Neural Regeneration Research ›› 2022, Vol. 17 ›› Issue (4): 854-866.doi: 10.4103/1673-5374.321001

Previous Articles     Next Articles

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

Manuel A. Fernandez-Parrilla1, David Reyes-Corona1, Yazmin M. Flores-Martinez2, Rasajna Nadella3, Michael J. Bannon4, Lourdes Escobedo1, Minerva Maldonado-Berny1, Jaime Santoyo-Salazar5, Luis O. Soto-Rojas6, Claudia Luna-Herrera7, Jose Ayala-Davila1, Juan A. Gonzalez-Barrios8, Gonzalo Flores9, Maria E. Gutierrez-Castillo10, Armando J. Espadas-Alvarez10, Irma A. Martínez-Dávila1, Porfirio Nava1, Daniel Martinez-Fong1, 11, *   

  1. 1Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados, Ciudad de México, México; 2Programa Institucional de Biomedicina Molecular, Escuela Nacional de Medicina y Homeopatía, Instituto Politécnico Nacional, Ciudad de México, México; 3Department of Biosciences, IIIT-Srikakulam, Rajiv Gandhi University of Knowledge Technologies (RGUKT), Andhra Pradesh, India; 4Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI, USA; 5Departamento de Física, Centro de Investigación y de Estudios Avanzados, Ciudad de México, México; 6Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla de Baz, Edo. de México, México; 7Departamento de Fisiología, Escuela Nacional de Ciencias Biológicas, Ciudad de México, México; 8Laboratorio de Medicina Genómica, Hospital Regional “1° de Octubre”, ISSSTE, Ciudad de México, México; 9Laboratorio de Neuropsiquiatría, Instituto de Fisiología, Benemérita Universidad Autónoma de Puebla, Puebla, Puebla, México; 10Departamento de Biociencias e Ingeniería, Centro Interdisciplinario de Investigaciones y Estudios sobre Medio Ambiente y Desarrollo, Instituto Politécnico Nacional, Ciudad de México, México; 11Programa de Nanociencias y nanotecnología, Centro de Investigación y de Estudios Avanzados, Ciudad de México, México
  • Online:2022-04-15 Published:2021-10-18
  • Contact: Daniel Martinez-Fong, MD, PhD, martinez.fong@gmail.com.
  • Supported by:
    This study was supported by the Consejo Nacional de Ciencia Tecnología (Conacyt) de México (Grant # 254686, to DMF). 

PDF

41

Abstract: 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 as a 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.

Key words: axonal growth, brain-derived neurotrophic factor, gene delivery, nanoparticles, neuritogenesis, neuronal cytoskeleton, neuroregeneration, neurorestoration, neurotrophic therapy, Parkinson’s disease, reinnervation, substantia nigra

CLC Number: