Neural Regeneration Research (Jan 2022)

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

  • 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 J Espadas-Alvarez,
  • Irma A Martínez-Dávila,
  • Porfirio Nava,
  • Daniel Martinez-Fong

DOI
https://doi.org/10.4103/1673-5374.321001
Journal volume & issue
Vol. 17, no. 4
pp. 854 – 866

Abstract

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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.

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