Peripheral administration of the Class-IIa HDAC inhibitor MC1568 partially protects against nigrostriatal neurodegeneration in the striatal 6-OHDA rat model of Parkinson’s disease

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dc.contributor.authorMazzocchi, Martinaen
dc.contributor.authorGoulding, Susan R.en
dc.contributor.authorMorales-Prieto, Noeliaen
dc.contributor.authorFoley, Taraen
dc.contributor.authorCollins, Louise M.en
dc.contributor.authorSullivan, Aideen M.en
dc.contributor.authorO'Keeffe, Gerard W.en
dc.contributor.funderScience Foundation Irelanden
dc.contributor.funderIrish Research Councilen
dc.contributor.funderHORIZON EUROPE Marie Sklodowska-Curie Actionsen
dc.date.accessioned2024-05-14T15:35:59Z
dc.date.available2024-05-14T15:35:59Z
dc.date.issued2022-02-25en
dc.description.abstractParkinson’s disease (PD) is a neurodegenerative disorder characterised by nigrostriatal dopaminergic (DA) neurodegeneration. There is a critical need for neuroprotective therapies, particularly those that do not require direct intracranial administration. Small molecule inhibitors of histone deacetylases (HDIs) are neuroprotective in in vitro and in vivo models of PD, however it is unknown whether Class IIa-specific HDIs are neuroprotective when administered peripherally. Here we show that 6-hydroxydopamine (6-OHDA) treatment induces protein kinase C (PKC)-dependent nuclear accumulation of the Class IIa histone deacetylase (HDAC)5 in SH-SY5Y cells and cultured DA neurons in vitro. Treatment of these cultures with the Class IIa-specific HDI, MC1568, partially protected against 6-OHDA-induced cell death. In the intrastriatal 6-OHDA lesion in vivo rat model of PD, MC1568 treatment (0.5 mg/kg i.p.) for 7 days reduced forelimb akinesia and partially protected DA neurons in the substantia nigra and their striatal terminals from 6-OHDA-induced neurodegeneration. MC1568 treatment prevented 6-OHDA-induced increases in microglial activation in the striatum and substantia nigra. Furthermore, MC1568 treatment decreased 6-OHDA-induced increases in nuclear HDAC5 in nigral DA neurons. These data suggest that peripheral administration of Class IIa-specific HDIs may be a potential therapy for neuroprotective in PD.en
dc.description.sponsorshipScience Foundation Ireland (SFI grant number 19/FFP/6666); Irish Research Council (grant number GOIPG/2017/945); Marie Skłodowska-Curie Fellowship programme (grant number MSCA-IF-2019 890290)en
dc.description.statusPeer revieweden
dc.description.versionPublished Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationMazzocchi, M., Goulding, S.R., Morales-Prieto, N., Foley, T., Collins, L.M., Sullivan, A.M. and O’Keeffe, G.W. (2022) ‘Peripheral administration of the Class-IIa HDAC inhibitor MC1568 partially protects against nigrostriatal neurodegeneration in the striatal 6-OHDA rat model of Parkinson’s disease’, Brain, Behavior, and Immunity, 102, pp. 151–160. Available at: https://doi.org/10.1016/j.bbi.2022.02.025.en
dc.identifier.doihttps://doi.org/10.1016/j.bbi.2022.02.025.en
dc.identifier.endpage160en
dc.identifier.issn0889-1591en
dc.identifier.journaltitleBrain, Behavior, and Immunityen
dc.identifier.startpage151en
dc.identifier.urihttps://hdl.handle.net/10468/15865
dc.identifier.volume102en
dc.language.isoenen
dc.publisherElsevieren
dc.relation.ispartofBrain, Behavior, and Immunityen
dc.rights© 2022 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectParkinson’s diseaseen
dc.subject6-hydroxydopamineen
dc.subjectNeuroprotectionen
dc.subjectHistone deacetylaseen
dc.subjectHDAC5en
dc.subjectHistone deacetylase inhibitoren
dc.titlePeripheral administration of the Class-IIa HDAC inhibitor MC1568 partially protects against nigrostriatal neurodegeneration in the striatal 6-OHDA rat model of Parkinson’s diseaseen
dc.typeArticle (peer-reviewed)en
oaire.citation.volume102en
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