LETHBRIDGE, NATASHA,LOUSIE (2011) Histamine H3 Receptor Heterogeneity in the Central Nervous System in Aging and Dementia. Doctoral thesis, Durham University.
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Author-imposed embargo until 27 February 2015.
The histamine H3R is a classic G-protein coupled receptor and is a potential therapeutic target for a number of central nervous system pathologies. Major pharmacological heterogeneity between and within species has hindered the clinical development of H3R-targeted drugs. The pharmacological heterogeneity displayed by the H3R is thought in part to be a result of alternative splicing of the H3R which generates a number of possible splice variants, some of which have been shown to be functional and others which appear to be non-functional in terms of ligand binding and signal transduction. mRNA encoding the different isoforms has been shown to be distributed throughout the central nervous system in a region specific manner. For the first time we have shown three of the common H3R isoforms (hH3 329, hH3 365, hH3 445) to be expressed in the human brain using a novel panel of immunological isoform specific probes. We provide preliminary evidence for raised levels of H3 445 and H3 329 isoforms in Parkinson’s disease and Lewy Body Dementia cases, respectively, compared to age-matched controls. We have shown a variety of H3R ligands display differential pharmacological properties at the three hH3R isoforms expressed in HEK 293 cells. Most notably a 5- and 10- fold lower affinity for a highly selective clinical lead H3R inverse antagonist, GSK189254, at the H3R 329 and H3R 329 + 365 isoforms, respectively. The pharmacological differences observed indicate, together with the availability of the immunological probes, that it will be possible to dissect the physiological roles of human H3 receptor isoforms.
The H3R is an attractive therapeutic target for age-related dementias. H3R antagonists have undergone a large number of pre-clinical assessments in which they display pro-cognitive effects, particularly in drug-induced amnesias. It is important to establish whether there are any changes in H3R expression in normal physiological aging and in age-related human dementias. Based on quantitative [3H] GSK189254 autoradiography, we have shown that H3Rs are largely preserved in key cortical and striatal brain regions in aged CD-1 and TASPM mice, as well as in aged humans. Furthermore, H3 receptors were largely unchanged in Lewy Body Dementia and Alzheimer’s disease cases, which provide further evidence validating the H3R as a promising target for age-related cognitive disorders. Psychotic symptoms are common features in both Lewy Body Dementia and Alzheimer’s disease. Interestingly, higher levels of H3R in the globus pallidus correlated with the presence of both delusions (+ 40% and + 37%) and hallucination symptoms (+22% and +14%) within these human dementias, consistent with the recent positive clinical use of H3R antagonists in psychotic disorders. In contrast, using a novel validated all-in-one behavioural elevated platform test in mice, evidence is provided for the lack of H3R involvement in anxiety behaviour, suggesting the lack of utility in human anxiety disorders.
|Item Type:||Thesis (Doctoral)|
|Award:||Doctor of Philosophy|
|Faculty and Department:||Faculty of Science > Biological and Biomedical Sciences, School of|
|Copyright:||Copyright of this thesis is held by the author|
|Deposited On:||06 Jun 2011 10:14|