Imperial College London
Alternate

ProfessorDavidDexter

Faculty of Medicine, Department of Brain Sciences

Visiting Professor of Neuropharmacology
 
 
 
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Contact

 

+44 (0)20 7594 6665d.dexter Website

 
 
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Location

 

E411Burlington DanesHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Harrison:2015:10.1111/bph.13208,
author = {Harrison, IF and Crum, WR and Vernon, AC and Dexter, DT},
doi = {10.1111/bph.13208},
journal = {British Journal of Pharmacology},
pages = {4200--4215},
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},
url = {http://dx.doi.org/10.1111/bph.13208},
volume = {172},
year = {2015}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Background and PurposeHistone 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 ApproachThe 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 ResultsDespite 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 ImplicationsThe 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 re
AU  - Harrison,IF
AU  - Crum,WR
AU  - Vernon,AC
AU  - Dexter,DT
DO  - 10.1111/bph.13208
EP  - 4215
PY  - 2015///
SN  - 1476-5381
SP  - 4200
TI  - 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
T2  - British Journal of Pharmacology
UR  - http://dx.doi.org/10.1111/bph.13208
UR  - http://hdl.handle.net/10044/1/30047
VL  - 172
ER  -
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