Neurotoxic and Neuroprotective Role of Exosomes in Parkinson’s Disease

Author(s): Biancamaria Longoni, Irene Fasciani, Shivakumar Kolachalam, Ilaria Pietrantoni, Francesco Marampon, Francesco Petragnano, Gabriella Aloisi, Maria F. Coppolino, Mario Rossi, Marco Scarselli, Roberto Maggio*

Journal Name: Current Pharmaceutical Design

Volume 25 , Issue 42 , 2019

Become EABM
Become Reviewer
Call for Editor


Exosomes are extracellular vesicles produced by eukaryotic cells that are also found in most biological fluids and tissues. While they were initially thought to act as compartments for removal of cellular debris, they are now recognized as important tools for cell-to-cell communication and for the transfer of pathogens between the cells. They have attracted particular interest in neurodegenerative diseases for their potential role in transferring prion-like proteins between neurons, and in Parkinson’s disease (PD), they have been shown to spread oligomers of α-synuclein in the brain accelerating the progression of this pathology. A potential neuroprotective role of exosomes has also been equally proposed in PD as they could limit the toxicity of α-synuclein by clearing them out of the cells. Exosomes have also attracted considerable attention for use as drug vehicles. Being nonimmunogenic in nature, they provide an unprecedented opportunity to enhance the delivery of incorporated drugs to target cells. In this review, we discuss current knowledge about the potential neurotoxic and neuroprotective role of exosomes and their potential application as drug delivery systems in PD.

Keywords: Exosomes, Parkinson’s disease, drug delivery, dopaminergic neurons, blood-brain barrier, biomarkers.

Kalia LV, Lang AE. Parkinson’s disease. Lancet 2015; 386(9996): 896-912.
[] [PMID: 25904081]
Dickson DW. Parkinson’s disease and Parkinsonism: neuropathology. Cold Spring Harb Perspect Med 2012; 2(8) pii: a009258
[] [PMID: 22908195]
Wakabayashi K, Tanji K, Odagiri S, Miki Y, Mori F, Takahashi H. The Lewy body in Parkinson’s disease and related neurodegenerative disorders. Mol Neurobiol 2013; 47(2): 495-508.
[] [PMID: 22622968]
Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M. Alpha-synuclein in Lewy bodies. Nature 1997; 388(6645): 839-40.
[] [PMID: 9278044]
McLean PJ, Kawamata H, Ribich S, Hyman BT. Membrane association and protein conformation of alpha-synuclein in intact neurons. Effect of Parkinson’s disease-linked mutations. J Biol Chem 2000; 275(12): 8812-6.
[] [PMID: 10722726]
Fusco G, Sanz-Hernandez M, De Simone A. Order and disorder in the physiological membrane binding of α-synuclein. Curr Opin Struct Biol 2018; 48: 49-57.
[] [PMID: 29100107]
Polymeropoulos MH, Lavedan C, Leroy E, et al. Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 1997; 276(5321): 2045-7.
[] [PMID: 9197268]
Xu L, Pu J. Alpha-synuclein in Parkinson’s disease: from pathogenetic dysfunction to potential clinical application. Parkinsons Dis 2016; 20161 720621
[] [PMID: 27610264]
Braak H, Del Tredici K, Rüb U, de Vos RAI, Jansen Steur ENH, Braak E. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 2003; 24(2): 197-211.
[] [PMID: 12498954]
Kordower JH, Chu Y, Hauser RA, Freeman TB, Olanow CW. Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson’s disease. Nat Med 2008; 14(5): 504-6.
[] [PMID: 18391962]
Li JY, Englund E, Holton JL, et al. Lewy bodies in grafted neurons in subjects with Parkinson’s disease suggest host-to-graft disease propagation. Nat Med 2008; 14(5): 501-3.
[] [PMID: 18391963]
Recasens A, Dehay B, Bové J, et al. Lewy body extracts from Parkinson disease brains trigger α-synuclein pathology and neurodegeneration in mice and monkeys. Ann Neurol 2014; 75(3): 351-62.
[] [PMID: 24243558]
Tomlinson PR, Zheng Y, Fischer R, et al. Identification of distinct circulating exosomes in Parkinson’s disease. Ann Clin Transl Neurol 2015; 2(4): 353-61.
[] [PMID: 25909081]
Wu X, Zheng T, Zhang B. Exosomes in Parkinson’s disease. Neurosci Bull 2017; 33(3): 331-8.
[] [PMID: 28025780]
Lee Y, El Andaloussi S, Wood MJ. Exosomes and microvesicles: extracellular vesicles for genetic information transfer and gene therapy. Hum Mol Genet 2012; 21(R1): R125-34.
[] [PMID: 22872698]
Pietrantoni I, Rossi M, Scarselli M, Fasciani I, Marampon F, Maggio R. Dichlorodiphenyltrichloroethane, an old pesticide with a new mechanism of toxicity. Curr Top Pharmacol 2018; 22: 69-76.
Johnstone RM, Adam M, Hammond JR, Orr L, Turbide C. Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes). J Biol Chem 1987; 262(19): 9412-20.
[PMID: 3597417]
Pant S, Hilton H, Burczynski ME. The multifaceted exosome: biogenesis, role in normal and aberrant cellular function, and frontiers for pharmacological and biomarker opportunities. Biochem Pharmacol 2012; 83(11): 1484-94.
[] [PMID: 22230477]
Rashed HM, Bayraktar EK, Helal G, et al. Exosomes: from garbage bins to promising therapeutic targets. Int J Mol Sci 2017; 18(3): 538.
Properzi F, Logozzi M, Fais S. Exosomes: the future of biomarkers in medicine. Biomarkers Med 2013; 7(5): 769-78.
[] [PMID: 24044569]
Meldolesi J. Exosomes and ectosomes in intercellular communication. Curr Biol 2018; 28(8): R435-44.
[] [PMID: 29689228]
Meldolesi J. Extracellular vesicles, news about their role in immune cells: physiology, pathology and diseases. Clin Exp Immunol 2019; 196(3): 318-27.
[] [PMID: 30756386]
Cheng L, Zhao W, Hill AF. Exosomes and their role in the intercellular trafficking of normal and disease associated prion proteins. Mol Aspects Med 2018; 60: 62-8.
[] [PMID: 29196098]
Yuyama K, Igarashi Y. Exosomes as carriers of Alzheimer’s amyloid-ß. Front Neurosci 2017; 11: 229.
[] [PMID: 28487629]
Sardar Sinha M, Ansell-Schultz A, Civitelli L, et al. Alzheimer’s disease pathology propagation by exosomes containing toxic amyloid-beta oligomers. Acta Neuropathol 2018; 136(1): 41-56.
[] [PMID: 29934873]
Xitong D, Xiaorong Z. Targeted therapeutic delivery using engineered exosomes and its applications in cardiovascular diseases. Gene 2016; 575(2 Pt 2): 377-84.
[] [PMID: 26341056]
Rufino-Ramos D, Albuquerque PR, Carmona V, Perfeito R, Nobre RJ, Pereira de Almeida L. Extracellular vesicles: novel promising delivery systems for therapy of brain diseases. J Control Release 2017; 262: 247-58.
[] [PMID: 28687495]
Silva AK, Luciani N, Gazeau F, et al. Combining magnetic nanoparticles with cell derived microvesicles for drug loading and targeting. Nanomedicine (Lond) 2015; 11(3): 645-55.
[] [PMID: 25596340]
Lee HJ, Patel S, Lee SJ. Intravesicular localization and exocytosis of alpha-synuclein and its aggregates. J Neurosci 2005; 25(25): 6016-24.
[] [PMID: 15976091]
Desplats P, Lee HJ, Bae EJ, et al. Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein. Proc Natl Acad Sci USA 2009; 106(31): 13010-5.
[] [PMID: 19651612]
Shi M, Liu C, Cook TJ, et al. Plasma exosomal α-synuclein is likely CNS-derived and increased in Parkinson’s disease. Acta Neuropathol 2014; 128(5): 639-50.
[] [PMID: 24997849]
Alvarez-Erviti L, Seow Y, Schapira AH, et al. Lysosomal dysfunction increases exosome-mediated alpha-synuclein release and transmission. Neurobiol Dis 2011; 42(3): 360-7.
[] [PMID: 21303699]
Danzer KM, Kranich LR, Ruf WP, et al. Exosomal cell-to-cell transmission of alpha synuclein oligomers. Mol Neurodegener 2012; 7: 42.
[] [PMID: 22920859]
Chang C, Lang H, Geng N, Wang J, Li N, Wang X. Exosomes of BV-2 cells induced by alpha-synuclein: important mediator of neurodegeneration in PD. Neurosci Lett 2013; 548: 190-5.
[] [PMID: 23792198]
Kunadt M, Eckermann K, Stuendl A, et al. Extracellular vesicle sorting of α-Synuclein is regulated by sumoylation. Acta Neuropathol 2015; 129(5): 695-713.
[] [PMID: 25778619]
Grey M, Dunning CJ, Gaspar R, et al. Acceleration of α-synuclein aggregation by exosomes. J Biol Chem 2015; 290(5): 2969-82.
[] [PMID: 25425650]
Schultheis PJ, Hagen TT, O’Toole KK, et al. Characterization of the P5 subfamily of P-type transport ATPases in mice. Biochem Biophys Res Commun 2004; 323(3): 731-8.
[] [PMID: 15381061]
Williams DR, Hadeed A, al-Din AS, Wreikat AL, Lees AJ. Kufor Rakeb disease: autosomal recessive, levodopa-responsive Parkinsonism with pyramidal degeneration, supranuclear gaze palsy, and dementia. Mov Disord 2005; 20(10): 1264-71.
[] [PMID: 15986421]
Ramirez A, Heimbach A, Gründemann J, et al. Hereditary Parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase. Nat Genet 2006; 38(10): 1184-91.
[] [PMID: 16964263]
Gitler AD, Chesi A, Geddie ML, et al. Alpha-synuclein is part of a diverse and highly conserved interaction network that includes PARK9 and manganese toxicity. Nat Genet 2009; 41(3): 308-15.
[] [PMID: 19182805]
Ramonet D, Podhajska A, Stafa K, et al. PARK9-associated ATP13A2 localizes to intracellular acidic vesicles and regulates cation homeostasis and neuronal integrity. Hum Mol Genet 2012; 21(8): 1725-43.
[] [PMID: 22186024]
Kong SM, Chan BK, Park JS, et al. Parkinson’s disease-linked human PARK9/ATP13A2 maintains zinc homeostasis and promotes α-Synuclein externalization via exosomes. Hum Mol Genet 2014; 23(11): 2816-33.
[] [PMID: 24603074]
Phuyal S, Skotland T, Hessvik NP, et al. The ether lipid precursor hexadecylglycerol stimulates the release and changes the composition of exosomes derived from PC-3 cells. J Biol Chem 2015; 290(7): 4225-37.
[] [PMID: 25519911]
Krämer-Albers EM, Bretz N, Tenzer S, et al. Oligodendrocytes secrete exosomes containing major myelin and stress-protective proteins: trophic support for axons? Proteomics Clin Appl 2007; 1(11): 1446-61.
[] [PMID: 21136642]
Savina A, Furlán M, Vidal M, Colombo MI. Exosome release is regulated by a calcium-dependent mechanism in K562 cells. J Biol Chem 2003; 278(22): 20083-90.
[] [PMID: 12639953]
Hessvik NP, Llorente A. Current knowledge on exosome biogenesis and release. Cell Mol Life Sci 2018; 75(2): 193-208.
[] [PMID: 28733901]
Kilic T, Valinhas ATS, Wall I, Renaud P, Carrara S. Label-free detection of hypoxia-induced extracellular vesicle secretion from MCF-7 cells. Sci Rep 2018; 8(1): 9402.
[] [PMID: 29925885]
Rahman MJ, Regn D, Bashratyan R, Dai YD. Exosomes released by islet-derived mesenchymal stem cells trigger autoimmune responses in NOD mice. Diabetes 2014; 63(3): 1008-20.
[] [PMID: 24170696]
de Gonzalo-Calvo D, van der Meer RW, Rijzewijk LJ, et al. Serum microRNA-1 and microRNA-133a levels reflect myocardial steatosis in uncomplicated type 2 diabetes. Sci Rep 2017; 7(1): 47.
[] [PMID: 28246388]
Pironti G, Strachan RT, Abraham D, et al. Circulating exosomes induced by cardiac pressure overload contain functional angiotensin II Type 1 receptors. Circulation 2015; 131(24): 2120-30.
[] [PMID: 25995315]
Datta A, Kim H, McGee L, et al. High-throughput screening identified selective inhibitors of exosome biogenesis and secretion: a drug repurposing strategy for advanced cancer. Sci Rep 2018; 8(1): 8161.
[] [PMID: 29802284]
Németh A, Orgovan N, Sódar BW, et al. Antibiotic-induced release of small extracellular vesicles (exosomes) with surface-associated DNA. Sci Rep 2017; 7(1): 8202.
[] [PMID: 28811610]
De Gregorio F, Pellegrino M, Picchietti S, et al. The insecticide 1,1,1-trichloro-2,2-bis(p-chlorophenyl) ethane (DDT) alters the membrane raft location of the TSH receptor stably expressed in Chinese hamster ovary cells. Toxicol Appl Pharmacol 2011; 253(2): 121-9.
[] [PMID: 21466821]
Tamboli IY, Barth E, Christian L, et al. Statins promote the degradation of extracellular amyloid beta-peptide by microglia via stimulation of exosome-associated insulin-degrading enzyme (IDE) secretion. J Biol Chem 2010; 285(48): 37405-14.
[] [PMID: 20876579]
Saunderson SC, Schuberth PC, Dunn AC, et al. Induction of exosome release in primary B cells stimulated via CD40 and the IL-4 receptor. J Immunol 2008; 180(12): 8146-52.
[] [PMID: 18523279]
Li L, Jay SM, Wang Y, Wu SW, Xiao Z. IL-12 stimulates CTLs to secrete exosomes capable of activating bystander CD8+T cells. Sci Rep 2017; 7(1): 13365.
[] [PMID: 29042682]
Panigrahi GK, Praharaj PP, Peak TC, et al. Hypoxia-induced exosome secretion promotes survival of African-American and Caucasian prostate cancer cells. Sci Rep 2018; 8(1): 3853.
[] [PMID: 29497081]
Heathfield SK, Parker B, Zeef LA, Bruce IN, Alexander MY. Certolizumab pegol attenuates the pro-inflammatory state in endothelial cells in a manner that is atheroprotective. Clin Exp Rheumatol 2013; 31(2): 225-33.
[PMID: 23295110]
Badimon L, Suades R, Arderiu G, Peña E, Chiva-Blanch G, Padró T. Microvesicles in atherosclerosis and angiogenesis: from bench to bedside and reverse. Front Cardiovasc Med 2017; 4: 77.
[] [PMID: 29326946]
Chalmin F, Ladoire S, Mignot G, et al. Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells. J Clin Invest 2010; 120(2): 457-71.
[] [PMID: 20093776]
Chiva-Blanch G, Suades R, Padró T, et al. Microparticle shedding by erythrocytes, monocytes and vascular smooth muscular cells is reduced by aspirin in diabetic patients. Rev Esp Cardiol (Engl Ed) 2016; 69(7): 672-80.
[] [PMID: 27103451]
Rossi M, Taddei AR, Fasciani I, Maggio R, Giorgi F. The cell biology of the thyroid-disrupting mechanism of dichlorodiphenyltrichloroethane (DDT). J Endocrinol Invest 2018; 41(1): 67-73.
[] [PMID: 28639207]
Channa K, Röllin HB, Nøst TH, Odland JØ, Sandanger TM. Prenatal exposure to DDT in malaria endemic region following indoor residual spraying and in non-malaria coastal regions of South Africa. Sci Total Environ 2012; 429: 183-90.
[] [PMID: 22578843]
Dong K. Insect sodium channels and insecticide resistance. Invert Neurosci 2007; 7(1): 17-30.
[] [PMID: 17206406]
Rossi M, Dimida A, Dell’anno MT, et al. The thyroid disruptor 1,1,1-trichloro-2,2-bis(p-chlorophenyl)-ethane appears to be an uncompetitive inverse agonist for the thyrotropin receptor. J Pharmacol Exp Ther 2007; 320(1): 465-74.
[] [PMID: 17062616]
Rossi M, Dimida A, Ferrarini E, et al. Presence of a putative steroidal allosteric site on glycoprotein hormone receptors. Eur J Pharmacol 2009; 623(1-3): 155-9.
[] [PMID: 19766106]
Picchietti S, Belardinelli M, Taddei AR, et al. Thyroid disruptor 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT) prevents internalization of TSH receptor. Cell Tissue Res 2009; 336(1): 31-40.
[] [PMID: 19214582]
Buff K, Berndt J. Interaction of DDT (1,1,1-trichloro-2,2-bis(p-chlorophenyl)-ethane with liposomal phospholipids. Biochim Biophys Acta 1981; 643(1): 205-12.
[] [PMID: 7236688]
Antunes-Madeira MC, Madeira VM. Membrane fluidity as affected by the organochlorine insecticide DDT. Biochim Biophys Acta 1990; 1023(3): 469-74.
[] [PMID: 2334734]
Osborne MP. DDT, γ-HCH and the cyclodienes Comprehensive insect physiology biochemistry and pharmacology. Oxford: Pergamon Press 1985; pp. 131-82.
Williams CS, Chung RA. Ultrastructural effects of DDT on cells grown in vitro. J Environ Pathol Toxicol Oncol 1987; 7(3): 35-58.
[PMID: 3559916]
Von Bartheld CS, Altick AL. Multivesicular bodies in neurons: distribution, protein content, and trafficking functions. Prog Neurobiol 2011; 93(3): 313-40.
[] [PMID: 21216273]
Rossi M, Scarselli M, Fasciani I, Maggio R, Giorgi F. Dichlorodiphenyltrichloroethane (DDT) induced extracellular vesicle formation: a potential role in organochlorine increased risk of Parkinson’s disease. Acta Neurobiol Exp (Warsz) 2017; 77(2): 113-7.
[] [PMID: 28691715]
Fleming L, Mann JB, Bean J, Briggle T, Sanchez-Ramos JR. Parkinson’s disease and brain levels of organochlorine pesticides. Ann Neurol 1994; 36(1): 100-3.
[] [PMID: 7517654]
Chhillar N, Singh NK, Banerjee BD, et al. Organochlorine pesticide levels and risk of Parkinson’s disease in north Indian population. ISRN Neurol 2013; 2013371034
[] [PMID: 23936670]
Singh N, Chhillar N, Banerjee B, Bala K, Basu M, Mustafa M. Organochlorine pesticide levels and risk of Alzheimer’s disease in north Indian population. Hum Exp Toxicol 2013; 32(1): 24-30.
[] [PMID: 22899726]
Richardson JR, Roy A, Shalat SL, et al. Elevated serum pesticide levels and risk for Alzheimer disease. JAMA Neurol 2014; 71(3): 284-90.
[] [PMID: 24473795]
Chen A, Zhang J, Zhou L, et al. DDT serum concentration and menstruation among young Chinese women. Environ Res 2005; 99(3): 397-402.
[] [PMID: 16307982]
De Jager C, Farias P, Barraza-Villarreal A, et al. Reduced seminal parameters associated with environmental DDT exposure and p,p′-DDE concentrations in men in Chiapas, Mexico: a cross-sectional study. J Androl 2006; 27(1): 16-27.
[] [PMID: 16400073]
Pike LJ. Lipid rafts: bringing order to chaos. J Lipid Res 2003; 44(4): 655-67.
[] [PMID: 12562849]
He R, Yan X, Guo J, Xu Q, Tang B, Sun Q. Recent advances in biomarkers for Parkinson’s disease. Front Aging Neurosci 2018; 10: 305.
[] [PMID: 30364199]
Hughes AJ, Daniel SE, Ben-Shlomo Y, Lees AJ. The accuracy of diagnosis of Parkinsonian syndromes in a specialist movement disorder service. Brain 2002; 125(Pt 4): 861-70.
[] [PMID: 11912118]
Meara J, Bhowmick BK, Hobson P. Accuracy of diagnosis in patients with presumed Parkinson’s disease. Age Ageing 1999; 28(2): 99-102.
[] [PMID: 10350403]
Raposo G, Stoorvogel W. Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol 2013; 200(4): 373-83.
[] [PMID: 23420871]
Zhao ZH, Chen ZT, Zhou RL, Zhang X, Ye QY, Wang YZ. Increased DJ-1 and α-synuclein in plasma neural-derived exosomes as potential markers for Parkinson’s disease. Front Aging Neurosci 2019; 10: 438.
[] [PMID: 30692923]
Tofaris GK. A critical assessment of exosomes in the pathogenesis and stratification of Parkinson’s disease. J Parkinsons Dis 2017; 7(4): 569-76.
[] [PMID: 28922170]
Fraser KB, Moehle MS, Daher JP, et al. LRRK2 secretion in exosomes is regulated by 14-3-3. Hum Mol Genet 2013; 22(24): 4988-5000.
[] [PMID: 23886663]
Ho DH, Yi S, Seo H, Son I, Seol W. Increased DJ-1 in urine exosome of Korean males with Parkinson’s disease. BioMed Res Int 2014; 2014 704678
[] [PMID: 25478574]
Stuendl A, Kunadt M, Kruse N, et al. Induction of α-synuclein aggregate formation by CSF exosomes from patients with Parkinson’s disease and dementia with Lewy bodies. Brain 2016; 139(2): 481-94.
[] [PMID: 26647156]
Cao Z, Wu Y, Liu G, et al. α-Synuclein in salivary extracellular vesicles as a potential biomarker of Parkinson’s disease. Neurosci Lett 2019; 696: 114-20.
[] [PMID: 30579996]
Cerri S, Ghezzi C, Sampieri M, et al. The exosomal/total α-synuclein ratio in plasma is associated with glucocerebrosidase activity and correlates with measures of disease severity in PD patients. Front Cell Neurosci 2018; 12: 125.
[] [PMID: 29867358]
Fraser KB, Rawlins AB, Clark RG, et al. Parkinson’s disease biomarker program consortium. Ser(P)-1292 LRRK2 in urinary exosomes is elevated in idiopathic Parkinson’s disease. Mov Disord 2016; 31(10): 1543-50.
[] [PMID: 27297049]
Shi M, Kovac A, Korff A, et al. CNS tau efflux via exosomes is likely increased in Parkinson’s disease but not in Alzheimer’s disease. Alzheimers Dement 2016; 12(11): 1125-31.
[] [PMID: 27234211]
Ohmichi T, Mitsuhashi M, Tatebe H, Kasai T, Ali El-Agnaf OM, Tokuda T. Quantification of brain-derived extracellular vesicles in plasma as a biomarker to diagnose Parkinson’s and related diseases. Parkinsonism Relat Disord 2019; 61: 82-7.
[] [PMID: 30502924]
Yao YF, Qu MW, Li GC, Zhang FB, Rui HC. Circulating exosomal miRNAs as diagnostic biomarkers in Parkinson’s disease. Eur Rev Med Pharmacol Sci 2018; 22(16): 5278-83.
[PMID: 30178852]
Gui Y, Liu H, Zhang L, Lv W, Hu X. Altered microRNA profiles in cerebrospinal fluid exosome in Parkinson disease and Alzheimer disease. Oncotarget 2015; 6(35): 37043-53.
[] [PMID: 26497684]
Tang K, Zhang Y, Zhang H, et al. Delivery of chemotherapeutic drugs in tumour cell-derived microparticles. Nat Commun 2012; 3: 1282.
[] [PMID: 23250412]
Dias V, Junn E, Mouradian MM. The role of oxidative stress in Parkinson’s disease. J Parkinsons Dis 2013; 3(4): 461-91.
[PMID: 24252804]
Yan MH, Wang X, Zhu X. Mitochondrial defects and oxidative stress in Alzheimer disease and Parkinson disease. Free Radic Biol Med 2013; 62: 90-101.
[] [PMID: 23200807]
Youdim MB, Edmondson D, Tipton KF. The therapeutic potential of monoamine oxidase inhibitors. Nat Rev Neurosci 2006; 7(4): 295-309.
[] [PMID: 16552415]
Nagatsu T, Sawada M. Molecular mechanism of the relation of monoamine oxidase B inhibitors to Parkinson’s disease: possible implications of glial cells. J Neural Transm (Vienna) 2006; 71: 53-65.
Kumar MJ, Andersen JK. Perspectives on MAO-B in aging and neurological disease: where do we go from here? Mol Neurobiol 2004; 30(1): 77-89.
[] [PMID: 15247489]
Hastings TG. Enzymatic oxidation of dopamine: the role of prostaglandin H synthase. J Neurochem 1995; 64(2): 919-24.
[] [PMID: 7830086]
Graham DG. Oxidative pathways for catecholamines in the genesis of neuromelanin and cytotoxic quinones. Mol Pharmacol 1978; 14(4): 633-43.
[PMID: 98706]
Valadi H, Ekström K, Bossios A, Sjöstrand M, Lee JJ, Lötvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 2007; 9(6): 654-9.
[] [PMID: 17486113]
Eldh M, Ekström K, Valadi H, et al. Exosomes communicate protective messages during oxidative stress; possible role of exosomal shuttle RNA. PLoS One 2010; 5(12) e15353
[] [PMID: 21179422]
Haney MJ, Klyachko NL, Zhao Y, et al. Exosomes as drug delivery vehicles for Parkinson’s disease therapy. J Control Release 2015; 207: 18-30.
[] [PMID: 25836593]
Jin H, Kanthasamy A, Ghosh A, Anantharam V, Kalyanaraman B, Kanthasamy AG. Mitochondria-targeted antioxidants for treatment of Parkinson’s disease: preclinical and clinical outcomes. Biochim Biophys Acta 2014; 1842(8): 1282-94.
[] [PMID: 24060637]
Ambani LM, Van Woert MH, Murphy S. Brain peroxidase and catalase in Parkinson disease. Arch Neurol 1975; 32(2): 114-8.
[] [PMID: 1122174]
Abraham S, Soundararajan CC, Vivekanandhan S, Behari M. Erythrocyte antioxidant enzymes in Parkinson’s disease. Indian J Med Res 2005; 121(2): 111-5.
[PMID: 15756044]
Pardridge WM. Drug transport across the blood-brain barrier. J Cereb Blood Flow Metab 2012; 32(11): 1959-72.
[] [PMID: 22929442]
Dauer W, Przedborski S. Parkinson’s disease: mechanisms and models. Neuron 2003; 39(6): 889-909.
[] [PMID: 12971891]
Carlsson T, Björklund T, Kirik D. Restoration of the striatal dopamine synthesis for Parkinson’s disease: viral vector-mediated enzyme replacement strategy. Curr Gene Ther 2007; 7(2): 109-20.
[] [PMID: 17430130]
Connolly BS, Lang AE. Pharmacological treatment of Parkinson disease: a review. JAMA 2014; 311(16): 1670-83.
[] [PMID: 24756517]
Krishna R, Ali M, Moustafa AA. Effects of combined MAO-B inhibitors and levodopa vs. monotherapy in Parkinson’s disease. Front Aging Neurosci 2014; 6: 180.
[] [PMID: 25120478]
Maggio R, Scarselli M, Capannolo M, Millan MJ. Novel dimensions of D3 receptor function: Focus on heterodimerisation, transactivation and allosteric modulation. Eur Neuropsychopharmacol 2015; 25(9): 1470-9.
[] [PMID: 25453482]
Stremersch S, De Smedt S C, Raemdonck K. Therapeutic and diagnostic applications of extracellular vesicles J Control Release 2016; 244(PartB): 167-83.
Qu M, Lin Q, Huang L, et al. Dopamine-loaded blood exosomes targeted to brain for better treatment of Parkinson’s disease. J Control Release 2018; 287: 156-66.
[] [PMID: 30165139]
Keshtkar S, Azarpira N, Ghahremani MH. Mesenchymal stem cell-derived extracellular vesicles: novel frontiers in regenerative medicine. Stem Cell Res Ther 2018; 9(1): 63.
[] [PMID: 29523213]
Dominici M, Le Blanc K, Mueller I, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006; 8(4): 315-7.
[] [PMID: 16923606]
Chamberlain G, Fox J, Ashton B, Middleton J. Concise review: mesenchymal stem cells: their phenotype, differentiation capacity, immunological features, and potential for homing. Stem Cells 2007; 25(11): 2739-49.
[] [PMID: 17656645]
Phinney DG. Biochemical heterogeneity of mesenchymal stem cell populations: clues to their therapeutic efficacy. Cell Cycle 2007; 6(23): 2884-9.
[] [PMID: 18000405]
Teixeira FG, Carvalho MM, Neves-Carvalho A, et al. Secretome of mesenchymal progenitors from the umbilical cord acts as modulator of neural/glial proliferation and differentiation. Stem Cell Rev Rep 2015; 11(2): 288-97.
[] [PMID: 25420577]
Gao F, Chiu SM, Motan DA, et al. Mesenchymal stem cells and immunomodulation: current status and future prospects. Cell Death Dis 2016; 7 e2062
[] [PMID: 26794657]
Longoni B, Mosca F. Stem cell-based immunomodulation in type 1 diabetes: beyond the regenerative approach. Curr Pharm Des 2011; 17(29): 3229-42.
[] [PMID: 21864271]
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(6): 933-46.
[] [PMID: 21082892]
Vittorio O, Quaranta P, Raffa V, et al. Magnetic carbon nanotubes: a new tool for shepherding mesenchymal stem cells by magnetic fields. Nanomedicine (Lond) 2011; 6(1): 43-54.
[] [PMID: 21182417]
Marote A, Teixeira FG, Mendes-Pinheiro B, Salgado AJ. MSCs-derived exosomes: cell-secreted nanovesicles with regenerative potential. Front Pharmacol 2016; 7: 231.
[] [PMID: 27536241]
Teixeira FG, Carvalho MM, Sousa N, Salgado AJ. Mesenchymal stem cells secretome: a new paradigm for central nervous system regeneration? Cell Mol Life Sci 2013; 70(20): 3871-82.
[] [PMID: 23456256]
Salgado AJ, Sousa JC, Costa BM, et al. Mesenchymal stem cells secretome as a modulator of the neurogenic niche: basic insights and therapeutic opportunities. Front Cell Neurosci 2015; 9: 249.
[] [PMID: 26217178]
Konala VB, Mamidi MK, Bhonde R, Das AK, Pochampally R, Pal R. The current landscape of the mesenchymal stromal cell secretome: a new paradigm for cell-free regeneration. Cytotherapy 2016; 18(1): 13-24.
[] [PMID: 26631828]
Martins LF, Costa RO, Pedro JR, et al. Mesenchymal stem cells secretome-induced axonal outgrowth is mediated by BDNF. Sci Rep 2017; 7(1): 4153.
[] [PMID: 28646200]
Sarugaser R, Lickorish D, Baksh D, Hosseini MM, Davies JE. Human umbilical cord perivascular (HUCPV) cells: a source of mesenchymal progenitors. Stem Cells 2005; 23(2): 220-9.
[] [PMID: 15671145]
Jarmalavičiūtė A, Tunaitis V, Pivoraitė U, Venalis A, Pivoriūnas A. Exosomes from dental pulp stem cells rescue human dopaminergic neurons from 6-hydroxy-dopamine-induced apoptosis. Cytotherapy 2015; 17(7): 932-9.
[] [PMID: 25981557]
Lotharius J, Dugan LL, O’Malley KL. Distinct mechanisms underlie neurotoxin-mediated cell death in cultured dopaminergic neurons. J Neurosci 1999; 19(4): 1284-93.
[] [PMID: 9952406]
Nosrat IV, Smith CA, Mullally P, Olson L, Nosrat CA. Dental pulp cells provide neurotrophic support for dopaminergic neurons and differentiate into neurons in vitro; implications for tissue engineering and repair in the nervous system. Eur J Neurosci 2004; 19(9): 2388-98.
[] [PMID: 15128393]
Donato R, Miljan EA, Hines SJ, et al. Differential development of neuronal physiological responsiveness in two human neural stem cell lines. BMC Neurosci 2007; 8: 36.
[] [PMID: 17531091]
Alvarez-Erviti L, Seow Y, Yin H, Betts C, Lakhal S, Wood MJ. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol 2011; 29(4): 341-5.
[] [PMID: 21423189]
Narbute K, Piļipenko V, Pupure J, et al. 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. Stem Cells Transl Med 2019; 8(5): 490-9.
[] [PMID: 30706999]
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.
[] [PMID: 25698603]
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.
[] [PMID: 24613235]
Teixeira FG, Carvalho MM, Panchalingam KM, et al. Impact of the secretome of human mesenchymal stem cells on brain structure and animal behavior in a rat model of Parkinson’s disease. Stem Cells Transl Med 2017; 6(2): 634-46.
[] [PMID: 28191785]
Teixeira FG, Panchalingam KM, Assunção-Silva R, et al. Modulation of the mesenchymal stem cell secretome using computer-controlled bioreactors: impact on neuronal cell proliferation, survival and differentiation. Sci Rep 2016; 6: 27791.
[] [PMID: 27301770]

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Published on: 07 January, 2020
Page: [4510 - 4522]
Pages: 13
DOI: 10.2174/1381612825666191113103537
Price: $65

Article Metrics

PDF: 39
HTML: 10