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 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.
Center for Translational Research in Neurodegenerative Disease, Department of Neurology, University of Florida, Gainesville, Florida, United States of America.
Nikolaus R
NR
McFarland
MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Charlestown, Massachusetts, United States of America.
Hemi
H
Dimant
MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Charlestown, Massachusetts, United States of America.
Laura
L
Kibuuka
Division of Neurology and Inherited Metabolic Diseases, Children's Hospital, Heidelberg University Hospital, Ruprecht-Karls University Heidelberg, Heidelberg, Germany.
Darius
D
Ebrahimi-Fakhari
MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Charlestown, Massachusetts, United States of America.
Cody A
CA
Desjardins
Deparment of Neurology, Universitatsklinikum Ulm, Ulm, Germany.
Karin M
KM
Danzer
MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Charlestown, Massachusetts, United States of America.
Michael
M
Danzer
MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Charlestown, Massachusetts, United States of America.
Zhanyun
Z
Fan
MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Charlestown, Massachusetts, United States of America.
Michael A
MA
Schwarzschild
Pfizer Neuroscience Research Unit, Cambridge, Massachusetts, United States of America.
Warren
W
Hirst
Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, United States of America.
Pamela J
PJ
McLean
D000818:Animals; D001549:Benzamides / Q000627:therapeutic use*; D004298:Dopamine / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000627:therapeutic use*; D008297:Male; D017072:Neostriatum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011743:Pyrimidines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051844:alpha-Synuclein / Q000378:metabolism*; D062367:ortho-Aminobenzoates / Q000627:therapeutic use*
C548545:2-fluoro-6-(tetrahydrofuran-3-ylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; D001549:Benzamides; D018841:HSP90 Heat-Shock Proteins; D007211:Indoles; D011743:Pyrimidines; C000594730:SNX-9114; D051844:alpha-Synuclein; D062367:ortho-Aminobenzoates; D004298:Dopamine