Canagliflozin attenuates neurodegeneration and ameliorates dyskinesia through targeting the NLRP3/Nurr1/GSK-3β/SIRT3 pathway and autophagy modulation in rotenone-lesioned rats

• Published in: International immunopharmacology 2024-12, Vol.146, p.113839, Article 113839
• Main Authors: Abdelaziz, Ahmed M., Rasheed, Nora O. Abdel, Zaki, Hala F., Salem, Hesham A., El-Sayed, Rehab M.
• Format: Article
• Language: English
• Subjects: Beclin-1; Canagliflozin; Dyskinesia; GSK-3β; NLRP3; Nurr1; Parkinson’s disease; PGC-1α; Rotenone; SIRT3; β-catenin
• ISSN: 1567-5769; 1878-1705; 1878-1705
• DOI: 10.1016/j.intimp.2024.113839

[Display omitted] •Canagliflozin alleviated locomotor dysfunction and L-dopa-induced dyskinesia.•Canagliflozin enhanced autophagy via modulating mTOR/beclin-1 pathway.•Canagliflozin suppressed the NLRP3/caspase-1/IL-1β inflammasome pathway.•Canagliflozin preserved neuronal integrity by modulating the Nurr1/GSK-3β/β-catenin.•Canagliflozin suppressed oxidative stress via PGC-1α/SIRT3 pathway activation. Despite a deep understanding of Parkinson’s disease (PD) and levodopa-induced dyskinesia (LID) pathogenesis, current therapies are insufficient to effectively manage the progressive nature of PD or halt LID. Growing hypotheses suggested the NOD-like receptor 3 (NLRP3) inflammasome and orphan nuclear receptor-related 1 (Nurr1)/glycogen synthase kinase-3β (GSK-3β) and peroxisome proliferator-activated receptor γ (PPARγ) coactivator-1α (PGC-1α)/sirtuin 3 (SIRT3) pathways as potential avenues for halting neuroinflammation and oxidative stress in PD. This study investigated for the first time the neuroprotective effect of canagliflozin against PD and LID in rotenone-intoxicated rats, emphasizing the crosstalk among the NLRP3/caspase-1 cascade, PGC-1α/SIRT3 pathway, mammalian target of rapamycin (mTOR)/beclin-1, and Nurr1/β-catenin/GSK-3β pathways as possible treatment strategies in PD and LID. Also, correlating NLRP3 expression with all evaluated parameters. The PD rat model was induced via eleven rotenone (1.5 mg/kg) subcutaneous injections day after day. Canagliflozin (20 mg/kg) and/or L-dopa/carbidopa (100/25 mg/kg) were orally administered daily from the beginning until the end of the experiment. Canagliflozin significantly improved neurobehavioral and histological assessments, whereas dyskinesia scores declined. The improvement was confirmed through tyrosine hydroxylase and β-catenin upregulation in contrast to NLRP3 and caspase-1 in substantia nigra pars compacta, as revealed immunohistochemically. In addition, canagliflozin induced a prominent elevation in dopamine, Nurr1, PGC-1α, SIRT3, and beclin-1, whereas mTOR and GSK-3β expressions were downregulated. Our results revealed the aspiring canagliflozin neuroprotective properties against PD and LID in rotenone-lesioned rats via the assumed anti-inflammatory activity and implication of NLRP3/caspase-1, Nurr1/GSK-3β/β-catenin, PGC-1α/SIRT3, and beclin-1/mTOR pathways.