Lu Chen, Zhang Jin, Shi Xiaopeng, Miao Shan, Bi Linlin, Zhang Song, Yang Qian, Zhou Xuanxuan, Zhang Meng, Xie Yanhua, Miao Qing, Wang Siwang
1. Institute of Materia, Fourth Military Medical University, Xi'an 710032, China;
2. Department of Hand Surgery, 401 Military Hospital, Qingdao 266071, China;
Int J Biol Sci. 2014 Mar 13;10(4):350-7. doi: 10.7150/ijbs.8366. eCollection 2014.
Parkinson's disease (PD) is the second most prevalent progressive neurodegenerative disease. Although several hypotheses have been proposed to explain the pathogenesis of PD, apoptotic cell death and oxidative stress are the most prevalent mechanisms. Tetramethylpyrazine (TMP) is a biological component that has been extracted from Ligusticum wallichii Franchat (ChuanXiong), which exhibits anti-apoptotic and antioxidant roles. In the current study, we aimed to investigate the possible protective effect of TMP against dopaminergic neuron injury in a rat model of Parkinson's disease induced by MPTP and to elucidate probable molecular mechanisms. The results showed that TMP could notably prevent MPTP-induced dopaminergic neurons damage, reflected by improvement of motor deficits, enhancement of TH expression and the content of dopamine and its metabolite, DOPAC. We observed MPTP-induced activation of mitochondrial apoptotic death pathway, evidenced by up-regulation of Bax, down-regulation of Bcl-2, release of cytochrome c and cleavage of caspase 3, which was significantly inhibited by TMP. Moreover, TMP could prevent MPTP-increased TBARS level and MPTP-decreased GSH level, indicating the antioxidant role of TMP in PD model. And the antioxidant role of TMP attributes to the prevention of MPTP-induced reduction of Nrf2 and GCLc expression. In conclusion, in MPTP-induced PD model, TMP prevents the down-regulation of Nrf2 and GCLc, maintaining redox balance and inhibiting apoptosis, leading to the attenuation of dopaminergic neuron damage. The effectiveness of TMP in treating PD potentially leads to interesting therapeutic perspectives.
帕金森病（PD）是第二常见的进行性神经退行性疾病。尽管已经提出了几种假说来解释PD的发病机制，但凋亡性细胞死亡和氧化应激是最常见的机制。川芎嗪（TMP）是从川芎中提取的一种生物成分，具有抗凋亡和抗氧化作用。在本研究中，我们旨在探讨TMP对1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的帕金森病大鼠模型中多巴胺能神经元损伤的可能保护作用，并阐明其可能的分子机制。结果表明，TMP可显著预防MPTP诱导的多巴胺能神经元损伤，表现为运动功能障碍改善、酪氨酸羟化酶（TH）表达增强以及多巴胺及其代谢产物3,4-二羟基苯乙酸（DOPAC）含量增加。我们观察到MPTP诱导线粒体凋亡死亡途径的激活，表现为促凋亡蛋白Bax上调、抗凋亡蛋白Bcl-2下调、细胞色素c释放以及半胱天冬酶3裂解，而TMP可显著抑制这些变化。此外，TMP可预防MPTP引起的丙二醛（TBARS）水平升高和MPTP导致的谷胱甘肽（GSH）水平降低，表明TMP在PD模型中的抗氧化作用。TMP的抗氧化作用归因于其预防MPTP诱导的核因子E2相关因子2（Nrf2）和谷氨酸-半胱氨酸连接酶催化亚基（GCLc）表达降低。总之，在MPTP诱导的PD模型中，TMP可防止Nrf2和GCLc下调，维持氧化还原平衡并抑制细胞凋亡，从而减轻多巴胺能神经元损伤。TMP治疗PD的有效性可能带来有趣的治疗前景。
