Overexpression of neurotrophic factors in nigral dopamine neurons is a promising approach to reverse neurodegeneration of the nigrostriatal dopamine system, a hallmark in Parkinson's disease. The human cerebral dopamine neurotrophic factor (hCDNF) has recently emerged asa strong candidate for Parkinson's disease therapy. This study shows that hCDNF expression in dopamine neurons using the neurotensin-polyplex nanoparticle system reverses 6-hydroxydopamine-induced morphological, biochemical, and behavioral alterations. Three independent electron microscopy techniques showed that the neurotensin-polyplex nanoparticles containing the hCDNF gene, ranging in size from 20 to 150 nm, enabled the expression of a secretable hCDNF in vitro. Their injection in the substantia nigra compacta on day 21 after the 6-hydroxydopamine lesion resulted in detectable hCDNF in dopamine neurons, whose levels remained constant throughout the study in the substantia nigra compacta and striatum. Compared with the lesioned group, tyrosine hydroxylase-positive (TH+) nigral cell population and TH+ fiber density rose in the substantia nigra compacta and striatum after hCDNF transfection. An increase in βIII-tubulin and growth-associated protein 43 phospho-S41 (GAP43p) followed TH+ cell recovery, as well as dopamine and its catabolite levels. Partial reversal (80％) of drug-activated circling behavior and full recovery of spontaneous motor and non-motor behavior were achieved. Brain-derived neurotrophic factor recovery in dopamine neurons that also occurred suggests its participation in the neurotrophic effects. These findings support the potential of nanoparticle-mediated hCDNF gene delivery to develop a disease-modifying treatment against Parkinson's disease. The Institutional Animal Care and Use Committee of Centro de Investigación y de Estudios Avanzados approved our experimental procedures for animal use (authorization No. 162-15) on June 9, 2019.

Manuel A.Fernandez-Parrilla

Departamento de Fisiología,Biofísica y Neurociencias,Centro de Investigación y de Estudios Avanzados,Ciudad de México,México;Programa Institucional de Biomedicina Molecular,Escuela Nacional de Medicina y Homeopatía,Instituto Politécnico Nacional,Ciudad de México,México;Department of Biosciences,IIIT-Srikakulam,Rajiv Gandhi University of Knowledge Technologies(RGUKT),Andhra Pradesh,India;Department of Pharmacology,Wayne State University School of Medicine,Detroit,MI,USA;Departamento de Física,Centro de Investigación y de Estudios Avanzados,Ciudad de México,México;Facultad de Estudios Superiores Iztacala,Universidad Nacional Autónoma de México,Tlalnepantla de Baz,Edo.de México,México;Departamento de Fisiología,Escuela Nacional de Ciencias Biológicas,Ciudad de México,México;Laboratorio de Medicina Genómica,Hospital Regional"1°de Octubre",ISSSTE,Ciudad de México,México;Laboratorio de Neuropsiquiatría,Instituto de Fisiología,Benemérita Universidad Autónoma de Puebla,Puebla,Puebla,México;Departamento de Biociencias e Ingeniería,Centro Interdisciplinario de Investigaciones y Estudios sobre Medio Ambiente y Desarrollo,Instituto Politécnico Nacional,Ciudad de México,México;Programa de Nanociencias y nanotecnología,Centro de Investigación y de Estudios Avanzados,Ciudad de México,México

中国神经再生研究（英文版）

[1]Manuel A.Fernandez-Parrilla-.Cerebral dopamine neurotrophic factor transfection in dopamine neurons using neurotensin-polyplex nanoparticles reverses 6-hydroxydopamine-induced nigrostriatal neurodegeneration)[J].中国神经再生研究（英文版）,2022(04):854-866

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