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Neurorestoration induced by the HDAC inhibitor sodium valproate in the lactacystin model of P arkinson's is associated with histone acetylation and up‐regulation of neurotrophic factors
Author(s) -
Harrison Ian F,
Crum William R,
Ver Anthony C,
Dexter David T
Publication year - 2015
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13208
Subject(s) - acetylation , lactacystin , histone deacetylase inhibitor , histone , histone h4 , valproic acid , chemistry , hdac4 , neurotrophin , histone deacetylase , pharmacology , microbiology and biotechnology , neuroscience , biochemistry , biology , proteasome inhibitor , apoptosis , receptor , epilepsy , gene
Background and Purpose Histone hypoacetylation is associated with P arkinson'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 S prague– D awley 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 .