Roflumilast escalates α-synuclein aggregate degradation in rotenone-induced Parkinson's disease in rats: Modulation of the ubiquitin-proteasome system and endoplasmic reticulum stress.

Autor: Desouky MA; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, 11566, Cairo, Egypt., George MY; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, 11566, Cairo, Egypt., Michel HE; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, 11566, Cairo, Egypt. Electronic address: heidieffat@pharma.asu.edu.eg., Elsherbiny DA; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, 11566, Cairo, Egypt.
Jazyk: angličtina
Zdroj: Chemico-biological interactions [Chem Biol Interact] 2023 Jul 01; Vol. 379, pp. 110491. Date of Electronic Publication: 2023 Apr 25.
DOI: 10.1016/j.cbi.2023.110491
Abstrakt: Perturbation of the protein homeostasis circuit is one of the principal attributes associated with many neurodegenerative disorders, such as Parkinson's disease (PD). This study aimed to explore the neuroprotective effect of roflumilast (ROF), a phosphodiesterase-4 inhibitor, in a rotenone-induced rat model of PD and investigate the potential underlying mechanisms. Interestingly, ROF (1 mg/kg, p.o.) attenuated motor impairment, prevented brain lesions, and rescued the dopaminergic neurons in rotenone-treated rats. Furthermore, it reduced misfolded α-synuclein burden. ROF also promoted the midbrain cyclic adenosine monophosphate level, which subsequently enhanced the 26S proteasome activity and the expression of the 20S proteasome. ROF counteracted rotenone-induced endoplasmic reticulum stress, which was demonstrated by its impact on activating transcription factor 6, glucose-regulated protein 78, and C/EBP homologous protein levels. Moreover, ROF averted rotenone-induced oxidative stress, as evidenced by its effects on the levels of nuclear factor erythroid 2-related factor 2, heme oxygenase-1, reduced glutathione, and lipid peroxides with a significant anti-apoptotic activity. Collectively, this study implies repurposing of ROF as a novel neuroprotective drug owning to its ability to restore normal protein homeostasis.
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 © 2023 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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