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Mechanistic Insight from Preclinical Models of Parkinson’s Disease Could Help Redirect Clinical Trial Efforts in GDNF Therapy

Parkinson’s disease (PD) is characterized by four pathognomonic hallmarks: (1) motor and non-motor deficits; (2) neuroinflammation and oxidative stress; (3) pathological aggregates of the α-synuclein (α-syn) protein; (4) neurodegeneration of the nigrostriatal system. Recent evidence sustains that th...

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Autores principales: Delgado-Minjares, Karen M., Martinez-Fong, Daniel, Martínez-Dávila, Irma A., Bañuelos, Cecilia, Gutierrez-Castillo, M. E., Blanco-Alvarez, Víctor Manuel, Cardenas-Aguayo, Maria-del-Carmen, Luna-Muñoz, José, Pacheco-Herrero, Mar, Soto-Rojas, Luis O.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8583859/
https://www.ncbi.nlm.nih.gov/pubmed/34769132
http://dx.doi.org/10.3390/ijms222111702
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author Delgado-Minjares, Karen M.
Martinez-Fong, Daniel
Martínez-Dávila, Irma A.
Bañuelos, Cecilia
Gutierrez-Castillo, M. E.
Blanco-Alvarez, Víctor Manuel
Cardenas-Aguayo, Maria-del-Carmen
Luna-Muñoz, José
Pacheco-Herrero, Mar
Soto-Rojas, Luis O.
author_facet Delgado-Minjares, Karen M.
Martinez-Fong, Daniel
Martínez-Dávila, Irma A.
Bañuelos, Cecilia
Gutierrez-Castillo, M. E.
Blanco-Alvarez, Víctor Manuel
Cardenas-Aguayo, Maria-del-Carmen
Luna-Muñoz, José
Pacheco-Herrero, Mar
Soto-Rojas, Luis O.
author_sort Delgado-Minjares, Karen M.
collection PubMed
description Parkinson’s disease (PD) is characterized by four pathognomonic hallmarks: (1) motor and non-motor deficits; (2) neuroinflammation and oxidative stress; (3) pathological aggregates of the α-synuclein (α-syn) protein; (4) neurodegeneration of the nigrostriatal system. Recent evidence sustains that the aggregation of pathological α-syn occurs in the early stages of the disease, becoming the first trigger of neuroinflammation and subsequent neurodegeneration. Thus, a therapeutic line aims at striking back α-synucleinopathy and neuroinflammation to impede neurodegeneration. Another therapeutic line is restoring the compromised dopaminergic system using neurotrophic factors, particularly the glial cell-derived neurotrophic factor (GDNF). Preclinical studies with GDNF have provided encouraging results but often lack evaluation of anti-α-syn and anti-inflammatory effects. In contrast, clinical trials have yielded imprecise results and have reported the emergence of severe side effects. Here, we analyze the discrepancy between preclinical and clinical outcomes, review the mechanisms of the aggregation of pathological α-syn, including neuroinflammation, and evaluate the neurorestorative properties of GDNF, emphasizing its anti-α-syn and anti-inflammatory effects in preclinical and clinical trials.
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spelling pubmed-85838592021-11-12 Mechanistic Insight from Preclinical Models of Parkinson’s Disease Could Help Redirect Clinical Trial Efforts in GDNF Therapy Delgado-Minjares, Karen M. Martinez-Fong, Daniel Martínez-Dávila, Irma A. Bañuelos, Cecilia Gutierrez-Castillo, M. E. Blanco-Alvarez, Víctor Manuel Cardenas-Aguayo, Maria-del-Carmen Luna-Muñoz, José Pacheco-Herrero, Mar Soto-Rojas, Luis O. Int J Mol Sci Review Parkinson’s disease (PD) is characterized by four pathognomonic hallmarks: (1) motor and non-motor deficits; (2) neuroinflammation and oxidative stress; (3) pathological aggregates of the α-synuclein (α-syn) protein; (4) neurodegeneration of the nigrostriatal system. Recent evidence sustains that the aggregation of pathological α-syn occurs in the early stages of the disease, becoming the first trigger of neuroinflammation and subsequent neurodegeneration. Thus, a therapeutic line aims at striking back α-synucleinopathy and neuroinflammation to impede neurodegeneration. Another therapeutic line is restoring the compromised dopaminergic system using neurotrophic factors, particularly the glial cell-derived neurotrophic factor (GDNF). Preclinical studies with GDNF have provided encouraging results but often lack evaluation of anti-α-syn and anti-inflammatory effects. In contrast, clinical trials have yielded imprecise results and have reported the emergence of severe side effects. Here, we analyze the discrepancy between preclinical and clinical outcomes, review the mechanisms of the aggregation of pathological α-syn, including neuroinflammation, and evaluate the neurorestorative properties of GDNF, emphasizing its anti-α-syn and anti-inflammatory effects in preclinical and clinical trials. MDPI 2021-10-28 /pmc/articles/PMC8583859/ /pubmed/34769132 http://dx.doi.org/10.3390/ijms222111702 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Delgado-Minjares, Karen M.
Martinez-Fong, Daniel
Martínez-Dávila, Irma A.
Bañuelos, Cecilia
Gutierrez-Castillo, M. E.
Blanco-Alvarez, Víctor Manuel
Cardenas-Aguayo, Maria-del-Carmen
Luna-Muñoz, José
Pacheco-Herrero, Mar
Soto-Rojas, Luis O.
Mechanistic Insight from Preclinical Models of Parkinson’s Disease Could Help Redirect Clinical Trial Efforts in GDNF Therapy
title Mechanistic Insight from Preclinical Models of Parkinson’s Disease Could Help Redirect Clinical Trial Efforts in GDNF Therapy
title_full Mechanistic Insight from Preclinical Models of Parkinson’s Disease Could Help Redirect Clinical Trial Efforts in GDNF Therapy
title_fullStr Mechanistic Insight from Preclinical Models of Parkinson’s Disease Could Help Redirect Clinical Trial Efforts in GDNF Therapy
title_full_unstemmed Mechanistic Insight from Preclinical Models of Parkinson’s Disease Could Help Redirect Clinical Trial Efforts in GDNF Therapy
title_short Mechanistic Insight from Preclinical Models of Parkinson’s Disease Could Help Redirect Clinical Trial Efforts in GDNF Therapy
title_sort mechanistic insight from preclinical models of parkinson’s disease could help redirect clinical trial efforts in gdnf therapy
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8583859/
https://www.ncbi.nlm.nih.gov/pubmed/34769132
http://dx.doi.org/10.3390/ijms222111702
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