title: Neurorestoration induced by the HDAC inhibitor sodium valproate in the lactacystin model of Parkinson's is associated with histone acetylation and up-regulation of neurotrophic factors.
abstract: OBJECTIVE
  Histone hypoacetylation is associated with Parkinson's disease (PD), due possibly to an imbalance in the activities of enzymes responsible for histone (de)acetylation; correction of which may be neuroprotective/neurorestorative. This hypothesis was tested using the anti-epileptic drug sodium valproate, a known histone deacetylase inhibitor (HDACI), utilizing a delayed-start study design in the lactacystin rat model of PD.
  
  
  METHODS
  The irreversible proteasome inhibitor lactacystin was unilaterally injected into the substantia nigra of Sprague-Dawley rats that subsequently received valproate for 28 days starting 7 days after lactacystin lesioning. Longitudinal motor behavioural testing, structural MRI and post-mortem assessment of nigrostriatal integrity were used to track changes in this model of PD and quantify neuroprotection/restoration. Subsequent cellular and molecular analyses were performed to elucidate the mechanisms underlying valproate's effects.
  
  
  RESULTS
  Despite producing a distinct pattern of structural re-modelling in the healthy and lactacystin-lesioned brain, delayed-start valproate administration induced dose-dependent 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-induced histone hypoacetylation and induced up-regulation of brain neurotrophic/neuroprotective factors.
  
  
  CONCLUSIONS
  The histone acetylation and up-regulation of neurotrophic/neuroprotective factors associated with valproate treatment culminate in a neuroprotective and neurorestorative phenotype in this animal model of PD. As valproate induced structural re-modelling of the brain, further research is required to determine whether valproate represents a viable candidate for disease treatment; however, the results suggest that HDACIs could hold potential as disease-modifying agents in PD.
authors.affiliation: UCL Centre for Advanced Biomedical Imaging, Division of Medicine, University College London, London, UK.|Parkinson's Disease Research Group, Centre for Neuroinflammation and Neurodegeneration, Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK.
authors.forename: Ian F
authors.initials: IF
authors.lastname: Harrison
authors.affiliation: Department of Neuroimaging, The James Black Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors.forename: William R
authors.initials: WR
authors.lastname: Crum
authors.affiliation: Department of Basic and Clinical Neuroscience, The James Black Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors.forename: Anthony C
authors.initials: AC
authors.lastname: Vernon
authors.affiliation: Parkinson's Disease Research Group, Centre for Neuroinflammation and Neurodegeneration, Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK.
authors.forename: David T
authors.initials: DT
authors.lastname: Dexter
mesh_terms: D000107:Acetylation; D000111:Acetylcysteine / Q000031:analogs & derivatives; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000502:physiology; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006657:Histones / Q000378:metabolism; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation; D014635:Valproic Acid / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D051100:Glial Cell Line-Derived Neurotrophic Factor; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D018696:Neuroprotective Agents; D019253:Proto-Oncogene Proteins c-bcl-2; C067713:lactacystin; D014635:Valproic Acid; D000111:Acetylcysteine