and promote
the density of TH-positive neurons. It appears that AD-MSCs could improve spatial memory impairment in PD.


  1. Reddy AP, Ravichandran J, Carkaci-Salli N. Neural regeneration therapies for Alzheimer’s and Parkinson’s disease-related disorders. Biochim Biophys Acta Mol Basis Dis. 2020; 1866(4): 16550.
  2. Jiang W, Liang G, Li X, Li Z, Gao X, Feng S, et al. Intracarotidtransplantation of autologous adipose-derived mesenchymal stem cells significantly improves neurological deficits in rats after MCAo. J Mater Sci Mater Med. 2014; 25(5): 1357-1366.
  3. Liu XL, Zhang W, Tang SJ. Intracranial transplantation of human adipose-derived stem cells promotes the expression of neurotrophic factors and nerve repair in rats of cerebral ischemia-reperfusion injury. Int J Clin Exp Pathol. 2013; 7(1): 174-183.
  4. Yuan Z, Zhou H, Zhou N, Dong D, Chu Y, Shen J, et al. Dynamic evaluation indices in spatial learning and memory of rat vascular dementia in the morris water maze. Sci Rep. 2019; 9(1): 7224.
  5. Weintraub D, Moberg PJ, Duda JE, Katz IR, Stern MB. Effect of psychiatric and other nonmotor symptoms on disability in Parkinson’s disease. J Am Geriatr Soc. 2004; 52(5): 784-788.
  6. Darbinyan LV, Hambardzumyan LE, Simonyan KV, Chavushyan VA, Manukyan LP, Sarkisian VH. Rotenone impairs hippocampal neuronal activity in a rat model of Parkinson’s disease. Pathophysiology. 2017; 24(1): 23-30.
  7. Tieu K. A guide to neurotoxic animal models of Parkinson’s disease. Cold Spring Harb Perspect Med. 2011; 1(1): a009316.
  8. Obeso JA, Rodriguez-Oroz MC, Goetz CG, Marin C, Kordower JH, Rodriguez M, et al. Missing pieces in the Parkinson’s disease puzzle. Nat Med. 2010; 16(6): 653-661.
  9. Sarabadani M, Tavana S, Mirzaeian L, Fathi R. Co-culture with peritoneum mesothelial stem cells supports the in vitro growth of mouse ovarian follicles. J Biomed Mater Res A. 2021; 109(12): 2685-2694.
  10. Shinozuka K, Dailey T, Tajiri N, Ishikawa H, Kim DW, Pabon M, et al. Stem cells for neurovascular repair in stroke. J Stem Cell Res Ther. 2013; 4(4): 12912.
  11. Chen C, Wang Y, Yang GY. Stem cell-mediated gene delivering for the treatment of cerebral ischemia: progress and prospectives. Curr Drug Targets. 2013; 14(1): 81-89.
  12. Ding X, Li Y, Liu Z, Zhang J, Cui Y, Chen X, et al. The sonic hedgehog pathway mediates brain plasticity and subsequent functional recovery after bone marrow stromal cell treatment of stroke in mice. J Cereb Blood Flow Metab. 2013; 33(7): 1015-1024.
  13. Du S, Guan J, Mao G, Liu Y, Ma S, Bao X, et al. Intra-arterial delivery of human bone marrow mesenchymal stem cells is a safe and effective way to treat cerebral ischemia in rats. Cell Transplant. 2014; 23 Suppl 1: S73-S82.
  14. Ferro MM, Bellissimo MI, Anselmo-Franci JA, Angellucci ME, Canteras NS, Da Cunha C. Comparison of bilaterally 6-OHDA- and MPTP-lesioned rats as models of the early phase of Parkinson’s disease: histological, neurochemical, motor and memory alterations. J Neurosci Methods. 2005; 148(1): 78-87.
  15. Nazari Z, Bahrehbar K, Golalipour MJ. Effect of MDMA exposure during pregnancy on cell apoptosis, astroglia, and microglia activity in rat offspring striatum. Iran J Basic Med Sci. 2022; 25(9): 1091- 1096.
  16. Mohammadi HS, Goudarzi I, Lashkarbolouki T, Abrari K, Elahdadi Salmani M. Chronic administration of quercetin prevent spatial learning and memory deficits provoked by chronic stress in rats. Behav Brain Res. 2014; 270: 196-205.
  17. Taghi GM, Ghasem Kashani Maryam H, Taghi L, Leili H, Leyla M. Characterization of in vitro cultured bone marrow and adipose tissue- derived mesenchymal stem cells and their ability to express neurotrophic factors. Cell Biol Int. 2012; 36(12): 1239-1249.
  18. Ning H, Liu G, Lin G, Yang R, Lue TF, Lin CS. Fibroblast growth factor 2 promotes endothelial differentiation of adipose tissue-derived stem cells. J Sex Med. 2009; 6(4): 967-979.
  19. Chi H, Guan Y, Li F, Chen Z. The effect of human umbilical cord mesenchymal stromal cells in protection of dopaminergic neurons from apoptosis by reducing oxidative stress in the early stage of a 6-ohda-induced parkinson’s disease model. Cell Transplant. 2019; 28 Suppl 1: 87S-99S.
  20. Ramezani M, Mirzaeian L, Ghezelayagh Z, Ghezelayagh Z, Ghorbanian MT. Comparing the mesenchymal stem cells proliferation rate with different labeling assessments. The Nucleus. 2023; 66(2): 1-7.
  21. Ghorbanian MT, Haji-Ghasem-Kashani M, Hossein-Pour L, Mirzaiyan L. Expression of nestin and nerve growth factors in adiposederived mesenchymal stem cells. Feyz J Kashan Univ Med Sci. 2012; 15(4): 322-330.
  22. Chen SQ, Cai Q, Shen YY, Wang PY, Li MH, Teng GY. Neural stem cell transplantation improves spatial learning and memory via neuronal regeneration in amyloid-β precursor protein/presenilin 1/tau triple transgenic mice. Am J Alzheimers Dis Other Demen. 2014; 29(2): 142-149.
  23. Rad SNH, Kashani MHG, Abrari K. Pre-treatment by rosemary extract or cell transplantation improves memory deficits of parkinson’s disease: when tradition meets the future. Braz Arch Biol Technol. 2021; 64.
  24. Lee JK, Jin HK, Endo S, Schuchman EH, Carter JE, Bae JS. Intracerebral transplantation of bone marrow-derived mesenchymal stem cells reduces amyloid-beta deposition and rescues memory deficits in Alzheimer’s disease mice by modulation of immune responses. Stem Cells. 2010; 28(2): 329-343.
  25. Na Kim H, Yeol Kim D, Hee Oh S, Sook Kim H, Suk Kim K, Hyu Lee P. Feasibility and efficacy of intra-arterial administration of mesenchymal stem cells in an animal model of double toxin-induced multiple system atrophy. Stem Cells Transl Med. 2017; 6(5): 1424-1433.
  26. Qin C, Lu Y, Wang K, Bai L, Shi G, Huang Y, et al. Transplantation of bone marrow mesenchymal stem cells improves cognitive deficits and alleviates neuropathology in animal models of Alzheimer’s disease: a meta-analytic review on potential mechanisms. Transl Neurodegener. 2020; 9(1): 20.
  27. Wang YL, Liu XS, Wang SS, Xue P, Zeng ZL, Yang XP, et al. Curcumin- activated mesenchymal stem cells derived from human umbilical cord and their effects on MPTP-mouse model of parkinson’s disease: a new biological therapy for parkinson’s disease. Stem Cells Int. 2020; 2020: 4636397.
  28. Ponte AL, Marais E, Gallay N, Langonné A, Delorme B, Hérault O, et al. The in vitro migration capacity of human bone marrow mesenchymal stem cells: comparison of chemokine and growth factor chemotactic activities. Stem Cells. 2007; 25(7): 1737-1745.
  29. Karp JM, Leng Teo GS. Mesenchymal stem cell homing: the devil is in the details. Cell Stem Cell. 2009; 4(3): 206-216.
  30. Kuroda Y, Kitada M, Wakao S, Dezawa M. Bone marrow mesenchymal cells: how do they contribute to tissue repair and are they really stem cells? Arch Immunol Ther Exp (Warsz). 2011; 59(5): 369-378.
  31. Zappa Villar MF, Lehmann M, García MG, Mazzolini G, Morel GR, Cónsole GM, et al. Mesenchymal stem cell therapy improves spatial memory and hippocampal structure in aging rats. Behav Brain Res. 2019; 374: 111887.
  32. Ghorbanian MT, Tiraihi T, Mesbah-Namin SA, Fathollahi Y. Selegiline is an efficient and potent inducer for bone marrow stromal cell differentiation into neuronal phenotype. Neurol Res. 2010; 32(2): 185-193.
  33. Zhang BP, Wu L, Wu XW, Wang F, Zhao X. Dexmedetomidine protects against degeneration of dopaminergic neurons and improves motor activity in Parkinson’s disease mice model. Saudi J Biol Sci. 2021; 28(6): 3198-3203.
  34. Norden DM, Muccigrosso MM, Godbout JP. Microglial priming and enhanced reactivity to secondary insult in aging, and traumatic CNS injury, and neurodegenerative disease. Neuropharmacology. 2015; 96(Pt A): 29-41.
  35. Dabrowska S, Andrzejewska A, Janowski M, Lukomska B. Immunomodulatory and regenerative effects of mesenchymal stem cells and extracellular vesicles: therapeutic outlook for inflammatory and degenerative diseases. Front Immunol. 2021; 11: 591065.
  36. Sofroniew MV. Astrocyte barriers to neurotoxic inflammation. Nat Rev Neurosci. 2015; 16(5): 249-263.
  37. Wang Q, Liu Y, Zhou J. Neuroinflammation in Parkinson’s disease and its potential as therapeutic target. Transl Neurodegener. 2015; 4: 19.
  38. Rappold PM, Tieu K. Astrocytes and therapeutics for Parkinson’s disease. Neurotherapeutics. 2010; 7(4): 413-423.