Quinacrine and niclosamide promote neurite growth in midbrain dopaminergic neurons through the canonical BMP-Smad pathway and protect against neurotoxin and a-synuclein-induced neurodegeneration

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dc.contributor.authorGoulding, Susan R.
dc.contributor.authorLévesque, Martin
dc.contributor.authorSullivan, Aideen M.
dc.contributor.authorCollins, Louise M.
dc.contributor.authorO'Keeffe, Gerard W.
dc.contributor.funderMunster Technological University, Irelanden
dc.contributor.funderScience Foundation Irelanden
dc.date.accessioned2021-04-08T12:54:48Z
dc.date.available2021-04-08T12:54:48Z
dc.date.issued2021-03-12
dc.date.updated2021-04-08T12:44:59Z
dc.description.abstractParkinson's disease is a neurodegenerative disorder characterised by nigrostriatal dopaminergic degeneration, and intracellular a-synuclein aggregation. Current pharmacological treatments are solely symptomatic so there is a need to identify agents that can slow or stop dopaminergic degeneration. One proposed class of therapeutics are neurotrophic factors which promote the survival of nigrostriatal dopaminergic neurons. However, neurotrophic factors need to be delivered directly to the brain. An alternative approach may be to identify pharmacological agents which can reach the brain to stimulate neurotrophic factor expression and/or their signalling pathways in dopaminergic neurons. BMP2 is a neurotrophic factor that is expressed in the human substantia nigra; exogenous BMP2 administration protects against dopaminergic degeneration in in vitro models of PD. In this study, we investigated the neurotrophic potential of two FDA-approved drugs, quinacrine and niclosamide, that are modulators of BMP2 signalling. We report that quinacrine and niclosamide, like BMP2, significantly increased neurite length, as a readout of neurotrophic action, in SH-SY5Y cells and dopaminergic neurons in primary cultures of rat ventral mesencephalon. We also show that these effects of quinacrine and niclosamide require the activation of BMP-Smad signalling. Finally, we demonstrate that quinacrine and niclosamide are neuroprotective against degeneration induced by the neurotoxins, MPP+ and 6-OHDA, and by viral-mediated overexpression of a-synuclein in vitro. Collectively, this study identifies two drugs, that are safe for use in patients' to 'are approved for human use, that exert neurotrophic effects on dopaminergic neurons through modulation of BMP-Smad signalling. This rationalises the further study of drugs that target the BMP-Smad pathway as potential neuroprotective pharmacotherapy for Parkinson's disease.en
dc.description.sponsorshipMunster Technological University (RISAM PhD scholarship (R00094948)); Science Foundation Ireland (SFI under the grant numbers 15/CDA/3498)en
dc.description.statusPeer revieweden
dc.description.versionAccepted Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationGoulding, S. R., Lévesque, M., Sullivan, A. M., Collins, L. M. and O’Keeffe, G. W. (2021) 'Quinacrine and Niclosamide Promote Neurite Growth in Midbrain Dopaminergic Neurons Through the Canonical BMP-Smad Pathway and Protect Against Neurotoxin and α-Synuclein-Induced Neurodegeneration', Molecular Neurobiology, (12 pp). doi: 10.1007/s12035-021-02351-8en
dc.identifier.doi10.1007/s12035-021-02351-8en
dc.identifier.endpage12en
dc.identifier.issn1559-1182
dc.identifier.journaltitleMolecular Neurobiologyen
dc.identifier.startpage1en
dc.identifier.urihttps://hdl.handle.net/10468/11185
dc.language.isoenen
dc.publisherSpringeren
dc.relation.projectinfo:eu-repo/grantAgreement/SFI/SFI Career Development Award/15/CDA/3498/IE/Development of GDF5 neurotrophic factor therapy for Parkinson_s disease./en
dc.relation.urihttps://link.springer.com/article/10.1007%2Fs12035-021-02351-8
dc.rights© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2021en
dc.subjectQuinacrineen
dc.subjectNiclosamideen
dc.subjectAlpha synucleinen
dc.subjectDegenerationen
dc.subjectSmad signallingen
dc.subjectParkinson's diseaseen
dc.titleQuinacrine and niclosamide promote neurite growth in midbrain dopaminergic neurons through the canonical BMP-Smad pathway and protect against neurotoxin and a-synuclein-induced neurodegenerationen
dc.typeArticle (peer-reviewed)en
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