title: Intracarotid Infusion of Mesenchymal Stem Cells in an Animal Model of Parkinson's Disease, Focusing on Cell Distribution and Neuroprotective and Behavioral Effects.
abstract: Mesenchymal stem cells (MSCs) have been proposed as a potential therapeutic tool for Parkinson's disease (PD) and systemic administration of these cells has been tested in preclinical and clinical studies. However, no information on survival and actual capacity of MSCs to reach the brain has been provided. In this study, we evaluated homing of intraarterially infused rat MSCs (rMSCs) in the brain of rats bearing a 6-hydroxydopamine (6-OHDA)-induced lesion of the nigrostriatal tract, to establish whether the toxin-induced damage is sufficient to grant MSC passage across the blood-brain barrier (BBB) or if a transient BBB disruption is necessary. The rMSC distribution in peripheral organs and the effects of cell infusion on neurodegenerative process and motor deficits were also investigated. rMSCs were infused 14 days after 6-OHDA injection. A hyperosmolar solution of mannitol was used to transiently permeabilize the BBB. Behavioral impairment was assessed by adjusting step test and response to apomorphine. Animals were sacrificed 7 and 28 days after cell infusion. Our work shows that appreciable delivery of rMSCs to the brain of 6-OHDA-lesioned animals can be obtained only after mannitol pretreatment. A notable percentage of infused cells accumulated in peripheral organs. Infusion of rMSCs did not modify the progression of 6-OHDA-induced damage or the motor impairment at the stepping test, but induced progressive normalization of the pathological response (contralateral turning) to apomorphine administration. These findings suggest that many aspects should be further investigated before considering any translation of MSC systemic administration into the clinical setting for PD treatment.
  
  
  CONCLUSIONS
  This study demonstrates that mesenchymal stem cells infused through the carotid artery do not efficiently cross the blood-brain barrier in rats with a Parkinson's disease-like degeneration of nigrostriatal neurons, unless a permeabilizing agent (e.g., mannitol) is used. The infusion did not reduce the neuronal damage and associated motor impairment, but abolished the motor abnormalities these animals typically show when challenged with a dopaminergic agonist. Therefore, although arterially infused mesenchymal stem cells did not show neurorestorative effects in this study's Parkinson's disease model, they appeared to normalize the pathological responsiveness of striatal neurons to dopaminergic stimulation. This capability should be further explored in future studies.
authors.affiliation: Laboratory of Functional Neurochemistry, Center for Research in Neurodegenerative Diseases, and Laboratory of Neurophysiology of Integrative Autonomic Systems, "C. Mondino" National Neurological Institute, Pavia, Italy; Immunology and Transplantation Laboratory/Cell Factory/Pediatric Hematology/Oncology Department, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Cerri
authors.affiliation: Laboratory of Functional Neurochemistry, Center for Research in Neurodegenerative Diseases, and Laboratory of Neurophysiology of Integrative Autonomic Systems, "C. Mondino" National Neurological Institute, Pavia, Italy; Immunology and Transplantation Laboratory/Cell Factory/Pediatric Hematology/Oncology Department, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
authors.forename: Rosaria
authors.initials: R
authors.lastname: Greco
authors.affiliation: Laboratory of Functional Neurochemistry, Center for Research in Neurodegenerative Diseases, and Laboratory of Neurophysiology of Integrative Autonomic Systems, "C. Mondino" National Neurological Institute, Pavia, Italy; Immunology and Transplantation Laboratory/Cell Factory/Pediatric Hematology/Oncology Department, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Levandis
authors.affiliation: Laboratory of Functional Neurochemistry, Center for Research in Neurodegenerative Diseases, and Laboratory of Neurophysiology of Integrative Autonomic Systems, "C. Mondino" National Neurological Institute, Pavia, Italy; Immunology and Transplantation Laboratory/Cell Factory/Pediatric Hematology/Oncology Department, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Ghezzi
authors.affiliation: Laboratory of Functional Neurochemistry, Center for Research in Neurodegenerative Diseases, and Laboratory of Neurophysiology of Integrative Autonomic Systems, "C. Mondino" National Neurological Institute, Pavia, Italy; Immunology and Transplantation Laboratory/Cell Factory/Pediatric Hematology/Oncology Department, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
authors.forename: Antonina Stefania
authors.initials: AS
authors.lastname: Mangione
authors.affiliation: Laboratory of Functional Neurochemistry, Center for Research in Neurodegenerative Diseases, and Laboratory of Neurophysiology of Integrative Autonomic Systems, "C. Mondino" National Neurological Institute, Pavia, Italy; Immunology and Transplantation Laboratory/Cell Factory/Pediatric Hematology/Oncology Department, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
authors.forename: Marie-Therese
authors.initials: MT
authors.lastname: Fuzzati-Armentero
authors.affiliation: Laboratory of Functional Neurochemistry, Center for Research in Neurodegenerative Diseases, and Laboratory of Neurophysiology of Integrative Autonomic Systems, "C. Mondino" National Neurological Institute, Pavia, Italy; Immunology and Transplantation Laboratory/Cell Factory/Pediatric Hematology/Oncology Department, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
authors.forename: Arianna
authors.initials: A
authors.lastname: Bonizzi
authors.affiliation: Laboratory of Functional Neurochemistry, Center for Research in Neurodegenerative Diseases, and Laboratory of Neurophysiology of Integrative Autonomic Systems, "C. Mondino" National Neurological Institute, Pavia, Italy; Immunology and Transplantation Laboratory/Cell Factory/Pediatric Hematology/Oncology Department, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
authors.forename: Maria Antonietta
authors.initials: MA
authors.lastname: Avanzini
authors.affiliation: Laboratory of Functional Neurochemistry, Center for Research in Neurodegenerative Diseases, and Laboratory of Neurophysiology of Integrative Autonomic Systems, "C. Mondino" National Neurological Institute, Pavia, Italy; Immunology and Transplantation Laboratory/Cell Factory/Pediatric Hematology/Oncology Department, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Maccario
authors.affiliation: Laboratory of Functional Neurochemistry, Center for Research in Neurodegenerative Diseases, and Laboratory of Neurophysiology of Integrative Autonomic Systems, "C. Mondino" National Neurological Institute, Pavia, Italy; Immunology and Transplantation Laboratory/Cell Factory/Pediatric Hematology/Oncology Department, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy fabio.blandini@mondino.it.
authors.forename: Fabio
authors.initials: F
authors.lastname: Blandini
mesh_terms: D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects*; D001812:Blood-Brain Barrier / Q000187:drug effects; D002339:Carotid Arteries; D002452:Cell Count; D058948:Cell Tracking; D003342:Corpus Striatum / Q000187:drug effects* / Q000473:pathology; D004195:Disease Models, Animal; D018491:Dopamine Agonists / Q000494:pharmacology; D007269:Injections, Intra-Arterial; D007276:Injections, Intraventricular; D008297:Male; D008353:Mannitol / Q000494:pharmacology; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000502:physiology*; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D009994:Osmolar Concentration; D016627:Oxidopamine / Q000633:toxicity; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D010539:Permeability / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar
chemical_list: D018491:Dopamine Agonists; D008353:Mannitol; D016627:Oxidopamine; D001058:Apomorphine
keywords: Behavioral analyses; Intracarotid infusion; Mannitol; Mesenchymal stem cells; Neuroprotection; Parkinson’s disease