Chronic treatment with novel small molecule Hsp90 inhibitors rescues striatal dopamine levels but not α-synuclein-induced neuronal cell loss

Nikolaus R. McFarland, Hemi Dimant, Laura Kibuuka, Darius Ebrahimi-Fakhari, Cody A. Desjardins, Karin M. Danzer, Michael Danzer, Zhanyun Fan, Michael A. Schwarzschild, Warren Hirst, Pamela J McLean

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21 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article numbere86048
JournalPLoS One
Volume9
Issue number1
DOIs
StatePublished - Jan 20 2014

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ASJC Scopus subject areas

  • Medicine(all)
  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

McFarland, N. R., Dimant, H., Kibuuka, L., Ebrahimi-Fakhari, D., Desjardins, C. A., Danzer, K. M., Danzer, M., Fan, Z., Schwarzschild, M. A., Hirst, W., & McLean, P. J. (2014). Chronic treatment with novel small molecule Hsp90 inhibitors rescues striatal dopamine levels but not α-synuclein-induced neuronal cell loss. PLoS One, 9(1), [e86048]. https://doi.org/10.1371/journal.pone.0086048