Upregulation of the PI3K/AKT and Nrf2 Pathways by the DPP‑4 Inhibitor Sitagliptin Renders Neuroprotection in Chemically Induced Parkinson’s Disease Mouse Models

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216305%3A26220%2F25%3APU156326" target="_blank" >RIV/00216305:26220/25:PU156326 - isvavai.cz</a>

Result on the web

<a href="https://pubmed.ncbi.nlm.nih.gov/40127285/" target="_blank" >https://pubmed.ncbi.nlm.nih.gov/40127285/</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1021/acschemneuro.5c00112" target="_blank" >10.1021/acschemneuro.5c00112</a>

Result language

angličtina

Original language name

Upregulation of the PI3K/AKT and Nrf2 Pathways by the DPP‑4 Inhibitor Sitagliptin Renders Neuroprotection in Chemically Induced Parkinson’s Disease Mouse Models

Original language description

Parkinson’s disease (PD) is one of the most common progressive neurodegenerative pathologies that leads to dopaminergic deficiency and motor manifestations. Alpha-synuclein aggregation is a characteristic hallmark of PD pathogenesis. These aggregates facilitate the formation of Lewy bodies and degeneration. The epidemiological evidence demonstrates a definitive association of diabetes with PD risk. Considering this, many antidiabetic agents such as GLP-1 agonists and DPP-4 inhibitors are being explored as alternative PD therapeutics. This study evaluated the neuroprotective effect of the DPP-4 inhibitor sitagliptin mediated by the PI3K/AKT and Nrf2 pathways in PD models. In silico studies were conducted to determine the binding affinity, stability, and ADMET properties of DPP-4 inhibitors with target proteins. Sitagliptin (15 mg/kg p.o.) was administered in rotenone (30 mg/kg p.o. for 28 days)-induced and MPTP/P (25 mg/kg i.p. MPTP and 100 mg/kg probenecid i.p. twice a week for 5 weeks)-induced PD mouse (C57/BL6) models. Neurobehavioral assessments were carried out throughout the study. Biochemical (GSH, MDA), molecular estimations (AKT, Nrf2, PI3K, GSK-3β, GLP1, CREB, BDNF, NF-κB, alpha-synuclein), histopathological studies, and immunohistochemistry were carried out at the end of the study. The in-silico studies demonstrate better binding, stability, and ADMET profile of sitagliptin with both target proteins. Sitagliptin restored cognitive and motor deficits in both rotenone- and MPTP/P-induced mouse models. There was upregulation of PI3K, AKT, Nrf2, CREB, and BDNF levels and downregulation of GSK-3β, NF-κB, and alpha-synuclein levels in both models after treatment with sitagliptin. However, GLP1 levels were not significantly restored, indicating a GLP1-independent mechanism. It also restored histopathological alterations and TH+ neuronal loss induced by rotenone and MPTP/P. These findings demonstrate that sitagliptin exhibits neuroprotective action mediated by upr

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

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OECD FORD branch

30401 - Health-related biotechnology

Project

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Continuities

S - Specificky vyzkum na vysokych skolach

Publication year

2025

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

ACS CHEM NEUROSCI

ISSN

1948-7193

e-ISSN

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Volume of the periodical

2025

Issue of the periodical within the volume

16

Country of publishing house

US - UNITED STATES

Number of pages

15

Pages from-to

1402-1417

UT code for WoS article

001450944300001

EID of the result in the Scopus database

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