TY - JOUR
T1 - Cerebral dopamine neurotrophic factor transfection in dopamine neurons using neurotensin-polyplex nanoparticles reverses 6-hydroxydopamine-induced nigrostriatal neurodegeneration
AU - Fernandez-Parrilla, Manuel
AU - Reyes-Corona, David
AU - Flores-Martinez, Yazmin
AU - Nadella, Rasajna
AU - Bannon, Michael
AU - Escobedo, Lourdes
AU - Maldonado-Berny, Minerva
AU - Santoyo-Salazar, Jaime
AU - Soto-Rojas, Luis
AU - Luna-Herrera, Claudia
AU - Ayala-Davila, Jose
AU - Gonzalez-Barrios, Juan
AU - Flores, Gonzalo
AU - Gutierrez-Castillo, Maria
AU - Espadas-Alvarez, Armando
AU - Martínez-Dávila, Irma
AU - Nava, Porfirio
AU - Martinez-Fong, Daniel
N1 - Publisher Copyright:
© 2022 Wolters Kluwer Medknow Publications. All rights reserved.
PY - 2022/4
Y1 - 2022/4
N2 - 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.
AB - 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.
KW - Axonal growth
KW - Brain-derived neurotrophic factor
KW - Gene delivery
KW - Nanoparticles
KW - Neuritogenesis
KW - Neuronal cytoskeleton
KW - Neuroregeneration
KW - Neurorestoration
KW - Neurotrophic therapy
KW - Parkinson's disease
KW - Reinnervation
KW - Substantia nigra
UR - http://www.scopus.com/inward/record.url?scp=85114287916&partnerID=8YFLogxK
U2 - 10.4103/1673-5374.321001
DO - 10.4103/1673-5374.321001
M3 - Artículo
C2 - 34472486
AN - SCOPUS:85114287916
SN - 1673-5374
VL - 17
SP - 854
EP - 866
JO - Neural Regeneration Research
JF - Neural Regeneration Research
IS - 4
ER -