State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials, Ministry of Education, College of Life Sciences, Nankai University, Tianjin 300071, China.
Department of Anatomy, School of Medicine, Nankai University, Tianjin 300071, China.
Behav Brain Res. 2020 Feb 3;379:112337. doi: 10.1016/j.bbr.2019.112337. Epub 2019 Nov 4.
L-3,4-dihydroxyphenylalanine (L-DOPA) is currently the main drug used to treat Parkinson's disease (PD). However, long-term use of l-DOPA causes substantial side effects, and we hope to find a biological active ingredient that synergizes with a low-dose of l-DOPA to achieve the same therapeutic effect as that of a high-dose of l-DOPA. The natural product parthenolide (PTL) is the active ingredient in the medicinal plant feverfew (Tanacetum parthenium) and has antioxidant and anti-inflammatory properties. ACT001, a fumarate salt form of dimethylaminomicheliolide (DMAMCL), is a derivative of parthenolide and has comparable effects to those of PTL but exhibits higher stability in the plasma and is available at a lower cost. In our study, we used ACT001 in combination with l-DOPA to treat 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced Parkinson's disease in mice. Specifically, ACT001 significantly reduced motor dysfunction and dopaminergic neurodegeneration in MPTP-treated mice. Furthermore, ACT001 abolished MPTP-induced α-synuclein overexpression, astrocyte activation and interleukin-1β (IL-1β) production in the substantia nigra and striatum of the mouse brain. In addition, ACT001 increased the levels of the anti-apoptotic signalling molecule Bcl-2 and the pAkt/Akt ratio and reduced the levels of the pro-apoptotic signalling molecule Bax and the activation of Caspase3 in the substantia nigra and striatum. We found that the effects of the co-administration of ACT001 and l-DOPA (5 mg/kg) were equivalent to those of the administration of 8 mg/kg l-DOPA in MPTP-induced Parkinson's disease in mice. Then, this evidence suggests that l-DOPA + ACT001 may be used for the treatment of PD.
L-3,4-二羟基苯丙氨酸（L-DOPA）是目前治疗帕金森病（PD）的主要药物。然而，长期使用 L-DOPA 会引起明显的副作用，我们希望找到一种与低剂量 L-DOPA 协同作用的生物活性成分，以达到与高剂量 L-DOPA 相同的治疗效果。天然产物小白菊内酯（PTL）是药用植物小白菊（Tanacetum parthenium）的活性成分，具有抗氧化和抗炎作用。DMAMCL 的富马酸盐衍生物 ACT001 是小白菊内酯的衍生物，其作用与 PTL 相当，但在血浆中更稳定，成本更低。在我们的研究中，我们使用 ACT001 联合 L-DOPA 治疗 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的小鼠帕金森病。具体来说，ACT001 显著减轻了 MPTP 处理的小鼠的运动功能障碍和多巴胺能神经退行性变。此外，ACT001 消除了 MPTP 在小鼠大脑黑质和纹状体中诱导的α-突触核蛋白过表达、星形胶质细胞激活和白细胞介素-1β（IL-1β）产生。此外，ACT001 增加了抗凋亡信号分子 Bcl-2 的水平和 pAkt/Akt 比值，并降低了促凋亡信号分子 Bax 的水平和 Caspase3 的激活在黑质和纹状体。我们发现，ACT001 与 L-DOPA（5mg/kg）联合给药的效果相当于在 MPTP 诱导的帕金森病小鼠中给予 8mg/kg L-DOPA 的效果。然后，这一证据表明 L-DOPA+ACT001 可能用于治疗 PD。
