eprintid: 1476676
rev_number: 25
eprint_status: archive
userid: 608
dir: disk0/01/47/66/76
datestamp: 2016-03-16 12:12:20
lastmod: 2021-09-23 22:22:33
status_changed: 2016-03-16 12:12:20
type: article
metadata_visibility: show
creators_name: Harrison, IF
creators_name: Anis, HK
creators_name: Dexter, DT
title: Associated degeneration of ventral tegmental area dopaminergic neurons in the rat nigrostriatal lactacystin model of parkinsonism and their neuroprotection by valproate
ispublished: pub
divisions: UCL
divisions: B02
divisions: C10
divisions: D17
divisions: FI6
keywords: Dopamine, Histone deacetylase inhibitor, Lactacystin, Parkinson’s disease, Substantia Nigra pars compacta, Valproate, Ventral tegmental area
note: © 2015 The Authors. Published by Elsevier Ireland Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
abstract: Parkinson's disease (PD) manifests clinically as bradykinesia, rigidity, and development of a resting tremor, primarily due to degeneration of dopaminergic nigrostriatal pathways in the brain. Intranigral administration of the irreversible ubiquitin proteasome system inhibitor, lactacystin, has been used extensively to model nigrostriatal degeneration in rats, and study the effects of candidate neuroprotective agents on the integrity of the dopaminergic nigrostriatal system. Recently however, adjacent extra-nigral brain regions such as the ventral tegmental area (VTA) have been noted to also become affected in this model, yet their integrity in studies of candidate neuroprotective agents in the model have largely been overlooked. Here we quantify the extent and distribution of dopaminergic degeneration in the VTA of rats intranigrally lesioned with lactacystin, and quantify the extent of VTA dopaminergic neuroprotection after systemic treatment with an epigenetic therapeutic agent, valproate, shown previously to protect dopaminergic SNpc neurons in this model. We found that unilateral intranigral administration of lactacystin resulted in a 53.81% and 31.72% interhemispheric loss of dopaminergic SNpc and VTA neurons, respectively. Daily systemic treatment of lactacystin lesioned rats with valproate however resulted in dose-dependant neuroprotection of VTA neurons. Our findings demonstrate that not only is the VTA also affected in the intranigral lactacystin rat model of PD, but that this extra-nigral brain region is substrate for neuroprotection by valproate, an agent shown previously to induce neuroprotection and neurorestoration of SNpc dopaminergic neurons in this model. Our results therefore suggest that valproate is a candidate for extra-nigral as well as intra-nigral neuroprotection.
date: 2016-02-12
date_type: published
official_url: http://dx.doi.org/10.1016/j.neulet.2015.12.052
oa_status: green
full_text_type: pub
pmcid: PMC4756273
language: eng
primo: open
primo_central: open_green
article_type_text: Journal Article
verified: verified_manual
elements_id: 1098643
doi: 10.1016/j.neulet.2015.12.052
pii: S0304-3940(15)30343-8
language_elements: eng
lyricists_name: Harrison, Ian
lyricists_id: IHARR57
actors_name: Barczynska, Patrycja
actors_id: PBARC91
actors_role: owner
full_text_status: public
publication: Neuroscience Letters
volume: 614
pagerange: 16-23
event_location: Ireland
issn: 1872-7972
citation:        Harrison, IF;    Anis, HK;    Dexter, DT;      (2016)    Associated degeneration of ventral tegmental area dopaminergic neurons in the rat nigrostriatal lactacystin model of parkinsonism and their neuroprotection by valproate.                   Neuroscience Letters , 614    pp. 16-23.    10.1016/j.neulet.2015.12.052 <https://doi.org/10.1016/j.neulet.2015.12.052>.       Green open access   
 
document_url: https://discovery.ucl.ac.uk/id/eprint/1476676/1/1-s2.0-S0304394015303438-main.pdf