McFarland Nikolaus R, Dimant Hemi, Kibuuka Laura, Ebrahimi-Fakhari Darius, Desjardins Cody A, Danzer Karin M, Danzer Michael, Fan Zhanyun, Schwarzschild Michael A, Hirst Warren, McLean Pamela J
Center for Translational Research in Neurodegenerative Disease, Department of Neurology, University of Florida, Gainesville, Florida, United States of America.
MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Charlestown, Massachusetts, United States of America.
PLoS One. 2014 Jan 20;9(1):e86048. doi: 10.1371/journal.pone.0086048. eCollection 2014.
Hsp90 inhibitors such as geldanamycin potently induce Hsp70 and reduce cytotoxicity due to α-synuclein expression, although their use has been limited due to toxicity, brain permeability, and drug design. We recently described the effects of a novel class of potent, small molecule Hsp90 inhibitors in cells overexpressing α-synuclein. Screening yielded several candidate compounds that significantly reduced α-synuclein oligomer formation and cytotoxicity associated with Hsp70 induction. In this study we examined whether chronic treatment with candidate Hsp90 inhibitors could protect against α-synuclein toxicity in a rat model of parkinsonism. Rats were injected unilaterally in the substantia nigra with AAV8 expressing human α-synuclein and then treated with drug for approximately 8 weeks by oral gavage. Chronic treatment with SNX-0723 or the more potent, SNX-9114 failed to reduce dopaminergic toxicity in the substantia nigra compared to vehicle. However, SNX-9114 significantly increased striatal dopamine content suggesting a positive neuromodulatory effect on striatal terminals. Treatment was generally well tolerated, but higher dose SNX-0723 (6-10 mg/kg) resulted in systemic toxicity, weight loss, and early death. Although still limited by potential toxicity, Hsp90 inhibitors tested herein demonstrate oral efficacy and possible beneficial effects on dopamine production in a vertebrate model of parkinsonism that warrant further study.
诸如格尔德霉素之类的热休克蛋白90（Hsp90）抑制剂可有效诱导热休克蛋白70（Hsp70）并降低因α-突触核蛋白表达而产生的细胞毒性，尽管由于毒性、脑通透性和药物设计问题，其应用受到了限制。我们最近描述了一类新型强效小分子Hsp90抑制剂在过表达α-突触核蛋白的细胞中的作用。筛选产生了几种候选化合物，这些化合物可显著减少α-突触核蛋白寡聚体的形成以及与Hsp70诱导相关的细胞毒性。在本研究中，我们检测了用候选Hsp90抑制剂进行长期治疗是否能在帕金森病大鼠模型中预防α-突触核蛋白毒性。大鼠单侧黑质注射表达人α-突触核蛋白的腺相关病毒8型（AAV8），然后通过口服灌胃给药约8周。与赋形剂相比，用SNX - 0723或更强效的SNX - 9114进行长期治疗未能降低黑质中的多巴胺能毒性。然而，SNX - 9114显著增加了纹状体多巴胺含量，表明对纹状体终末有积极的神经调节作用。治疗通常耐受性良好，但较高剂量的SNX - 0723（6 - 10 mg/kg）导致全身毒性、体重减轻和早期死亡。尽管仍受潜在毒性的限制，但本文测试的Hsp90抑制剂在帕金森病脊椎动物模型中显示出口服疗效以及对多巴胺产生可能的有益作用，值得进一步研究。
