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Testing alternatives: the use of adipose-derived mesenchymal stem cells to slow neurodegeneration in a rat model of Parkinson’s disease

  • Fatma Y. Meligy
  • Dalia A. ElgamalEmail author
  • Eman S. H. Abd Allah
  • Naglaa K. Idriss
  • Nagwa M. Ghandour
  • Ehab M. R. Bayoumy
  • Azza Sayed Abdelrehim Khalil
  • Mohamed M. El Fiky
  • Mostafa Elkhashab
Original Article

Abstract

Parkinson’s disease (PD) is a chronic neurodegenerative disease. Unfortunately, the effectiveness of anti-Parkinson treatments gradually diminishes owing to the progressive degeneration of the dopaminergic terminals. The research described here investigated the effect of adipose-derived mesenchymal stem cells (AD-MSC) versus that of an anti-Parkinson drug in a rat model of Parkinsonism. Forty adult rats were divided into four equal groups, each group receiving a different treatment: vehicle, rotenone, rotenone + AD-MSC, or rotenone + carbidopa/levodopa. Behavioral tests were carried out before and at the end of the treatment and specimens harvested from the midbrain were processed for light and electron microscopy. Genetic expression of glial fibrillary acidic protein (GFAP) and Nestin mRNA was assessed. Expression of the Lamin-B1 and Vimentin genes was measured, along with plasma levels of Angiopoietin-2 and dopamine. Treatment with rotenone induced pronounced motor deficits, as well as neuronal and glial alterations. The AD-MSC group showed improvements in motor function in the live animals and in the microscopic picture presented by their tissues. The fold change of both genes (GFAP and Nestin) decreased significantly in the AD-MSC and carbidopa/levodopa groups compared to the group with Parkinson’s disease. Plasma levels of Angiopoietin-2 and dopamine were significantly increased after treatment (P < 0.001) compared to levels in the rats with Parkinson’s disease. AD-MSC reduced neuronal degeneration more efficiently than did the anti-Parkinson drug in a rat model of Parkinsonism.

Keywords

Pole test Rotarod Substantia nigra Electron microscopy GFAP Nestin fold change 

Abbreviations

AD-MSC

Adipose-derived mesenchymal stem cells

PD

Parkinson’s disease

CP

Cerebral peduncle

SN

Substantia nigra

SNc

Substantia nigra pars compacta

SNr

Substantia nigra pars reticulate

TH

Tyrosine hydroxylase

GFAP

Glial fibrillary acidic protein

Vim

Vimentin

Nes

Nestin

FACS

Fluorescence-activated cell sorting

BBB

Blood–brain barrier

Notes

Acknowledgments

The authors thank Professor Sanaa A. M.Elgayar for her support in electron microscopy processing and examination.

Funding

This research received no funding from any funding agencies.

Compliance with ethical standards

Conflict of interest

The authors have no conflicts of interest to disclose.

Ethical approval

The study protocol was approved by the Ethical Committee of the Faculty of Medicine, Assiut University. Assiut, Egypt. Approval reference number; 17300077.

Informed consent

The donors of the adipose tissue from which the MSCs were separated gave written informed consent prior to the study for their use and publication of the data.

References

  1. 1.
    Tanner CM, Goldman SM (1996) Epidemiology of Parkinson’s disease. Neurol Clin 14:317–335CrossRefGoogle Scholar
  2. 2.
    Zhang ZN, Zhang JS, Xiang J, Yu ZH, Zhang W, Cai M, Li XT, Wu T, Li WW, Cai DF (2017) Subcutaneous rotenone rat model of Parkinson’s disease: dose exploration study. Brain Res 1655:104–113CrossRefGoogle Scholar
  3. 3.
    Olanow CW, Tatton WG (1999) Etiology and pathogenesis of Parkinson’s disease. Annu Rev Neurosci 22:123–144CrossRefGoogle Scholar
  4. 4.
    Carta AR, Mulas G, Bortolanza M, Duarte T, Pillai E, Fisone G, Vozari RR, Del-Bel E (2017) l-DOPA-induced dyskinesia and neuroinflammation: do microglia and astrocytes play a role? Eur J Neurosci 45:73–91CrossRefGoogle Scholar
  5. 5.
    Pekny M, Wilhelmsson U, Bogestal YR, Pekna M (2007) The role of astrocytes and complement system in neural plasticity. Int Rev Neurobiol 82:95–111CrossRefGoogle Scholar
  6. 6.
    Ekmark-Lewen S, Lewen A, Israelsson C, Li GL, Farooque M, Olsson Y, Ebendal T, Hillered L (2010) Vimentin and GFAP responses in astrocytes after contusion trauma to the murine brain. Restor Neurol Neurosci 28:311–321Google Scholar
  7. 7.
    Hallmann R, Horn N, Selg M, Wendler O, Pausch F, Sorokin LM (2005) Expression and function of laminins in the embryonic and mature vasculature. Physiol Rev 85:979–1000CrossRefGoogle Scholar
  8. 8.
    Fujiwara H, Gu J, Sekiguchi K (2004) Rac regulates integrin-mediated endothelial cell adhesion and migration on laminin-8. Exp Cell Res 292:67–77CrossRefGoogle Scholar
  9. 9.
    Carbone M, Duty S, Rattray M (2012) Riluzole neuroprotection in a Parkinson’s disease model involves suppression of reactive astrocytosis but not GLT-1 regulation. BMC Neurosci 13:38CrossRefPubMedCentralGoogle Scholar
  10. 10.
    Nakagawa T, Schwartz JP (2004) Gene expression profiles of reactive astrocytes in dopamine-depleted striatum. Brain Pathol 14:275–280CrossRefGoogle Scholar
  11. 11.
    Jucker M, Tian M, Norton DD, Sherman C, Kusiak JW (1996) Laminin alpha 2 is a component of brain capillary basement membrane: reduced expression in dystrophic dy mice. Neuroscience 71:1153–1161CrossRefGoogle Scholar
  12. 12.
    Zhang P, Li J, Liu Y, Chen X, Lu H, Kang Q, Li W, Gao M (2011) Human embryonic neural stem cell transplantation increases subventricular zone cell proliferation and promotes peri-infarct angiogenesis after focal cerebral ischemia. Neuropathology 31:384–391CrossRefGoogle Scholar
  13. 13.
    Mine Y, Tatarishvili J, Oki K, Monni E, Kokaia Z, Lindvall O (2013) Grafted human neural stem cells enhance several steps of endogenous neurogenesis and improve behavioral recovery after middle cerebral artery occlusion in rats. Neurobiol Dis 52:191–203CrossRefGoogle Scholar
  14. 14.
    Choi HS, Kim HJ, Oh JH, Park HG, Ra JC, Chang KA, Suh YH (2015) Therapeutic potentials of human adipose-derived stem cells on the mouse model of Parkinson’s disease. Neurobiol Aging 36:2885–2892CrossRefGoogle Scholar
  15. 15.
    Sharma N, Nehru B (2013) Beneficial effect of vitamin E in rotenone induced model of PD: behavioural, neurochemical and biochemical study. Exp Neurobiol 22:214–223CrossRefPubMedCentralGoogle Scholar
  16. 16.
    Javed H, Azimullah S, Abul Khair SB, Ojha S, Haque ME (2016) Neuroprotective effect of nerolidol against neuroinflammation and oxidative stress induced by rotenone. BMC Neurosci 17:58CrossRefPubMedCentralGoogle Scholar
  17. 17.
    Abo-Grisha N, Essawy S, Abo-Elmatty DM, Abdel-Hady Z (2013) Effects of intravenous human umbilical cord blood CD34 + stem cell therapy versus levodopa in experimentally induced Parkinsonism in mice. Arch Med Sci 9:1138–1151CrossRefPubMedCentralGoogle Scholar
  18. 18.
    Lu J, Kanji S, Aggarwal R, Das M, Joseph M, Wu LC, Mao HQ, Pompili VJ, Hadjiconstantinou M, Das H (2013) Hematopoietic stem cells improve dopaminergic neuron in the MPTP-mice. Front Biosci 18:970–981CrossRefGoogle Scholar
  19. 19.
    Fischer UM, Harting MT, Jimenez F, Monzon-Posadas WO, Xue H, Savitz SI, Laine GA, Cox CS Jr (2009) Pulmonary passage is a major obstacle for intravenous stem cell delivery: the pulmonary first-pass effect. Stem Cells Dev 18:683–692CrossRefGoogle Scholar
  20. 20.
    Chompoopong S, Jarungjitaree S, Punbanlaem T, Rungruang T, Chongthammakun S, Kettawan A, Taechowisan T (2016) Neuroprotective effects of germinated brown rice in rotenone-induced Parkinson’s-like disease rats. NeuroMol Med 18:334–346CrossRefGoogle Scholar
  21. 21.
    Recchia A, Rota D, Debetto P, Peroni D, Guidolin D, Negro A, Skaper SD, Giusti P (2008) Generation of a alpha-synuclein-based rat model of Parkinson’s disease. Neurobiol Dis 30:8–18CrossRefGoogle Scholar
  22. 22.
    von Wrangel C, Schwabe K, John N, Krauss JK, Alam M (2015) The rotenone-induced rat model of Parkinson’s disease: behavioral and electrophysiological findings. Behav Brain Res 279:52–61CrossRefGoogle Scholar
  23. 23.
    Sedelis M, Schwarting RK, Huston JP (2001) Behavioral phenotyping of the MPTP mouse model of Parkinson’s disease. Behav Brain Res 125:109–125CrossRefGoogle Scholar
  24. 24.
    Singh N, Bansal Y, Bhandari R, Marwaha L, Singh R, Chopra K, Kuhad A (2017) Resveratrol protects against ICV collagenase-induced neurobehavioral and biochemical deficits. J Inflamm 14:14CrossRefGoogle Scholar
  25. 25.
    Woode E, Amidu N, Owiredu WKBA, Boakye-Gyasi E, Laing EF, Ansah C, Duwiejua M (2009) Anxiogenic-like effects of a root extract of sphenocentrum jollyanum pierre in murine behavioural models. J Pharmacoland Toxicol 4:91–106CrossRefGoogle Scholar
  26. 26.
    Lee HC, An SG, Lee HW, Park JS, Cha KS, Hong TJ, Park JH, Lee SY, Kim SP, Kim YD, Chung SW, Bae YC, Shin YB, Kim JI, Jung JS (2012) Safety and effect of adipose tissue-derived stem cell implantation in patients with critical limb ischemia: a pilot study. Circ J 76:1750–1760CrossRefGoogle Scholar
  27. 27.
    Yamamoto N, Akamatsu H, Hasegawa S, Yamada T, Nakata S, Ohkuma M, Miyachi E, Marunouchi T, Matsunaga K (2007) Isolation of multipotent stem cells from mouse adipose tissue. J Dermatol Sci 48:43–52CrossRefGoogle Scholar
  28. 28.
    Kozina EA, Khaindrava VG, Kudrin VS, Kucherianu VG, Klodt PD, Bocharov EV, Raevskii KS, Kryzhanovskii GN, Ugriumov MV (2010) Experimental modeling of functional deficiency of the nigrostriatal dopaminergic system in mice. Ross Fiziol Zh Im I M Sechenova 96:270–282Google Scholar
  29. 29.
    Wang T, Liu YY, Wang X, Yang N, Zhu HB, Zuo PP (2010) Protective effects of octacosanol on 6-hydroxydopamine-induced Parkinsonism in rats via regulation of ProNGF and NGF signaling. Acta Pharmacol Sin 31:765–774CrossRefPubMedCentralGoogle Scholar
  30. 30.
    Gupta PD (1983) Ultrastructural study on semithin section. Sci Tools 30:6–7Google Scholar
  31. 31.
    Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25:402–408CrossRefGoogle Scholar
  32. 32.
    Fernandez M, Negro S, Slowing K, Fernandez-Carballido A, Barcia E (2011) An effective novel delivery strategy of rasagiline for Parkinson’s disease. Int J Pharm 419:271–280CrossRefGoogle Scholar
  33. 33.
    Matsuura K, Kabuto H, Makino H, Ogawa N (1997) Pole test is a useful method for evaluating the mouse movement disorder caused by striatal dopamine depletion. J Neurosci Methods 73:45–48CrossRefGoogle Scholar
  34. 34.
    Zaitone SA, Abo-Elmatty DM, Elshazly SM (2012) Piracetam and vinpocetine ameliorate rotenone-induced Parkinsonism in rats. Indian J Pharmacol 44:774–779CrossRefPubMedCentralGoogle Scholar
  35. 35.
    Ooigawa H, Nawashiro H, Fukui S, Otani N, Osumi A, Toyooka T, Shima K (2006) The fate of Nissl-stained dark neurons following traumatic brain injury in rats: difference between neocortex and hippocampus regarding survival rate. Acta Neuropathol 112:471–481CrossRefGoogle Scholar
  36. 36.
    Fa YH, Ni JQ, Wu XJ, Tan JQ, Wu YW (2016) Evaluation of the early response and mechanism of treatment of Parkinson’s disease with L-dopa using (18)F-fallypride micro-positron emission tomography scanning. Exp Ther Med 11:101–109CrossRefGoogle Scholar
  37. 37.
    Zhang QS, Heng Y, Mou Z, Huang JY, Yuan YH, Chen NH (2017) Reassessment of subacute MPTP-treated mice as animal model of Parkinson’s disease. Acta Pharmacol Sin 38:1317–1328CrossRefPubMedCentralGoogle Scholar
  38. 38.
    Anglade P, Vyas S, Javoy-Agid F, Herrero MT, Michel PP, Marquez J, Mouatt-Prigent A, Ruberg M, Hirsch EC, Agid Y (1997) Apoptosis and autophagy in nigral neurons of patients with Parkinson’s disease. Histol Histopathol 12:25–31Google Scholar
  39. 39.
    Rendon WO, Martinez-Alonso E, Tomas M, Martinez-Martinez N, Martinez-Menarguez JA (2013) Golgi fragmentation is Rab and SNARE dependent in cellular models of Parkinson’s disease. Histochem Cell Biol 139:671–684CrossRefGoogle Scholar
  40. 40.
    Cannon JR, Tapias V, Na HM, Honick AS, Drolet RE, Greenamyre JT (2009) A highly reproducible rotenone model of Parkinson’s disease. Neurobiol Dis 34:279–290CrossRefPubMedCentralGoogle Scholar
  41. 41.
    Exner N, Treske B, Paquet D, Holmstrom K, Schiesling C, Gispert S, Carballo-Carbajal I, Berg D, Hoepken HH, Gasser T, Kruger R, Winklhofer KF, Vogel F, Reichert AS, Auburger G, Kahle PJ, Schmid B, Haass C (2007) Loss-of-function of human PINK1 results in mitochondrial pathology and can be rescued by parkin. J Neurosci 27:12413–12418CrossRefGoogle Scholar
  42. 42.
    Poole AC, Thomas RE, Andrews LA, McBride HM, Whitworth AJ, Pallanck LJ (2008) The PINK1/Parkin pathway regulates mitochondrial morphology. Proc Natl Acad Sci USA 105:1638–1643CrossRefGoogle Scholar
  43. 43.
    Niranjan R, Nath C, Shukla R (2010) The mechanism of action of MPTP-induced neuroinflammation and its modulation by melatonin in rat astrocytoma cells, C6. Free Radic Res 44:1304–1316CrossRefGoogle Scholar
  44. 44.
    Cali C, Baghabra J, Boges DJ, Holst GR, Kreshuk A, Hamprecht FA, Srinivasan M, Lehvaslaiho H, Magistretti PJ (2016) Three-dimensional immersive virtual reality for studying cellular compartments in 3D models from EM preparations of neural tissues. J Comp Neurol 524:23–38CrossRefGoogle Scholar
  45. 45.
    Devos D, Lebouvier T, Lardeux B, Biraud M, Rouaud T, Pouclet H, Coron E, Bruley des Varannes S, Naveilhan P, Nguyen JM, Neunlist M, Derkinderen P (2013) Colonic inflammation in Parkinson’s disease. Neurobiol Dis 50:42–48CrossRefGoogle Scholar
  46. 46.
    Gao HM, Liu B, Zhang W, Hong JS (2003) Critical role of microglial NADPH oxidase-derived free radicals in the in vitro MPTP model of Parkinson’s disease. FASEB J 17:1954–1956CrossRefGoogle Scholar
  47. 47.
    Chen X, Lan X, Roche I, Liu R, Geiger JD (2008) Caffeine protects against MPTP-induced blood-brain barrier dysfunction in mouse striatum. J Neurochem 107:1147–1157PubMedCentralGoogle Scholar
  48. 48.
    Lee H, Pienaar IS (2014) Disruption of the blood-brain barrier in Parkinson’s disease: curse or route to a cure? Front Biosci 19:272–280CrossRefGoogle Scholar
  49. 49.
    ElAli A, Theriault P, Rivest S (2014) The role of pericytes in neurovascular unit remodeling in brain disorders. Int J Mol Sci 15:6453–6474CrossRefPubMedCentralGoogle Scholar
  50. 50.
    Dore-Duffy P, Cleary K (2011) Morphology and properties of pericytes. Methods Mol Biol 686:49–68CrossRefGoogle Scholar
  51. 51.
    Mayer CA, Brunkhorst R, Niessner M, Pfeilschifter W, Steinmetz H, Foerch C (2013) Blood levels of glial fibrillary acidic protein (GFAP) in patients with neurological diseases. PLoS ONE 8:e62101CrossRefPubMedCentralGoogle Scholar
  52. 52.
    Cabezas R, Avila M, Gonzalez J, El-Bacha RS, Baez E, Garcia-Segura LM, Jurado Coronel JC, Capani F, Cardona-Gomez GP, Barreto GE (2014) Astrocytic modulation of blood brain barrier: perspectives on Parkinson’s disease. Front Cell Neurosci 8:211CrossRefPubMedCentralGoogle Scholar
  53. 53.
    Bouchez G, Sensebe L, Vourc’h P, Garreau L, Bodard S, Rico A, Guilloteau D, Charbord P, Besnard JC, Chalon S (2008) Partial recovery of dopaminergic pathway after graft of adult mesenchymal stem cells in a rat model of Parkinson’s disease. Neurochem Int 52:1332–1342CrossRefGoogle Scholar
  54. 54.
    van den Berge SA, Kevenaar JT, Sluijs JA, Hol EM (2012) Dementia in Parkinson’s Disease correlates with alpha-synuclein pathology but not with cortical astrogliosis. Parkinsons Dis 2012:420957PubMedCentralGoogle Scholar
  55. 55.
    Hendrickson ML, Rao AJ, Demerdash ON, Kalil RE (2011) Expression of nestin by neural cells in the adult rat and human brain. PLoS ONE 6:e18535CrossRefPubMedCentralGoogle Scholar
  56. 56.
    Nagel S, Rohr F, Weber C, Kier J, Siemers F, Kruse C, Danner S, Brandenburger M, Matthiessen AE (2013) Multipotent nestin-positive stem cells reside in the stroma of human eccrine and apocrine sweat glands and can be propagated robustly in vitro. PLoS ONE 8:e78365CrossRefPubMedCentralGoogle Scholar
  57. 57.
    Freed CR, Greene PE, Breeze RE, Tsai WY, DuMouchel W, Kao R, Dillon S, Winfield H, Culver S, Trojanowski JQ, Eidelberg D, Fahn S (2001) Transplantation of embryonic dopamine neurons for severe Parkinson’s disease. N Engl J Med 344:710–719CrossRefGoogle Scholar
  58. 58.
    Olanow CW, Goetz CG, Kordower JH, Stoessl AJ, Sossi V, Brin MF, Shannon KM, Nauert GM, Perl DP, Godbold J, Freeman TB (2003) A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson’s disease. Ann Neurol 54:403–414CrossRefGoogle Scholar
  59. 59.
    Chang KA, Kim HJ, Joo Y, Ha S, Suh YH (2014) The therapeutic effects of human adipose-derived stem cells in Alzheimer’s disease mouse models. Neurodegener Dis 13:99–102CrossRefGoogle Scholar
  60. 60.
    Rosova I, Dao M, Capoccia B, Link D, Nolta JA (2008) Hypoxic preconditioning results in increased motility and improved therapeutic potential of human mesenchymal stem cells. Stem Cells 26:2173–2182CrossRefPubMedCentralGoogle Scholar
  61. 61.
    Baum O, Gubeli J, Frese S, Torchetti E, Malik C, Odriozola A, Graber F, Hoppeler H, Tschanz SA (2015) Angiogenesis-related ultrastructural changes to capillaries in human skeletal muscle in response to endurance exercise. J Appl Physiol 119:1118–1126CrossRefGoogle Scholar
  62. 62.
    Ryu S, Lee SH, Kim SU, Yoon BW (2016) Human neural stem cells promote proliferation of endogenous neural stem cells and enhance angiogenesis in ischemic rat brain. Neural Regen Res 11:298–304CrossRefPubMedCentralGoogle Scholar
  63. 63.
    Olsson AK, Dimberg A, Kreuger J, Claesson-Welsh L (2006) VEGF receptor signalling—in control of vascular function. Nat Rev Mol Cell Biol 7:359–371CrossRefGoogle Scholar
  64. 64.
    Lopatina T, Bruno S, Tetta C, Kalinina N, Porta M, Camussi G (2014) Platelet-derived growth factor regulates the secretion of extracellular vesicles by adipose mesenchymal stem cells and enhances their angiogenic potential. Cell Commun Signal 12:26CrossRefPubMedCentralGoogle Scholar
  65. 65.
    Tan CY, Lai RC, Wong W, Dan YY, Lim SK, Ho HK (2014) Mesenchymal stem cell-derived exosomes promote hepatic regeneration in drug-induced liver injury models. Stem Cell Res Ther 5:76CrossRefPubMedCentralGoogle Scholar
  66. 66.
    Lee JK, Park SR, Jung BK, Jeon YK, Lee YS, Kim MK, Kim YG, Jang JY, Kim CW (2013) Exosomes derived from mesenchymal stem cells suppress angiogenesis by down-regulating VEGF expression in breast cancer cells. PLoS ONE 8:e84256CrossRefPubMedCentralGoogle Scholar
  67. 67.
    Ratushnyy A, Ezdakova M, Yakubets D, Buravkova L (2018) Angiogenic Activity of Human Adipose-Derived Mesenchymal Stem Cells Under Simulated Microgravity. Stem Cells Dev 27:831–837CrossRefGoogle Scholar
  68. 68.
    Chen H, Fang J, Li F, Gao L, Feng T (2015) Risk factors and safe dosage of levodopa for wearing-off phenomenon in Chinese patients with Parkinson’s disease. Neurol Sci 36:1217–1223CrossRefGoogle Scholar

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© Springer Nature B.V. 2019

Authors and Affiliations

  1. 1.Department of Histology and Cell Biology, Faculty of MedicineAssiut UniversityAssiutEgypt
  2. 2.Department of Medical Physiology, Faculty of MedicineAssiut UniversityAssiutEgypt
  3. 3.Department of Medical Biochemistry, Faculty of MedicineAssiut UniversityAssiutEgypt
  4. 4.Department of Forensic Medicine and Clinical Toxicology, Faculty of MedicineAssiut UniversityAssiutEgypt
  5. 5.Department of Plastic Surgery, Faculty of MedicineAssiut UniversityAssiutEgypt
  6. 6.Department of Rehabilitation Sciences, College of Health and Rehabilitation SciencesPrincess Nourah Bint Abdulrahman UniversityRiyadhSaudi Arabia
  7. 7.Department of Anatomy and Embryology, Faculty of MedicineMenoufia UniversityMenoufiaEgypt
  8. 8.Department of NeurosurgeryHackensack University Medical CenterHackensackUSA

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