Hadjihambi, Anna;
(2017)
Neurochemistry of the Hepatic Encephalopathy.
Doctoral thesis (Ph.D), UCL (University College London).
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A. Hadjihambi, UCL, PhD thesis final report.pdf - Accepted Version Download (27MB) | Preview |
Abstract
The pathogenesis of hepatic encephalopathy (HE) in cirrhosis is multifactorial and the role of ammonia remains controversial. Experimental studies conducted in animal (rat) models of HE, in combination with pharmacological approaches, were used to test the hypothesis that during HE, chronic exposure to elevated ammonia concentrations alters cerebral oxygenation, compromises lactate transport between astrocytes and neurons, and impairs uptake of neurotransmitters. It was also hypothesised that HE impairs glymphatic clearance mechanisms, either as a cause or a consequence of the disease, which exacerbates the detrimental central nervous effects of the accumulated toxins. The results of the experiments described in this thesis suggest that in HE: a) ammonia compromises cerebral oxygenation, but does not affect cerebrovascular reactivity, b) ammonia mediates cortical hemichannel dysfunction and impairs channel-mediated lactate release, potentially interfering with the astrocyte-neuron lactate shuttle, c) hyperammonemia results in a significant increase in cortical extracellular glutamate concentration, which is exacerbated under hypoxic conditions, and d) efficacy of glymphatic clearance is affected in discrete regions of the brain, which aligns with specific cognitive/behavioral impairments. These findings provide the first evidence of a critical pathophysiological role of ammonia in inducing neuronal energy deficit in HE due to impaired cerebral oxygenation, compromised hemichannel-mediated lactate transport between astrocytes and neurons and affected glymphatic clearance.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Neurochemistry of the Hepatic Encephalopathy |
| Event: | UCL (University College London) |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| UCL classification: | UCL > Provost and Vice Provost Offices 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 |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10038691 |
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