TY - JOUR
T1 - Mechanistic insight from preclinical models of parkinson’s disease could help redirect clinical trial efforts in gdnf therapy
AU - Delgado‐minjares, Karen M.
AU - Martinez‐fong, Daniel
AU - Martínez‐dávila, Irma A.
AU - Bañuelos, Cecilia
AU - Gutierrez‐castillo, M. E.
AU - Blanco‐alvarez, Víctor Manuel
AU - Cardenas‐aguayo, Maria Del Carmen
AU - Luna‐muñoz, José
AU - Pacheco‐herrero, Mar
AU - Soto‐rojas, Luis O.
N1 - Publisher Copyright:
© 2021, MDPI. All rights reserved.
PY - 2021/11/1
Y1 - 2021/11/1
N2 - 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, becom-ing 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‐inflam-matory effects. In contrast, clinical trials have yielded imprecise results and have reported the emer-gence of severe side effects. Here, we analyze the discrepancy between preclinical and clinical out-comes, review the mechanisms of the aggregation of pathological α‐syn, including neuroinflamma-tion, and evaluate the neurorestorative properties of GDNF, emphasizing its anti‐α‐syn and anti-inflammatory effects in preclinical and clinical trials.
AB - 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, becom-ing 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‐inflam-matory effects. In contrast, clinical trials have yielded imprecise results and have reported the emer-gence of severe side effects. Here, we analyze the discrepancy between preclinical and clinical out-comes, review the mechanisms of the aggregation of pathological α‐syn, including neuroinflamma-tion, and evaluate the neurorestorative properties of GDNF, emphasizing its anti‐α‐syn and anti-inflammatory effects in preclinical and clinical trials.
KW - Anti‐inflammatory therapy
KW - Anti‐α‐synuclein therapy
KW - Neurodegenerative diseases
KW - Neuroinflammation
KW - Neurorestoration
KW - Neurotrophic factors
KW - α‐synuclein
UR - http://www.scopus.com/inward/record.url?scp=85117923885&partnerID=8YFLogxK
U2 - 10.3390/ijms222111702
DO - 10.3390/ijms222111702
M3 - Artículo de revisión
C2 - 34769132
AN - SCOPUS:85117923885
SN - 1661-6596
VL - 22
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
IS - 21
M1 - 11702
ER -