Chronic treatment with novel small molecule Hsp90 inhibitors rescues striatal dopamine levels but not α-synuclein-induced neuronal cell loss
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 i...
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| Main Authors: | , , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
January 20, 2014
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| In: |
PLOS ONE
Year: 2014, Volume: 9, Issue: 1 |
| ISSN: | 1932-6203 |
| DOI: | 10.1371/journal.pone.0086048 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1371/journal.pone.0086048 Verlag, lizenzpflichtig, Volltext: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0086048 
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| Author Notes: | 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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| 245 | 1 | 0 | |a Chronic treatment with novel small molecule Hsp90 inhibitors rescues striatal dopamine levels but not α-synuclein-induced neuronal cell loss |c 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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| 520 | |a 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. | ||
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