Harrison, IF;
Powell, NM;
Dexter, DT;
(2019)
The Histone Deacetylase Inhibitor Nicotinamide Exacerbates Neurodegeneration in the Lactacystin Rat Model of Parkinson's Disease.
Journal of Neurochemistry
, 148
(1)
pp. 136-156.
10.1111/jnc.14599.
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Abstract
Histone hypoacetylation is associated with dopaminergic neurodegeneration in Parkinson's disease (PD), due to an imbalance in the activities of the enzymes responsible for histone (de)acetylation. Correction of this imbalance, with histone deacetylase (HDAC) inhibiting agents, could be neuroprotective. We therefore hypothesise that nicotinamide, being a selective inhibitor of HDAC class III as well as having modulatory effects on mitochondrial energy metabolism, would be neuroprotective in the lactacystin rat model of PD, which recapitulates the formation of neurotoxic accumulation of altered proteins within the substantia nigra to cause progressive dopaminergic cell death. Rats received nicotinamide for 28 days, starting 7 days after unilateral injection of the irreversible proteasome inhibitor, lactacystin, into the substantia nigra. Longitudinal motor behavioural testing and structural MRI were used to track changes in this model of PD, and assessment of nigrostriatal integrity, histone acetylation, and brain gene expression changes post-mortem used to quantify nicotinamide induced neuroprotection. Counterintuitively, nicotinamide dose-dependently exacerbated neurodegeneration of dopaminergic neurons, behavioural deficits, and structural brain changes in the lactacystin-lesioned rat. Nicotinamide treatment induced histone hyperacetylation and overexpression of numerous neurotrophic and anti-apoptotic factors in the brain, yet failed to result in neuroprotection, rather exacerbated dopaminergic pathology. These findings highlight the importance of inhibitor specificity within HDAC isoforms for therapeutic efficacy in PD, demonstrating the contrasting effects of HDAC class III inhibition upon cell survival in this animal model of the disease. This article is protected by copyright. All rights reserved.
| Type: | Article |
|---|---|
| Title: | The Histone Deacetylase Inhibitor Nicotinamide Exacerbates Neurodegeneration in the Lactacystin Rat Model of Parkinson's Disease |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1111/jnc.14599 |
| Publisher version: | http://doi.org/10.1111/jnc.14599 |
| Language: | English |
| Additional information: | Copyright © 2018 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry, J. Neurochem. (2018) 10.1111/jnc.14599 This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
| Keywords: | histone deacetylase inhibitor, lactacystin, neurodegeneration, nicotinamide, Parkinson’s disease, sirtuins. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Department of Imaging |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10062496 |
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