Chronic Treatment with Novel Small Molecule Hsp90 Inhibitors Rescues Striatal Dopamine Levels but Not α-Synuclein-Induced Neuronal Cell Loss.docVIP

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Chronic Treatment with Novel Small Molecule Hsp90 Inhibitors Rescues Striatal Dopamine Levels but Not α-Synuclein-Induced Neuronal Cell Loss.doc

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Chronic Treatment with Novel Small Molecule Hsp90 Inhibitors Rescues Striatal Dopamine Levels but Not α-Synuclein-Induced Neuronal Cell Loss

ChronicTreatmentwithNovelSmallMoleculeHsp90 InhibitorsRescuesStriatalDopamineLevelsbutNota- Synuclein-InducedNeuronalCellLoss NikolausR.McFarland1*.,HemiDimant2.,LauraKibuuka2,DariusEbrahimi-Fakhari3, CodyA.Desjardins2,KarinM.Danzer4,MichaelDanzer2,ZhanyunFan2,MichaelA.Schwarzschild2, WarrenHirst5,PamelaJ.McLean6* 1Center for Translational Research in Neurodegenerative Disease, Department of Neurology, University of Florida, Gainesville, Florida, United States of America, 2MassGeneralInstituteforNeurodegenerativeDisease,DepartmentofNeurology,MassachusettsGeneralHospital,Charlestown,Massachusetts,UnitedStatesofAmerica, 3DivisionofNeurologyandInheritedMetabolicDiseases,Children’sHospital,HeidelbergUniversityHospital,Ruprecht-KarlsUniversityHeidelberg,Heidelberg,Germany, 4Deparment of Neurology, Universitatsklinikum Ulm, Ulm, Germany, 5Pfizer Neuroscience Research Unit, Cambridge, Massachusetts, United States of America, 6DepartmentofNeuroscience,MayoClinic,Jacksonville,Florida,UnitedStatesofAmerica Abstract Hsp90 inhibitors such as geldanamycin potently induce Hsp70 and reduce cytotoxicity due to a-synuclein expression, althoughtheirusehasbeenlimitedduetotoxicity,brainpermeability,anddrugdesign.Werecentlydescribedtheeffects ofanovelclassofpotent,smallmoleculeHsp90inhibitorsincellsoverexpressing a-synuclein.Screeningyieldedseveral candidate compounds that significantly reduced a-synuclein oligomer formation and cytotoxicity associated with Hsp70 induction.InthisstudyweexaminedwhetherchronictreatmentwithcandidateHsp90inhibitorscouldprotectagainsta- synuclein toxicity in a rat model of parkinsonism. Rats were injected unilaterally in the substantia nigra with AAV8 expressinghumana-synucleinandthentreatedwithdrugforapproximately8weeksbyoralgavage.Chronictreatment withSNX-0723orthemorepotent,SNX-9114failedtoreducedopaminergictoxicityinthesubstantianigracomparedto vehicle.However,SNX-9114significantlyincreasedstriataldopaminecontentsuggestingapositiveneuromodulator