title: Morphological Changes in a Severe Model of Parkinson's Disease and Its Suitability to Test the Therapeutic Effects of Microencapsulated Neurotrophic Factors.
abstract: The unilateral 6-hydroxydopamine (6-OHDA) lesion of medial forebrain bundle (MFB) in rats affords us to study the advanced stages of Parkinson's disease (PD). Numerous evidences suggest synergic effects when various neurotrophic factors are administered in experimental models of PD. The aim of the present work was to assess the morphological changes along the rostro-caudal axis of caudo-putamen complex and substantia nigra (SN) in the referred model in order to test the suitability of a severe model to evaluate new neurorestorative therapies. Administration of 6-OHDA into MFB in addition to a remarkable depletion of dopamine in the nigrostriatal system induced an increase of glial fibrillary acidic protein (GFAP)-positive cells in SN and an intense immunoreactivity for OX-42, vascular endothelial growth factor (VEGF), and Lycopersycum esculentum agglutinin (LEA) in striatum and SN. Tyrosine hydroxylase (TH) immunostaining revealed a significant decrease of the TH-immunopositive striatal volume in 6-OHDA group from rostral to caudal one. The loss of TH-immunoreactive (TH-ir) neurons and axodendritic network (ADN) was higher in caudal sections. Morphological recovery after the implantation of microspheres loaded with VEGF and glial cell line-derived neurotrophic factor (GDNF) in parkinsonized rats was related to the preservation of the TH-ir cell number and ADN in the caudal region of the SN. In addition, these findings support the neurorestorative role of VEGF+GDNF in the dopaminergic system and the synergistic effect between both factors. On the other hand, a topological distribution of the dopaminergic system was noticeable in the severe model, showing a selective vulnerability to 6-OHDA and recovering after treatment.
authors.affiliation: Laboratory of Clinical and Experimental Neuroscience (LaNCE), Department of Neuroscience, University of the Basque Country UPV/EHU, Leioa, Vizcaya, Spain. catalina.requejo@ehu.eus.
authors.forename: C
authors.identifier: http://orcid.org/0000-0002-5440-5455
authors.initials: C
authors.lastname: Requejo
authors.affiliation: Department of Pharmacology, University of the Basque Country (UPV/EHU), Leioa, Vizcaya, Spain.
authors.forename: J A
authors.initials: JA
authors.lastname: Ruiz-Ortega
authors.affiliation: Laboratory of Clinical and Experimental Neuroscience (LaNCE), Department of Neuroscience, University of the Basque Country UPV/EHU, Leioa, Vizcaya, Spain.
authors.forename: H
authors.initials: H
authors.lastname: Bengoetxea
authors.affiliation: Laboratory of Clinical and Experimental Neuroscience (LaNCE), Department of Neuroscience, University of the Basque Country UPV/EHU, Leioa, Vizcaya, Spain.
authors.forename: A
authors.initials: A
authors.lastname: García-Blanco
authors.affiliation: NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV/EHU), Vitoria, Alava, Spain.|Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Vitoria, Alava, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Herrán
authors.affiliation: Department of Pharmacology, University of the Basque Country (UPV/EHU), Leioa, Vizcaya, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Aristieta
authors.affiliation: NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV/EHU), Vitoria, Alava, Spain.|Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Vitoria, Alava, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Igartua
authors.affiliation: NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV/EHU), Vitoria, Alava, Spain.|Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Vitoria, Alava, Spain.
authors.forename: J L
authors.initials: JL
authors.lastname: Pedraz
authors.affiliation: Department of Pharmacology, University of the Basque Country (UPV/EHU), Leioa, Vizcaya, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Ugedo
authors.affiliation: NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV/EHU), Vitoria, Alava, Spain.|Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Vitoria, Alava, Spain.
authors.forename: R M
authors.initials: RM
authors.lastname: Hernández
authors.affiliation: Laboratory of Clinical and Experimental Neuroscience (LaNCE), Department of Neuroscience, University of the Basque Country UPV/EHU, Leioa, Vizcaya, Spain.|Group Nanoneurosurgery, Institute of Health Research Biocruces, Barakaldo, Spain.|Faculty of Health Science, Universidad Autónoma de Chile, Santiago de Chile, Chile.
authors.forename: J V
authors.initials: JV
authors.lastname: Lafuente
mesh_terms: D000818:Animals; D004339:Drug Compounding / Q000379:methods; D005260:Female; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000008:administration & dosage*; D018696:Neuroprotective Agents / Q000008:administration & dosage; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012720:Severity of Illness Index; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage*
chemical_list: D051100:Glial Cell Line-Derived Neurotrophic Factor; D018696:Neuroprotective Agents; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat
keywords: 6-OHDA; GDNF; Neuroregeneration; Parkinson’s disease; Rostro-caudal gradient; VEGF