Increased antiparkinson efficacy of the combined administration of VEGF- and GDNF-loaded nanospheres in a partial lesion model of Parkinson’s disease

Abstract

Enara Herrán,1,2 Catalina Requejo,3 Jose Angel Ruiz-Ortega,4 Asier Aristieta,4 Manoli Igartua,1,2 Harkaitz Bengoetxea,3 Luisa Ugedo,4 Jose Luis Pedraz,1,2 Jose Vicente Lafuente,3 Rosa Maria Hernández1,2 1NanoBioCel Group, Laboratory of Pharmaceutics, University of the Basque Country (UPV/EHU), School of Pharmacy, Vitoria, Spain; 2Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Vitoria, Spain; 3LaNCE, Department of Neurosciences, University of the Basque Country (UPV/EHU), Leioa, Spain; 4Department of Pharmacology, University of the Basque Country (UPV/EHU), Leioa, Spain Abstract: Current research efforts are focused on the application of growth factors, such as glial cell line-derived neurotrophic factor (GDNF) and vascular endothelial growth factor (VEGF), as neuroregenerative approaches that will prevent the neurodegenerative process in Parkinson’s disease. Continuing a previous work published by our research group, and with the aim to overcome different limitations related to growth factor administration, VEGF and GDNF were encapsulated in poly(lactic-co-glycolic acid) nanospheres (NS). This strategy facilitates the combined administration of the VEGF and GDNF into the brain of 6-hydroxydopamine (6-OHDA) partially lesioned rats, resulting in a continuous and simultaneous drug release. The NS particle size was about 200 nm and the simultaneous addition of VEGF NS and GDNF NS resulted in significant protection of the PC-12 cell line against 6-OHDA in vitro. Once the poly(lactic-co-glycolic acid) NS were implanted into the striatum of 6-OHDA partially lesioned rats, the amphetamine rotation behavior test was carried out over 10 weeks, in order to check for in vivo efficacy. The results showed that VEGF NS and GDNF NS significantly decreased the ­number of amphetamine-induced rotations at the end of the study. In addition, tyrosine hydroxylase immunohistochemical analysis in the striatum and the external substantia nigra confirmed a significant enhancement of neurons in the VEGF NS and GDNF NS treatment group. The synergistic effect of VEGF NS and GDNF NS allows for a reduction of the dose by half, and may be a valuable neurogenerative/neuroreparative approach for treating Parkinson’s disease. Keywords: nanoparticles, PLGA, 6-OHDA, neuroregeneration, neurotrophic factors, tyrosine hydroxylase