Department of Pharmacology and Toxicology, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran; Herbal Medicine and natural product Research Center, Hamadan University of Medical Sciences, Hamadan, Iran.
Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.
Biomed Pharmacother. 2018 Aug;104:127-136. doi: 10.1016/j.biopha.2018.05.020. Epub 2018 May 15.
Several lines of evidence show that apoptosis, oxidative stress and neuroinflammation are associated with the development of Parkinson's disease (PD). In the present study, we investigated the effect of pre-treatment with silymarin (SM) on oxidative stress, apoptosis and toll-like receptor 4 (TLR4) expression in substantia nigra pars copmacta (SNc) of 6-hydroxydopamine (6-OHDA)-lesioned rats.
Animals were pretreated with 100, 200 or 300 mg/kg of SM daily for 5 days and at 6th day 6-OHDA (8 μg/2 μl) was infused unilaterally into the central region of the SNc.
6-OHDA decreased the total glutathione and antioxidant enzymes activity in the SNc. Interestingly, we found that 6-OHDA caused to TLR4 up regulation. The SNc levels of glutathione, superoxide dismutase, glutathione peroxidase, glutathione reductase and catalase were significantly higher in the SM pretreated rats. SM strongly decreased 6-OHDA-induced elevation of SNc apoptosis, caspase-3 and Bax/Bcl-2 ratio. Furthermore, SM markedly (p < 0.001) prevented from SNc over expression of TLR4 caused by 6-OHDA. A significantly high positive correlation was seen between TLR4 activity with caspase-3 protein levels (r = 0.896, P < 0.01), Bax protein levels (r = 0.96, P < 0.01).
Pre-treatment of 6-OHDA-lesioned rats with SM reduces SNc neuronal apoptosis possibly through inhibition of TLR4 over expression. Further clinical study should be carried out to prove potential application of SM for protection against PD in susceptible individuals.
有几条证据表明，细胞凋亡、氧化应激和神经炎症与帕金森病（PD）的发展有关。在本研究中，我们研究了预先用水飞蓟素（SM）处理对 6-羟多巴胺（6-OHDA）损伤大鼠黑质致密部（SNc）中氧化应激、细胞凋亡和 toll 样受体 4（TLR4）表达的影响。
动物每天用 100、200 或 300mg/kg 的 SM 预处理 5 天，第 6 天 6-OHDA（8μg/2μl）单侧注入 SNc 中央区。
6-OHDA 降低了 SNc 中的总谷胱甘肽和抗氧化酶活性。有趣的是，我们发现 6-OHDA 导致 TLR4 上调。SM 预处理大鼠 SNc 中的谷胱甘肽、超氧化物歧化酶、谷胱甘肽过氧化物酶、谷胱甘肽还原酶和过氧化氢酶水平明显升高。SM 强烈降低了 6-OHDA 诱导的 SNc 细胞凋亡、caspase-3 和 Bax/Bcl-2 比值的升高。此外，SM 显著（p<0.001）阻止了 6-OHDA 引起的 SNc TLR4 过表达。TLR4 活性与 caspase-3 蛋白水平（r=0.896，P<0.01）、Bax 蛋白水平（r=0.96，P<0.01）之间存在显著的正相关。
预先用 SM 处理 6-OHDA 损伤大鼠可减少 SNc 神经元凋亡，可能是通过抑制 TLR4 过表达。应进行进一步的临床研究，以证明 SM 在易感个体中预防 PD 的潜在应用。
