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

• Verfasst von: McFarland, Nikolaus R. [VerfasserIn]
• Verfasst von: Dimant, Hemi [VerfasserIn]
• Verfasst von: Kibuuka, Laura [VerfasserIn]
• Verfasst von: Ebrahimi-Fakhari, Darius [VerfasserIn]
• Verfasst von: Desjardins, Cody A. [VerfasserIn]
• Verfasst von: Danzer, Karin M. [VerfasserIn]
• Verfasst von: Danzer, Michael [VerfasserIn]
• Verfasst von: Fan, Zhanyun [VerfasserIn]
• Verfasst von: Schwarzschild, Michael A. [VerfasserIn]
• Verfasst von: Hirst, Warren [VerfasserIn]
• Verfasst von: McLean, Pamela J. [VerfasserIn]
• Titel: Chronic treatment with novel small molecule Hsp90 inhibitors rescues striatal dopamine levels but not α-synuclein-induced neuronal cell loss
• Verf.angabe: 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
• E-Jahr: 2014
• Jahr: January 20, 2014
• Umfang: 8 S.
• Fussnoten: Gesehen am 28.10.2020
• Titel Quelle: Enthalten in: PLOS ONE
• Ort Quelle: San Francisco, California, US : PLOS, 2006
• Jahr Quelle: 2014
• Band/Heft Quelle: 9(2014,1) artikel-Nummer e86048, 8 Seiten
• ISSN Quelle: 1932-6203
• DOI: doi:10.1371/journal.pone.0086048
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Body weight
• Sach-SW: Dopamine
• Sach-SW: Dopaminergics
• Sach-SW: Drug therapy
• Sach-SW: Neostriatum
• Sach-SW: Parkinson disease
• Sach-SW: Small molecules
• Sach-SW: Toxicity
• K10plus-PPN: 1736843532

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.