Cerebral dopamine neurotrophic factor transfection in dopamine neurons using neurotensin-polyplex nanoparticles reverses 6-hydroxydopamine-induced nigrostriatal neurodegeneration
| Autor: | Manuel A. Fernandez-Parrilla, Minerva Maldonado-Berny, Yazmin M. Flores-Martinez, Jose Ayala-Davila, David Reyes-Corona, Claudia Luna-Herrera, Daniel Martinez-Fong, Rasajna Nadella, Maria E. Gutierrez-Castillo, Jaime Santoyo-Salazar, Luis O Soto-Rojas, Juan Antonio González-Barrios, Irma A Martínez-Dávila, Gonzalo Flores, Michael J. Bannon, Armando J. Espadas-Alvarez, Lourdes Escobedo, Porfirio Nava |
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| Rok vydání: | 2021 |
| Předmět: |
medicine.medical_specialty
neurotrophic therapy Parkinson's disease neuronal cytoskeleton Substantia nigra Striatum axonal growth brain-derived neurotrophic factor gene delivery nanoparticles neuritogenesis neuroregeneration neurorestoration parkinson’s disease reinnervation substantia nigra Developmental Neuroscience Neurotrophic factors Dopamine Internal medicine medicine RC346-429 Cerebral dopamine neurotrophic factor Brain-derived neurotrophic factor Chemistry Pars compacta medicine.disease Endocrinology nervous system Neurology. Diseases of the nervous system medicine.drug Research Article |
| Zdroj: | Neural Regeneration Research Neural Regeneration Research, Vol 17, Iss 4, Pp 854-866 (2022) |
| ISSN: | 1673-5374 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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