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Title: Mechanisms underlying the neuroprotective effects of histone deacetylase inhibitors
Author: Durham, Benjamin Stuart
ISNI:       0000 0004 5372 2103
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2015
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Histone deacetylase (HDAC) inhibitors prevent neuronal death in in vivo models of cerebral ischaemia, brain injuries and neurodegenerative disease. However the molecular mechanisms underlying this are not fully understood and neither the cell type nor the specific HDAC isoform responsible is known. To address these questions, I investigated the effects of selectively inhibiting HDAC isoforms in different neural cell models of the pathophysiological mechanisms implicated in these brain conditions. Initially, the efficacy of HDAC inhibitors to protect cerebellar granule neurones from glutamate excitotoxicity and oxygen glucose deprivation (OGD) was examined. It was found that inhibiting HDACs did not protect isolated neurones from these insults. To determine if HDAC inhibitors are neuroprotective through effects in other neural cells, I investigated if inhibiting HDACs in BV2 microglia could suppress the inflammatory response stimulated by lipopolysaccharide (LPS). Using this model, the data presented in this thesis shows for the first time that selective inhibition of class I HDAC isoforms, or knockdown of HDAC1 or HDAC2 in microglia, suppresses the expression of pro-inflammatory mediators interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-α). Investigating the possible underlying mechanisms suggests an increase in protein expression is not important and HDAC inhibitors have an anti-inflammatory effect by increasing the acetylation state of pre-existing proteins. The data presented also suggests there is functional redundancy of HDAC1 & HDAC2 in regulating the inflammatory response. Therefore, selectively inhibiting either isoform may be a strategy to reduce neuroinflammation and by doing so protect neurones in cerebral ischaemia and other brain conditions, whilst minimising the side effects associated with pan-HDAC inhibition.
Supervisor: Wood, Ian Christopher Sponsor: Biotechnology and Biological Sciences Research Council (BBSRC)
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available