Chiu Simon, Terpstra Kristen J, Bureau Yves, Hou Jirui, Raheb Hana, Cernvosky Zack, Badmeav Vladimir, Copen John, Husni Mariwan, Woodbury-Farina Michael
J Complement Integr Med. 2013 Nov 7;10:/j/jcim.2013.10.issue-1/jcim-2013-0020/jcim-2013-0020.xml. doi: 10.1515/jcim-2013-0020.
Converging evidence suggests dysregulation of epigenetics in terms of histone-mediated acetylation/deacetylation imbalance in Parkinson's disease (PD). Targeting histone deacetylase (HDAC) in neuronal survival and neuroprotection may be beneficial in the treatment and prevention of neurodegenerative disorders. Few pharmacological studies use the transgenic model of PD to characterize the neuroprotection actions of a lead compound known to target HDAC in the brain.
In our study, we investigated neuroprotective effects of liposomal-formulated curcumin: Lipocurc™ targeting HDAC inhibitor in the DJ-1(Park 7)-gene knockout rat model of PD. Group I (DJ-1-KO-Lipocurc™) received Lipocurc™ 20 mg/kg iv 3× weekly for 8 weeks; Group II: DJ-1 KO controls (DJ-1 KO-PBS) received i.v. phosphate-buffered saline (PBS). Group III: DJ-1-Wild Type (DJ-1 WT-PBS) received PBS. We monitored various components of motor behavior, rotarod, dyskinesia, and open-field behaviors, both at baseline and at regular intervals. Toward the end of the 8 weeks, we measured neuronal apoptosis and dopamine (DA) neuron-specific tyrosine hydroxylase levels by immunohistochemistry methods at post-mortem.
We found that DJ-KO Group I and Group II, as compared with DJ-1 WT group, exhibited moderate degree of motor impairment on the rotarod test. Lipocurc™ treatment improved the motor behavior motor impairment to a greater extent than the PBS treatment. There was marked apoptosis in the DJ-1 WT group. Lipocurc™ significantly blocked neuronal apoptosis: the apoptotic index of DJ-1-KO-Lipocurc™ group was markedly reduced compared with the DJ-KO-PBS group (3.3 vs 25.0, p<0.001). We found preliminary evidence Lipocurc™ stimulated DA neurons in the substantia nigra. The ratio of immature to mature DA neurons in substantia nigra was statistically higher in the DJ-1-KO-Lipocurc™ group (p<0.025).
We demonstrated for the first time Lipocurc™'s anti-apoptotic and neurotrophic effects in theDJ-1-KO rat model of PD. Our promising findings warrant randomized controlled trial of Lipocurc™ in translating the novel nanotechnology-based epigenetics-driven drug discovery platform toward efficacious therapeutics in PD.
越来越多的证据表明，在帕金森病（PD）中，组蛋白介导的乙酰化/去乙酰化失衡导致表观遗传失调。针对组蛋白去乙酰化酶（HDAC）进行神经保护和神经元存活方面的研究，可能对神经退行性疾病的治疗和预防有益。很少有药理学研究使用PD转基因模型来表征已知靶向大脑中HDAC的先导化合物的神经保护作用。
在我们的研究中，我们研究了脂质体形式的姜黄素（Lipocurc™）的神经保护作用：它是一种靶向HDAC抑制剂，用于DJ-1（Park 7）基因敲除大鼠PD模型。第一组（DJ-1-KO-Lipocurc™）静脉注射Lipocurc™ 20 mg/kg，每周3次，共8周；第二组：DJ-1基因敲除对照组（DJ-1 KO-PBS）静脉注射磷酸盐缓冲盐水（PBS）。第三组：DJ-1野生型（DJ-1 WT-PBS）接受PBS。我们在基线和定期监测运动行为、转棒试验、运动障碍和旷场行为的各个组成部分。在8周结束时，我们通过免疫组化方法在死后测量神经元凋亡和多巴胺（DA）神经元特异性酪氨酸羟化酶水平。
我们发现，与DJ-1野生型组相比，DJ-KO第一组和第二组在转棒试验中表现出中度运动障碍。Lipocurc™治疗比PBS治疗在更大程度上改善了运动行为运动障碍。DJ-1野生型组有明显的细胞凋亡。Lipocurc™显著阻断神经元凋亡：DJ-1-KO-Lipocurc™组的凋亡指数与DJ-KO-PBS组相比明显降低（3.3对25.0，p<0.001）。我们发现初步证据表明Lipocurc™刺激黑质中的DA神经元。DJ-1-KO-Lipocurc™组黑质中未成熟DA神经元与成熟DA神经元的比例在统计学上更高（p<0.025）。
我们首次在DJ-1基因敲除大鼠PD模型中证明了Lipocurc™的抗凋亡和神经营养作用。我们有前景的研究结果保证了对Lipocurc™进行随机对照试验，以将基于纳米技术的新型表观遗传学驱动的药物发现平台转化为PD的有效治疗方法。
