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:	Karen M. Delgado-Minjares, Daniel Martinez-Fong, Irma A. Martínez-Dávila, Cecilia Bañuelos, M. E. Gutierrez-Castillo, Víctor Manuel Blanco-Alvarez, Maria-del-Carmen Cardenas-Aguayo, José Luna-Muñoz, Mar Pacheco-Herrero, Luis O. Soto-Rojas
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	neurodegenerative diseases α-synuclein neuroinflammation neurotrophic factors anti-α-synuclein therapy anti-inflammatory therapy Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/d402cb1c3197411e954425395eecb767
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spelling	oai:doaj.org-article:d402cb1c3197411e954425395eecb7672021-11-11T17:09:43ZMechanistic Insight from Preclinical Models of Parkinson’s Disease Could Help Redirect Clinical Trial Efforts in GDNF Therapy10.3390/ijms2221117021422-00671661-6596https://doaj.org/article/d402cb1c3197411e954425395eecb7672021-10-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/11702https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Parkinson’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.Karen M. Delgado-MinjaresDaniel Martinez-FongIrma A. Martínez-DávilaCecilia BañuelosM. E. Gutierrez-CastilloVíctor Manuel Blanco-AlvarezMaria-del-Carmen Cardenas-AguayoJosé Luna-MuñozMar Pacheco-HerreroLuis O. Soto-RojasMDPI AGarticleneurodegenerative diseasesα-synucleinneuroinflammationneurotrophic factorsanti-α-synuclein therapyanti-inflammatory therapyBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 11702, p 11702 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	neurodegenerative diseases α-synuclein neuroinflammation neurotrophic factors anti-α-synuclein therapy anti-inflammatory therapy Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	neurodegenerative diseases α-synuclein neuroinflammation neurotrophic factors anti-α-synuclein therapy anti-inflammatory therapy Biology (General) QH301-705.5 Chemistry QD1-999 Karen M. Delgado-Minjares Daniel Martinez-Fong Irma A. Martínez-Dávila Cecilia Bañuelos M. E. Gutierrez-Castillo Víctor Manuel Blanco-Alvarez Maria-del-Carmen Cardenas-Aguayo José Luna-Muñoz Mar Pacheco-Herrero Luis O. Soto-Rojas Mechanistic Insight from Preclinical Models of Parkinson’s Disease Could Help Redirect Clinical Trial Efforts in GDNF Therapy
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.
format	article
author	Karen M. Delgado-Minjares Daniel Martinez-Fong Irma A. Martínez-Dávila Cecilia Bañuelos M. E. Gutierrez-Castillo Víctor Manuel Blanco-Alvarez Maria-del-Carmen Cardenas-Aguayo José Luna-Muñoz Mar Pacheco-Herrero Luis O. Soto-Rojas
author_facet	Karen M. Delgado-Minjares Daniel Martinez-Fong Irma A. Martínez-Dávila Cecilia Bañuelos M. E. Gutierrez-Castillo Víctor Manuel Blanco-Alvarez Maria-del-Carmen Cardenas-Aguayo José Luna-Muñoz Mar Pacheco-Herrero Luis O. Soto-Rojas
author_sort	Karen M. Delgado-Minjares
title	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_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_sort	mechanistic insight from preclinical models of parkinson’s disease could help redirect clinical trial efforts in gdnf therapy
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/d402cb1c3197411e954425395eecb767
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Mechanistic Insight from Preclinical Models of Parkinson’s Disease Could Help Redirect Clinical Trial Efforts in GDNF Therapy

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