Abdelaziz Ahmed M, Rasheed Nora O Abdel, Zaki Hala F, Salem Hesham A, El-Sayed Rehab M
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Sinai University- Arish Branch, Arish 45511, Egypt.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
Int Immunopharmacol. 2025 Jan 27;146:113839. doi: 10.1016/j.intimp.2024.113839. Epub 2024 Dec 18.
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.
尽管对帕金森病（PD）和左旋多巴诱导的异动症（LID）的发病机制有深入了解，但目前的治疗方法仍不足以有效控制PD的进展性质或阻止LID。越来越多的假说认为，NOD样受体3（NLRP3）炎性小体、孤儿核受体相关蛋白1（Nurr1）/糖原合酶激酶-3β（GSK-3β）以及过氧化物酶体增殖物激活受体γ（PPARγ）共激活因子-1α（PGC-1α）/沉默调节蛋白3（SIRT3）途径是阻止PD神经炎症和氧化应激的潜在途径。
本研究首次调查了卡格列净对鱼藤酮中毒大鼠的PD和LID的神经保护作用，强调了NLRP3/半胱天冬酶-1级联、PGC-1α/SIRT3途径、哺乳动物雷帕霉素靶蛋白（mTOR）/贝克林-1以及Nurr1/β-连环蛋白/GSK-3β途径之间的相互作用，将其作为PD和LID可能的治疗策略。此外，将NLRP3表达与所有评估参数进行关联。
通过每天11次皮下注射鱼藤酮（1.5mg/kg）诱导建立PD大鼠模型。从实验开始到结束，每天口服给予卡格列净（20mg/kg）和/或左旋多巴/卡比多巴（100/25mg/kg）。
卡格列净显著改善了神经行为和组织学评估，而异动症评分下降。免疫组织化学显示，与黑质致密部的NLRP3和半胱天冬酶-1相比，酪氨酸羟化酶和β-连环蛋白上调证实了这种改善。此外，卡格列净使多巴胺、Nurr1、PGC-1α、SIRT3和贝克林-1显著升高，而mTOR和GSK-3β的表达下调。
我们的结果揭示了卡格列净在鱼藤酮损伤大鼠中对PD和LID具有潜在的神经保护特性，其机制可能是通过假定的抗炎活性以及NLRP3/半胱天冬酶-1、Nurr1/GSK-3β/β-连环蛋白、PGC-1α/SIRT3和贝克林-1/mTOR途径的作用。
