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Br J Pharmacol. 2015 Aug;172(16):4200-15. doi: 10.1111/bph.13208. Epub 2015 Jul 8.

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.

Author information

1
UCL Centre for Advanced Biomedical Imaging, Division of Medicine, University College London, London, UK.
2
Parkinson's Disease Research Group, Centre for Neuroinflammation and Neurodegeneration, Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK.
3
Department of Neuroimaging, The James Black Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
4
Department of Basic and Clinical Neuroscience, The James Black Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Abstract

BACKGROUND AND PURPOSE:

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.

EXPERIMENTAL APPROACH:

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.

KEY 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 AND IMPLICATIONS:

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.

PMID:
26040297
PMCID:
PMC4543623
DOI:
10.1111/bph.13208
[Indexed for MEDLINE]
Free PMC Article

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