eprintid: 10062496
rev_number: 35
eprint_status: archive
userid: 608
dir: disk0/10/06/24/96
datestamp: 2018-11-29 14:35:51
lastmod: 2021-09-17 22:19:36
status_changed: 2019-02-13 10:01:27
type: article
metadata_visibility: show
creators_name: Harrison, IF
creators_name: Powell, NM
creators_name: Dexter, DT
title: The Histone Deacetylase Inhibitor Nicotinamide Exacerbates Neurodegeneration in the Lactacystin Rat Model of Parkinson's Disease
ispublished: pub
divisions: UCL
divisions: B02
divisions: C10
divisions: D17
divisions: FI6
keywords: histone deacetylase inhibitor, lactacystin, neurodegeneration,
nicotinamide, Parkinson’s disease, sirtuins.
note: 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.
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.
date: 2019-01
date_type: published
official_url: http://doi.org/10.1111/jnc.14599
oa_status: green
full_text_type: pub
language: eng
primo: open
primo_central: open_green
verified: verified_manual
elements_id: 1589630
doi: 10.1111/jnc.14599
lyricists_name: Harrison, Ian
lyricists_id: IHARR57
actors_name: Joyce, Sophia
actors_id: SJOYC12
actors_role: owner
full_text_status: public
publication: Journal of Neurochemistry
volume: 148
number: 1
pagerange: 136-156
event_location: England
issn: 1471-4159
citation:        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 <https://doi.org/10.1111/jnc.14599>.       Green open access   
 
document_url: https://discovery.ucl.ac.uk/id/eprint/10062496/7/Joyce%20VoR%20Harrison_et_al-2019-Journal_of_Neurochemistry.pdf