Open AccessCerebral dopamine neurotrophic factor transfection in dopamine neurons using neurotensin-polyplex nanoparticles reverses 6-hydroxydopamine-induced nigrostriatal neurodegeneration
Author(s) -
Manuel A. Fernandez-Parrilla,
David Reyes-Corona,
Yazmin M. Flores-Martínez,
Rasajdella,
Michael J. Ban,
Lourdes Escobedo,
Minerva Maldonado-Berny,
J. Santoyo-Salazar,
Luis O. Soto-Rojas,
Claudia Luna-Herrera,
José Ayala-Dávila,
Juan Antonio González-Barrios,
Gonzalo Flores,
María Eugenia Gutiérrez-Castillo,
Armando J. Espadas-Álvarez,
Irma A. Martínez-Dávila,
Porfirio Nava,
Daniel MartínezFong
Publication year - 2022
Publication title -
neural regeneration research/neural regeneration research
Language(s) - Uncategorized
Resource type - Journals
SCImago Journal Rank - 0.93
H-Index - 38
eISSN - 1876-7958
pISSN - 1673-5374
DOI - 10.4103/1673-5374.321001
Subject(s) - pars compacta , substantia nigra , dopamine , neurotrophic factors , ventral tegmental area , neurodegeneration , striatum , brain derived neurotrophic factor , neuroscience , parkinson's disease , endocrinology , biology , medicine , dopaminergic , disease , receptor
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.