title: Therapeutic efficacy of intranasally delivered mesenchymal stem cells in a rat model of Parkinson disease.
abstract: Safe and effective cell delivery remains one of the main challenges in cell-based therapy of neurodegenerative disorders. Graft survival, sufficient enrichment of therapeutic cells in the brain, and avoidance of their distribution throughout the peripheral organs are greatly influenced by the method of delivery. Here we demonstrate for the first time noninvasive intranasal (IN) delivery of mesenchymal stem cells (MSCs) to the brains of unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rats. IN application (INA) of MSCs resulted in the appearance of cells in the olfactory bulb, cortex, hippocampus, striatum, cerebellum, brainstem, and spinal cord. Out of 1 × 10⁶ MSCs applied intranasally, 24% survived for at least 4.5 months in the brains of 6-OHDA rats as assessed by quantification of enhanced green fluorescent protein (EGFP) DNA. Quantification of proliferating cell nuclear antigen-positive EGFP-MSCs showed that 3% of applied MSCs were proliferative 4.5 months after application. INA of MSCs increased the tyrosine hydroxylase level in the lesioned ipsilateral striatum and substantia nigra, and completely eliminated the 6-OHDA-induced increase in terminal deoxynucleotidyl transferase (TdT)-mediated 2'-deoxyuridine, 5'-triphosphate (dUTP)-biotin nick end labeling (TUNEL) staining of these areas. INA of EGFP-labeled MSCs prevented any decrease in the dopamine level in the lesioned hemisphere, whereas the lesioned side of the control animals revealed significantly lower levels of dopamine 4.5 months after 6-OHDA treatment. Behavioral analyses revealed significant and substantial improvement of motor function of the Parkinsonian forepaw to up to 68% of the normal value 40-110 days after INA of 1 × 10⁶ cells. MSC-INA decreased the concentrations of inflammatory cytokines-interleukin-1β (IL-1β), IL-2, -6, -12, tumor necrosis factor (TNF), interferon-γ (IFN-γ, and granulocyte-macrophage colony-stimulating factor (GM-CSF)-in the lesioned side to their levels in the intact hemisphere. IN administration provides a highly promising noninvasive alternative to the traumatic surgical procedure of transplantation and allows targeted delivery of cells to the brain with the option of chronic application.
authors.affiliation: Department of Clinical Pharmacology, University Hospital of Tübingen, Tübingen, Germany. lusine.danielyan@med.uni-tuebingen.de
authors.forename: Lusine
authors.initials: L
authors.lastname: Danielyan
authors.forename: Richard
authors.initials: R
authors.lastname: Schäfer
authors.forename: Andreas
authors.initials: A
authors.lastname: von Ameln-Mayerhofer
authors.forename: Felix
authors.initials: F
authors.lastname: Bernhard
authors.forename: Stephan
authors.initials: S
authors.lastname: Verleysdonk
authors.forename: Marine
authors.initials: M
authors.lastname: Buadze
authors.forename: Ali
authors.initials: A
authors.lastname: Lourhmati
authors.forename: Tim
authors.initials: T
authors.lastname: Klopfer
authors.forename: Felix
authors.initials: F
authors.lastname: Schaumann
authors.forename: Barbara
authors.initials: B
authors.lastname: Schmid
authors.forename: Christoph
authors.initials: C
authors.lastname: Koehle
authors.forename: Barbara
authors.initials: B
authors.lastname: Proksch
authors.forename: Robert
authors.initials: R
authors.lastname: Weissert
authors.forename: Holger M
authors.initials: HM
authors.lastname: Reichardt
authors.forename: Jens
authors.initials: J
authors.lastname: van den Brandt
authors.forename: Gayane H
authors.initials: GH
authors.lastname: Buniatian
authors.forename: Matthias
authors.initials: M
authors.lastname: Schwab
authors.forename: Christoph H
authors.initials: CH
authors.lastname: Gleiter
authors.forename: William H
authors.initials: WH
authors.lastname: Frey
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation; D004195:Disease Models, Animal; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007378:Interleukins / Q000378:metabolism; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D017072:Neostriatum / Q000201:enzymology / Q000473:pathology; D016627:Oxidopamine; D010300:Parkinson Disease / Q000628:therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000201:enzymology / Q000473:pathology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D007378:Interleukins; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase