Crosstalk between SIRT1/Nrf2 signaling and NLRP3 inflammasome/pyroptosis as a mechanistic approach for the neuroprotective effect of linagliptin in Parkinson's disease.

Autor: Ghaith WZ; Egyptian Town Gas Company, Medical Department, Cairo, Egypt., Wadie W; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, 11562, Egypt., El-Yamany MF; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, 11562, Egypt. Electronic address: walaa.wadie@pharma.cu.edu.eg.
Jazyk: angličtina
Zdroj: International immunopharmacology [Int Immunopharmacol] 2025 Jan 03; Vol. 145, pp. 113716. Date of Electronic Publication: 2024 Dec 05.
DOI: 10.1016/j.intimp.2024.113716
Abstrakt: In recent years, special attention has been paid to highlighting the antiparkinsonian effect of linagliptin. However, the mechanism of its action has not yet been well investigated. The present study aimed to verify the neuroprotective effect of linagliptin in the rotenone model of Parkinson's disease (PD) and further explore its potential molecular mechanisms. Rats were intoxicated with rotenone (2 mg/kg/day; sc) and treated with linagliptin (10  mg/kg/day; po) for 14 consecutive days. The present finding showed that linagliptin ameliorated the histopathological changes of rotenone on substantia nigra and striata. Linagliptin decreased α-synuclein immunoreactivity along with an increase in tyrosine hydroxylase immunoreactivity and striatal dopamine content. This was reflected in the marked improvement of the behavior and motor deficits in rotenone-intoxicated rats. On the molecular level, linagliptin upregulated sirtuin 1 (SIRT1)/ nuclear factor erythroid 2-related factor 2 (Nrf2) signaling, reduced ionized calcium-binding adaptor molecule 1 (Iba1) protein expression, restored glutathione (GSH) content, and elevated heme oxygenase-1 (HO-1) level in rats with rotenone intoxication. Moreover, linagliptin inhibited NOD-like receptor protein 3 (NLRP3)/caspase-1/interleukin-1β (IL-1β) cascade with subsequent reduction in gasdermin D (GSDMD) expression. Therefore, the present study reveals the ability of linagliptin, through the activation of SIRT1/Nrf2 signaling, to suppress NLRP3 inflammasome-mediated pyroptosis and protect against rotenone-induced parkinsonism.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: