Department of Pharmacology and Toxicology, Faculty of Pharmacy, Sinai University, Egypt.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Sinai University, Egypt; Department of Pharmacology, Faculty of Medicine, Arish University, Egypt.
Life Sci. 2022 Dec 15;311(Pt A):121049. doi: 10.1016/j.lfs.2022.121049. Epub 2022 Oct 6.
Dyskinesia is characterized by abnormal involuntary movements (AIMs). Such movements are considered restrictive problem associated with the chronic use of L-dopa in Parkinson's disease (PD) treatment; the thing that renders the definite pathological mechanism unclear. However, there is a correlation between excitotoxicity of glutamatergic NMDA receptors, neuroinflammation, and oxidative stress in the lesioned nigrostriatal pathway; which mediates the firing of basal ganglia neurons involved in dyskinesia.
The current study investigated the novel neuroprotective effect of agmatine in ameliorating both PD and dyskinesia with a focus on its antioxidant, anti-inflammatory, and anti-apoptotic potentiality through Nrf2 activation and suppression of HMGB1/RAGE/TLR4/MYD88/NF-κB signaling pathway.
PD was induced in animals by ten consecutive doses of rotenone (3 mg/kg/day; s.c.). Agmatine (100 mg/kg/day; i.p.) was injected for 16 days after modeling PD either alone or in combination with L-dopa/carbidopa (50/25 mg/kg/day; i.p.).
A statically significant deteriorating effect was showed on the behavioral, neurochemical, histopathological, and immunochemical analysis of PD rats. Moreover, dyskinesia observed in PD rats that received L-dopa. Agmatine improved animals' behavior and abolished dyskinetic AIMs. It inhibited NMDA receptors expression in nigral tissues leading to inhibition of inflammatory and oxidative stress cascades. It increased both nigral TH immunoreactive cells and striatal dopamine contents. Besides, it increased the antioxidant defense mechanism of Nrf2/TAC contents along with a significant decrease of HMGB1/RAGE/TLR4/MYD88/NF-κB protein expression.
The current investigated data signifies the novel role of agmatine in ameliorating both PD and dyskinesia through mediating NMDA receptors, Nrf2, and HMGB1/RAGE/TLR4/NF-κB signaling pathways.
本研究通过 Nrf2 激活和抑制 HMGB1/RAGE/TLR4/MYD88/NF-κB 信号通路，探讨精氨酸在改善帕金森病（PD）和运动障碍中的新型神经保护作用，重点研究其抗氧化、抗炎和抗细胞凋亡的潜力。
通过连续 10 天给予鱼藤酮（3mg/kg/天，皮下注射）诱导动物发生 PD。在造模 PD 后，每天腹腔注射精氨酸（100mg/kg）16 天，或与左旋多巴/卡比多巴（50/25mg/kg/天，腹腔注射）联合使用。
PD 大鼠的行为、神经化学、组织病理学和免疫化学分析显示出明显的恶化效应。此外，接受左旋多巴的 PD 大鼠出现运动障碍。精氨酸改善了动物的行为并消除了运动障碍性异常不自主运动。它抑制了黑质组织中 NMDA 受体的表达，从而抑制了炎症和氧化应激级联反应。它增加了黑质 TH 免疫反应性细胞和纹状体多巴胺含量。此外，它增加了 Nrf2/TAC 含量的抗氧化防御机制，同时 HMGB1/RAGE/TLR4/MYD88/NF-κB 蛋白表达显著下降。
目前的研究数据表明，精氨酸通过调节 NMDA 受体、Nrf2 和 HMGB1/RAGE/TLR4/NF-κB 信号通路，在改善 PD 和运动障碍方面具有新的作用。
