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

J 2025

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

SONI, Ritu; Vaishali PANKAJ; Sudeep ROY; Amit Suresh KHAIRNAR; Jigna SHAH et al.

Základní údaje

Originální název

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

Autoři

SONI, Ritu; Vaishali PANKAJ; Sudeep ROY; Amit Suresh KHAIRNAR a Jigna SHAH

Vydání

ACS Chemical Neuroscience, WASHINGTON, AMER CHEMICAL SOC, 2025, 1948-7193

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

30210 Clinical neurology

Stát vydavatele

Spojené státy

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 3.900 v roce 2024

Označené pro přenos do RIV

Ano

Organizační jednotka

Lékařská fakulta

Klíčová slova anglicky

Parkinson's disease; DPP-4 inhibitors; sitagliptin; PI3K/AKT; Nrf2; alpha-synuclein

Štítky

rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 26. 2. 2026 13:22, Mgr. Tereza Miškechová

Anotace

V originále

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-3 beta, GLP1, CREB, BDNF, NF-kappa B, 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-3 beta, NF-kappa B, 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 upregulation of the PI3K/AKT and Nrf2 pathways in rotenone and MPTP/P mouse models of PD.

Citovat

SONI, Ritu; Vaishali PANKAJ; Sudeep ROY; Amit Suresh KHAIRNAR a Jigna SHAH. Upregulation of the PI3K/AKT and Nrf2 Pathways by the DPP-4 Inhibitor Sitagliptin Renders Neuroprotection in Chemically Induced Parkinson's Disease Mouse Models. ACS Chemical Neuroscience. WASHINGTON: AMER CHEMICAL SOC, 2025, roč. 16, č. 7, s. 1402-1417. ISSN 1948-7193. Dostupné z: https://doi.org/10.1021/acschemneuro.5c00112.

@article{2556884,
   author = {Soni, Ritu and Pankaj, Vaishali and Roy, Sudeep and Khairnar, Amit Suresh and Shah, Jigna},
   article_location = {WASHINGTON},
   article_number = {7},
   doi = {https://doi.org/10.1021/acschemneuro.5c00112},
   keywords = {Parkinson's disease; DPP-4 inhibitors; sitagliptin; PI3K/AKT; Nrf2; alpha-synuclein},
   language = {eng},
   issn = {1948-7193},
   journal = {ACS Chemical Neuroscience},
   title = {Upregulation of the PI3K/AKT and Nrf2 Pathways by the DPP-4 Inhibitor Sitagliptin Renders Neuroprotection in Chemically Induced Parkinson's Disease Mouse Models},
   url = {https://pubs.acs.org/doi/10.1021/acschemneuro.5c00112},
   volume = {16},
   year = {2025}
}

TY  - JOUR
ID  - 2556884
AU  - Soni, Ritu - Pankaj, Vaishali - Roy, Sudeep - Khairnar, Amit Suresh - Shah, Jigna
PY  - 2025
TI  - Upregulation of the PI3K/AKT and Nrf2 Pathways by the DPP-4 Inhibitor Sitagliptin Renders Neuroprotection in Chemically Induced Parkinson's Disease Mouse Models
JF  - ACS Chemical Neuroscience
VL  - 16
IS  - 7
SP  - 1402-1417
EP  - 1402-1417
PB  - AMER CHEMICAL SOC
SN  - 19487193
KW  - Parkinson's disease
KW  - DPP-4 inhibitors
KW  - sitagliptin
KW  - PI3K/AKT
KW  - Nrf2
KW  - alpha-synuclein
UR  - https://pubs.acs.org/doi/10.1021/acschemneuro.5c00112
N2  - 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-3 beta, GLP1, CREB, BDNF, NF-kappa B, 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-3 beta, NF-kappa B, 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 upregulation of the PI3K/AKT and Nrf2 pathways in rotenone and MPTP/P mouse models of PD.
ER  -

SONI, Ritu; Vaishali PANKAJ; Sudeep ROY; Amit Suresh KHAIRNAR a Jigna SHAH. Upregulation of the PI3K/AKT and Nrf2 Pathways by the DPP-4 Inhibitor Sitagliptin Renders Neuroprotection in Chemically Induced Parkinson's Disease Mouse Models. \textit{ACS Chemical Neuroscience}. WASHINGTON: AMER CHEMICAL SOC, 2025, roč.~16, č.~7, s.~1402-1417. ISSN~1948-7193. Dostupné z: https://doi.org/10.1021/acschemneuro.5c00112.

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