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Cited by 150Extracellular vesicles in diseaseParkinson's Disease Mechanisms and TreatmentsNanoparticle-Based Drug Delivery

Intranasal Administration of Extracellular Vesicles Derived from Human Teeth Stem Cells Improves Motor Symptoms and Normalizes Tyrosine Hydroxylase Expression in the Substantia Nigra and Striatum of the 6-Hydroxydopamine-Treated Rats

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Narbute, Karīna, Piļipenko, Vladimirs, Pupure, Jolanta, Dzirkale, Zane, Jonavičė, Ugnė, Tunaitis, Virginijus, Kriaučiūnaitė, Karolina, Jarmalavičiūtė, Akvilė +3 more·2019·Stem Cells Translational Medicine
DOI 10.1002/sctm.18-0162PMC PMC6477008
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Abstract

Parkinson's disease (PD) is the second most common neurodegenerative disorder affecting millions of people worldwide. At present, there is no effective cure for PD; treatments are symptomatic and do not halt progression of neurodegeneration. Extracellular vesicles (EVs) can cross the blood-brain barrier and represent promising alternative to the classical treatment strategies. In the present study, we examined therapeutic effects of intranasal administration of EVs derived from human exfoliated deciduous teeth stem cells (SHEDs) on unilateral 6-hydroxydopamine (6-OHDA) medial forebrain bundle (MFB) rat model of PD. CatWalk gait tests revealed that EVs effectively suppressed 6-OHDA-induced gait impairments. All tested gait parameters (stand, stride length, step cycle, and duty cycle) were significantly improved in EV-treated animals when compared with 6-OHDA-lesion group rats. Furthermore, EVs slowed down numbers of 6-OHDA-induced contralateral rotations in apomorphine test. Improvements in motor function correlated with normalization of tyrosine hydroxylase expression in the striatum and substantia nigra. In conclusion, we demonstrated, for the first time, the therapeutic efficacy of intranasal administration of EVs derived from SHEDs in a rat model of PD induced by 6-OHDA intra-MFB lesion. Our findings could be potentially exploited for the development of new treatment strategies against PD.

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  • Intranasal administration of SHED-derived EVs into a 6-OHDA MFB rat model of PD improved motor functions and increased tyrosine hydroxylase expression in the striatum and substantia nigra.

    “Following intranasal administration of SHED-derived EVs, the 6-OHDA-treated rats demonstrated improved motor functions and increased tyrosine hydroxylase expression in the striatum and substantia nigra.”

    From Extracellular vesicles as nanotheranostic platforms for targeted neurological disorder interventions (2024) · cites this paper as [254]

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  1. [4]Kriks S, Shim JW, Piao J et al. Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson's disease. Nature 2011; 480: 547– 551. 22056989 PMC3245796
  2. [5]Barker RA, Parmar M, Studer L et al. Human trials of stem cell‐derived dopamine neurons for Parkinson's disease: Dawn of a new era. Cell Stem Cell 2017; 21: 569– 573. 29100010
  3. [6]Kourembanas S. Exosomes: Vehicles of intercellular signaling, biomarkers, and vectors of cell therapy. Annu Rev Physiol 2015; 77: 13– 27. 25293529
  4. [7]Maas SLN, Breakefield XO, Weaver AM. Extracellular vesicles: Unique intercellular delivery vehicles. Trends Cell Biol 2017; 27: 172– 188. 27979573 PMC5318253
  5. [8]Alvarez‐Erviti L, Seow Y, Yin H et al. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol 2011; 29: 341– 345. 21423189
  6. [9]Yang T, Martin P, Fogarty B et al. Exosome delivered anticancer drugs across the blood‐brain barrier for brain cancer therapy in Danio rerio. Pharm Res 2015; 32: 2003– 2014. 25609010 PMC4520542
  7. [10]Gyorgy B, Hung ME, Breakefield XO et al. Therapeutic applications of extracellular vesicles: Clinical promise and open questions. Annu Rev Pharmacol Toxicol 2015; 55: 439– 464. 25292428 PMC4445965
  8. [11]Long Q, Upadhya D, Hattiangady B et al. Intranasal MSC‐derived A1‐exosomes ease inflammation, and prevent abnormal neurogenesis and memory dysfunction after status epilepticus. Proc Natl Acad Sci USA 2017; 114: E3536– E3545. 28396435 PMC5410779
  9. [12]Kim DK, Nishida H, An SY et al. Chromatographically isolated CD63+CD81+ extracellular vesicles from mesenchymal stromal cells rescue cognitive impairments after TBI. Proc Natl Acad Sci USA 2016; 113: 170– 175. 26699510 PMC4711859
  10. [13]Haney MJ, Zhao Y, Harrison EB et al. Specific transfection of inflamed brain by macrophages: A new therapeutic strategy for neurodegenerative diseases. PLoS One 2013; 8: e61852. 23620794 PMC3631190
  11. [14]Sun D, Zhuang X, Xiang X et al. A novel nanoparticle drug delivery system: The anti‐inflammatory activity of curcumin is enhanced when encapsulated in exosomes. Mol Ther 2010; 18: 1606– 1614. 20571541 PMC2956928
  12. [15]Kaukua N, Shahidi MK, Konstantinidou C et al. Glial origin of mesenchymal stem cells in a tooth model system. Nature 2014; 513: 551– 554. 25079316
  13. [16]Sakai K, Yamamoto A, Matsubara K et al. Human dental pulp‐derived stem cells promote locomotor recovery after complete transection of the rat spinal cord by multiple neuro‐regenerative mechanisms. J Clin Invest 2012; 122: 80– 90. 22133879 PMC3248299
  14. [17]Jarmalaviciute A, Tunaitis V, Strainiene E et al. A new experimental model for neuronal and glial differentiation using stem cells derived from human exfoliated deciduous teeth. J Mol Neurosci 2013; 51: 307– 317. 23797732
  15. [18]Fujii H, Matsubara K, Sakai K et al. Dopaminergic differentiation of stem cells from human deciduous teeth and their therapeutic benefits for Parkinsonian rats. Brain Res 1613; 2015: 59– 72. 25863132
  16. [19]Martens W, Sanen K, Georgiou M et al. Human dental pulp stem cells can differentiate into Schwann cells and promote and guide neurite outgrowth in an aligned tissue‐engineered collagen construct in vitro. FASEB J 2014; 28: 1634– 1643. 24352035 PMC4046066
  17. [20]Jarmalaviciute A, Tunaitis V, Pivoraite U et al. Exosomes from dental pulp stem cells rescue human dopaminergic neurons from 6‐hydroxy‐dopamine‐induced apoptosis. Cytotherapy 2015; 17: 932– 939. 25981557
  18. [21]Zhou M, Zhang W, Chang J et al. Gait analysis in three different 6‐hydroxydopamine rat models of Parkinson's disease. Neurosci Lett 2015; 584: 184– 189. 25449863
  19. [22]Hamers FP, Koopmans GC, Joosten EA. CatWalk‐assisted gait analysis in the assessment of spinal cord injury. J Neurotrauma 2006; 23: 537– 548. 16629635
  20. [23]Gabriel AF, Marcus MA, Honig WM et al. The CatWalk method: A detailed analysis of behavioral changes after acute inflammatory pain in the rat. J Neurosci Methods 2007; 163: 9– 16. 17382401
  21. [25]Kalra H, Simpson RJ, Ji H et al. Vesiclepedia: A compendium for extracellular vesicles with continuous community annotation. PLoS Biol 2012; 10:e1001450. PMC3525526 23271954
  22. [26]Boix J, von Hieber D, Connor B. Gait analysis for early detection of motor symptoms in the 6‐OHDA rat model of Parkinson's disease. Front Behav Neurosci 2018; 12: 39. 29559901 PMC5845681
  23. [27]Henning J, Strauss U, Wree A et al. Differential astroglial activation in 6‐hydroxydopamine models of Parkinson's disease. Neurosci Res 2008; 62: 246– 253. 18824050
  24. [28]Boix J, Padel T, Paul G. A partial lesion model of Parkinson's disease in mice—Characterization of a 6‐OHDA‐induced medial forebrain bundle lesion. Behav Brain Res 2015; 284: 196– 206. 25698603
  25. [29]Ma Y, Zhan M, OuYang L et al. The effects of unilateral 6‐OHDA lesion in medial forebrain bundle on the motor, cognitive dysfunctions and vulnerability of different striatal interneuron types in rats. Behav Brain Res 2014; 266: 37– 45. 24613235
  26. [30]Blandini F, Armentero MT, Martignoni E. The 6‐hydroxydopamine model: News from the past. Parkinsonism Relat Disord 2008; 14: S124– S129. 18595767
  27. [31]Schober A. Classic toxin‐induced animal models of Parkinson's disease: 6‐OHDA and MPTP. Cell Tissue Res 2004; 318: 215– 224. 15503155
  28. [32]Mazzio E, Reams R, Soliman K. The role of oxidative stress, impaired glycolysis and mitochondrial respiratory redox failure in the cytotoxic effects of 6‐hydroxydopamine in vitro. Brain Res 2004; 1004: 29– 44. 15033417
  29. [33]Botella JA, Bayersdorfer F, Schneuwly S. Superoxide dismutase overexpression protects dopaminergic neurons in a Drosophila model of Parkinson's disease. Neurobiol Dis 2008; 30: 65– 73. 18243716
  30. [34]Calabrese V, Cornelius C, Cuzzocrea S et al. Hormesis, cellular stress response and vitagenes as critical determinants in aging and longevity. Mol Aspects Med 2011; 32: 279– 304. 22020114
  31. [35]Dong Z, Wolfer DP, Lipp HP et al. Hsp70 gene transfer by adeno‐associated virus inhibits MPTP‐induced nigrostriatal degeneration in the mouse model of Parkinson disease. Mol Ther 2005; 11: 80– 88. 15585408
  32. [36]Ekimova IV, Plaksina DV, Pastukhov YF et al. New HSF1 inducer as a therapeutic agent in a rodent model of Parkinson's disease. Exp Neurol 2018; 306: 199– 208. 29704482
  33. [37]Cunningham TJ, Greenstein JI, Loewenstern J et al. Anti‐inflammatory peptide regulates the supply of heat shock protein 70 monomers: Implications for aging and age‐related disease. Rejuvenation Res 2015; 18: 136– 144. 25485461 PMC4403226
  34. [38]Wang J, Lou H, Pedersen CJ et al. 14‐3‐3zeta contributes to tyrosine hydroxylase activity in MN9D cells: Localization of dopamine regulatory proteins to mitochondria. J Biol Chem 2009; 284: 14011– 14019. 19289463 PMC2682849
  35. [39]Obsilova V, Nedbalkova E, Silhan J et al. The 14‐3‐3 protein affects the conformation of the regulatory domain of human tyrosine hydroxylase. Biochemistry 2008; 47: 1768– 1777. 18181650
  36. [40]Korshunova I, Caroni P, Kolkova K et al. Characterization of BASP1‐mediated neurite outgrowth. J Neurosci Res 2008; 86: 2201– 2213. 18438920
  37. [41]Caraveo G, Soste M, Cappelleti V et al. FKBP12 contributes to alpha‐synuclein toxicity by regulating the calcineurin‐dependent phosphoproteome. Proc Natl Acad Sci USA 2017; 114: E11313– E11322. 29229832 PMC5748183
  38. [42]Mirsaeidi M, Gidfar S, Vu A et al. Annexins family: Insights into their functions and potential role in pathogenesis of sarcoidosis. J Transl Med 2016; 14: 89. 27071553 PMC4830063
  39. [44]Han S, Zhang KH, Lu PH et al. Effects of annexins II and V on survival of neurons and astrocytes in vitro. Acta Pharmacol Sin 2004; 25: 602– 610. 15132826

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Authors
Narbute, K., Piļipenko, V., Pupure, J., Dzirkale, Z., Jonavičė, U., Tunaitis, V., Kriaučiūnaitė, K., Jarmalavičiūtė, A., Jansone, B., Kluša, V., & Pivoriūnas, A.
Affiliations
  • University of Latvia (LV)
  • State Research Institute Centre for Innovative Medicine (LT)
  • a Department of Pharmacology, Faculty of Medicine University of Latvia, Riga, Latvia
Corresponding author
Pivoriūnas, Augustas
ORCID
Venue
Stem Cells Translational Medicine
Publisher
Oxford University Press (OUP)
Published
2019-02-01
Volume
8
Issue
5
Pages
490-499
ISSN
  • 2157-6564 (ISSN-L)
  • 2157-6580
DOI
10.1002/sctm.18-0162
PMC
PMC6477008
OpenAlex
W2914375886
Cited by
150
References
5
Citations by year
2026: 10 · 2025: 20 · 2024: 20 · 2023: 22 · 2022: 23 · 2021: 23 · 2020: 22 · 2019: 9 · 2017: 1
FWCI
6.37
Type
journal article
Language
en
Open access
Licence
Locations
  • Stem Cells Translational Medicine (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • E-resource repository of the University of Latvia (University of Latvia) (submittedVersion, other-oa)
Funders
  • Patron of the University of Latvia SIA Mikrotīkls
  • Research Council of Lithuania
  • Lietuvos Mokslo Taryba
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
Keywords
Parkinson's disease, extracellular vesicles, stem cells from human exfoliated deciduous teeth, sheds, intranasal administration, 6-hydroxydopamine, medial forebrain bundle lesion, gait disturbance, apomorphine rotation, tyrosine hydroxylase, substantia nigra, striatum, motor symptoms, blood-brain barrier
MeSH terms
Extracellular Vesicles, Administration, Intranasal, Aged, Animals, Corpus Striatum, Disease Models, Animal, Humans, Male, Parkinson Disease, Stem Cells, Substantia Nigra, Tooth, Tyrosine 3-Monooxygenase, Oxidopamine, Rats, Wistar, Microscopy, Electron, Transmission, Rats

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