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Correction of this imbalance, with histone deacetylase (<jats:styled-content style=\"fixed-case\">HDAC<\/jats:styled-content>) inhibiting agents, could be neuroprotective. We therefore hypothesize that nicotinamide, being a selective inhibitor of <jats:styled-content style=\"fixed-case\">HDAC<\/jats:styled-content> class <jats:styled-content style=\"fixed-case\">III<\/jats:styled-content> as well as having modulatory effects on mitochondrial energy metabolism, would be neuroprotective in the lactacystin rat model of <jats:styled-content style=\"fixed-case\">PD<\/jats:styled-content>, which recapitulates the formation of neurotoxic accumulation of altered proteins within the substantia nigra to cause progressive dopaminergic cell death. Rats received nicotinamide for 28\u00a0days, starting 7\u00a0days after unilateral injection of the irreversible proteasome inhibitor, lactacystin, into the substantia nigra. Longitudinal motor behavioural testing and structural magnetic resonance imaging were used to track changes in this model of <jats:styled-content style=\"fixed-case\">PD<\/jats:styled-content>, and assessment of nigrostriatal integrity, histone acetylation and brain gene expression changes post\u2010mortem used to quantify nicotinamide\u2010induced neuroprotection. Counterintuitively, nicotinamide dose\u2010dependently exacerbated neurodegeneration of dopaminergic neurons, behavioural deficits and structural brain changes in the lactacystin\u2010lesioned rat. Nicotinamide treatment induced histone hyperacetylation and over\u2010expression of numerous neurotrophic and anti\u2010apoptotic factors in the brain, yet failed to result in neuroprotection, rather exacerbated dopaminergic pathology. These findings highlight the importance of inhibitor specificity within <jats:styled-content style=\"fixed-case\">HDAC<\/jats:styled-content> isoforms for therapeutic efficacy in <jats:styled-content style=\"fixed-case\">PD<\/jats:styled-content>, demonstrating the contrasting effects of <jats:styled-content style=\"fixed-case\">HDAC<\/jats:styled-content> class <jats:styled-content style=\"fixed-case\">III<\/jats:styled-content> inhibition upon cell survival in this animal model of the disease.<\/jats:p><\/jats:sec><jats:sec><jats:title>Open science badges<\/jats:title><jats:p><jats:inline-graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"graphic\/jnc14599-gra-0001.png\" xlink:title=\"image\"\/><\/jats:p><jats:p>This article has received a badge for *<jats:bold>Open Materials<\/jats:bold>* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/cos.io\/our-services\/open-science-badges\/\">https:\/\/cos.io\/our-services\/open-science-badges\/<\/jats:ext-link>.<\/jats:p><\/jats:sec><jats:sec><jats:label\/><jats:p>\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc14599-fig-0009-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><\/jats:sec>","DOI":"10.1111\/jnc.14599","type":"journal-article","created":{"date-parts":[[2018,9,30]],"date-time":"2018-09-30T11:40:15Z","timestamp":1538307615000},"page":"136-156","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":52,"title":["The histone deacetylase inhibitor nicotinamide exacerbates neurodegeneration in the lactacystin rat model of Parkinson's disease"],"prefix":"10.1111","volume":"148","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1250-4911","authenticated-orcid":false,"given":"Ian F.","family":"Harrison","sequence":"first","affiliation":[{"name":"UCL Centre for Advanced Biomedical Imaging Division of Medicine University College London London UK"},{"name":"Parkinson's Disease Research Group Division of Brain Sciences Department of Medicine Centre for Neuroinflammation and Neurodegeneration Imperial College London London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas M.","family":"Powell","sequence":"additional","affiliation":[{"name":"UCL Centre for Advanced Biomedical Imaging Division of Medicine University College London London UK"},{"name":"Translational Imaging Group Centre for Medical Image Computing University College London London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David T.","family":"Dexter","sequence":"additional","affiliation":[{"name":"Parkinson's Disease Research Group Division of Brain Sciences Department of Medicine Centre for Neuroinflammation and Neurodegeneration Imperial College London London 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