Mechanistic Insight from Preclinical Models of Parkinson’s Disease Could Help Redirect Clinical Trial Efforts in GDNF Therapy
Date
2021Author
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.
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Show full item recordAbstract
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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