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This hypothesis was tested using the anti\u2010epileptic drug sodium valproate, a known histone deacetylase inhibitor (\n                      <jats:styled-content style=\"fixed-case\">HDACI<\/jats:styled-content>\n                      ), utilizing a delayed\u2010start study design in the lactacystin rat model of\n                      <jats:styled-content style=\"fixed-case\">PD<\/jats:styled-content>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>\n                      The irreversible proteasome inhibitor lactacystin was unilaterally injected into the substantia nigra of\n                      <jats:styled-content style=\"fixed-case\">S<\/jats:styled-content>\n                      prague\u2013\n                      <jats:styled-content style=\"fixed-case\">D<\/jats:styled-content>\n                      awley rats that subsequently received valproate for 28 days starting 7 days after lactacystin lesioning. Longitudinal motor behavioural testing, structural\n                      <jats:styled-content style=\"fixed-case\">MRI<\/jats:styled-content>\n                      and\n                      <jats:italic>post\u2010mortem<\/jats:italic>\n                      assessment of nigrostriatal integrity were used to track changes in this model of\n                      <jats:styled-content style=\"fixed-case\">PD<\/jats:styled-content>\n                      and quantify neuroprotection\/restoration. Subsequent cellular and molecular analyses were performed to elucidate the mechanisms underlying valproate's effects.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>Despite producing a distinct pattern of structural re\u2010modelling in the healthy and lactacystin\u2010lesioned brain, delayed\u2010start valproate administration induced dose\u2010dependent neuroprotection\/restoration against lactacystin neurotoxicity, characterized by motor deficit alleviation, attenuation of morphological brain changes and restoration of dopaminergic neurons in the substantia nigra. Molecular analyses revealed that valproate alleviated lactacystin\u2010induced histone hypoacetylation and induced up\u2010regulation of brain neurotrophic\/neuroprotective factors.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions and Implications<\/jats:title>\n                    <jats:p>\n                      The histone acetylation and up\u2010regulation of neurotrophic\/neuroprotective factors associated with valproate treatment culminate in a neuroprotective and neurorestorative phenotype in this animal model of\n                      <jats:styled-content style=\"fixed-case\">PD<\/jats:styled-content>\n                      . As valproate induced structural re\u2010modelling of the brain, further research is required to determine whether valproate represents a viable candidate for disease treatment; however, the results suggest that\n                      <jats:styled-content style=\"fixed-case\">HDACIs<\/jats:styled-content>\n                      could hold potential as disease\u2010modifying agents in\n                      <jats:styled-content style=\"fixed-case\">PD<\/jats:styled-content>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.13208","type":"journal-article","created":{"date-parts":[[2015,6,4]],"date-time":"2015-06-04T07:26:16Z","timestamp":1433402776000},"page":"4200-4215","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":61,"title":["Neurorestoration induced by the\n                    <scp>HDAC<\/scp>\n                    inhibitor sodium valproate in the lactacystin model of\n                    <scp>P<\/scp>\n                    arkinson's is associated with histone acetylation and up\u2010regulation of neurotrophic factors"],"prefix":"10.1111","volume":"172","author":[{"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 Centre for Neuroinflammation and Neurodegeneration Division of Brain Sciences Department of Medicine Imperial College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William R","family":"Crum","sequence":"additional","affiliation":[{"name":"Department of Neuroimaging The James Black Centre Institute of Psychiatry, Psychology and Neuroscience King's College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony C","family":"Vernon","sequence":"additional","affiliation":[{"name":"Department of 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