Tags

Type your tag names separated by a space and hit enter

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.
Br J Pharmacol. 2015 Aug; 172(16):4200-15.BJ

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.

Authors+Show Affiliations

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.Department of Neuroimaging, The James Black Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.Department of Basic and Clinical Neuroscience, The James Black Centre, Institute of Psychiatry, Psychology and Neuroscience, King's 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.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26040297

Citation

Harrison, Ian F., et al. "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." British Journal of Pharmacology, vol. 172, no. 16, 2015, pp. 4200-15.
Harrison IF, Crum WR, Vernon AC, et al. 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. Br J Pharmacol. 2015;172(16):4200-15.
Harrison, I. F., Crum, W. R., Vernon, A. C., & Dexter, D. T. (2015). 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. British Journal of Pharmacology, 172(16), 4200-15. https://doi.org/10.1111/bph.13208
Harrison IF, et al. 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. Br J Pharmacol. 2015;172(16):4200-15. PubMed PMID: 26040297.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Harrison,Ian F, AU - Crum,William R, AU - Vernon,Anthony C, AU - Dexter,David T, Y1 - 2015/07/08/ PY - 2015/01/16/received PY - 2015/05/11/revised PY - 2015/06/01/accepted PY - 2015/6/5/entrez PY - 2015/6/5/pubmed PY - 2016/5/14/medline SP - 4200 EP - 15 JF - British journal of pharmacology JO - Br J Pharmacol VL - 172 IS - 16 N2 - 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. SN - 1476-5381 UR - https://www.unboundmedicine.com/medline/citation/26040297/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_ L2 - https://doi.org/10.1111/bph.13208 DB - PRIME DP - Unbound Medicine ER -