Cerebral dopamine neurotrophic factor transfection in dopamine neurons using neurotensin-polyplex nanoparticles reverses 6-hydroxydopamine-induced nigrostriatal neurodegeneration  

作　　者：Manuel A.Fernandez-Parrilla David Reyes-Corona Yazmin M.Flores-Martinez Rasajna Nadella Michael J.Bannon Lourdes Escobedo Minerva Maldonado-Berny Jaime Santoyo-Salazar Luis O.Soto-Rojas Claudia Luna-Herrera Jose Ayala-Davila Juan A.Gonzalez-Barrios Gonzalo Flores Maria E.Gutierrez-Castillo Armando JEspadas-Alvarez Irma A.Martínez-Dávila Porfirio Nava Daniel Martinez-Fong 

机构地区：[1]Departamento de Fisiología,Biofísica y Neurociencias,Centro de Investigación y de Estudios Avanzados,Ciudad de México,México [2]Programa Institucional de Biomedicina Molecular,Escuela Nacional de Medicina y Homeopatía,Instituto Politécnico Nacional,Ciudad de México,México [3]Department of Biosciences,IIIT-Srikakulam,Rajiv Gandhi University of Knowledge Technologies(RGUKT),Andhra Pradesh,India [4]Department of Pharmacology,Wayne State University School of Medicine,Detroit,MI,USA [5]Departamento de Física,Centro de Investigación y de Estudios Avanzados,Ciudad de México,México [6]Facultad de Estudios Superiores Iztacala,Universidad Nacional Autónoma de México,Tlalnepantla de Baz,Edo.de México,México [7]Departamento de Fisiología,Escuela Nacional de Ciencias Biológicas,Ciudad de México,México [8]Laboratorio de Medicina Genómica,Hospital Regional“1°de Octubre”,ISSSTE,Ciudad de México,México [9]Laboratorio de Neuropsiquiatría,Instituto de Fisiología,Benemérita Universidad Autónoma de Puebla,Puebla,Puebla,México [10]Departamento de Biociencias e Ingeniería,Centro Interdisciplinario de Investigaciones y Estudios sobre Medio Ambiente y Desarrollo,Instituto Politécnico Nacional,Ciudad de México,México [11]Programa de Nanociencias y nanotecnología,Centro de Investigación y de Estudios Avanzados,Ciudad de México,México

出　　处：《Neural Regeneration Research》2022年第4期854-866,共13页中国神经再生研究（英文版）

基　　金：supported by the Consejo Nacional de Ciencia Tecnología(Conacyt)de México(Grant#254686,to DMF)。

摘　　要：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(h CDNF)has recently emerged as a strong candidate for Parkinson's disease therapy.This study shows that h CDNF expression in dopamine neurons using the neurotensinpolyplex nanoparticle system reverses 6-hydroxydopamine-induced morphological,biochemical,and behavioral alterations.Three independent electron microscopy techniques showed that the neurotensin-polyplex nanoparticles containing the h CDNF gene,ranging in size from 20 to 150 nm,enabled the expression of a secretable h CDNF in vitro.Their injection in the substantia nigra compacta on day 21 after the 6-hydroxydopamine lesion resulted in detectable h CDNF 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 h CDNF transfection.An increase inβIII-tubulin and growth-associated protein 43 phospho-S41(GAP43 p)followed TH^(+)cell recovery,as well as dopamine and its catabolite levels.Partial reversal(80%)of drugactivated 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 h CDNF 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.

关 键 词：axonal growth brain-derived neurotrophic factor gene delivery NANOPARTICLES NEURITOGENESIS neuronal cytoskeleton neuroregeneration neurorestoration neurotrophic therapy Parkinson's disease REINNERVATION substantia nigra 

分 类 号：R741.02[医药卫生—神经病学与精神病学]