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Title: Investigating the molecular, metabolic, and psychological effects of minocycline
Author: Chan, Shi Yu
ISNI:       0000 0004 7653 2310
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2018
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An immune component has been suggested to underlie the pathophysiology of psychiatric diseases, and is thought to involve pro-inflammatory cytokines. Thus, there is the potential for drugs with anti-inflammatory properties to act as therapeutic agents for psychiatric illnesses. Minocycline has shown promise in pre-clinical animal models and early phase clinical trials for a variety of psychiatric disorders. Previous studies on minocycline have also shown its ability to suppress microglia activity and reduce inflammatory cytokine levels, and its behavioural effects on depressive-like behaviour in animals and humans. However, the underlying mechanisms that lead to minocycline's psychotropic effects are not clear. This dissertation investigated the proposal that the anti-inflammatory mechanisms of minocycline underlie its psychotropic effects, as well as explored the pathways that mediate inflammation-induced behavioural changes. To that end, four studies were conducted. The first study looked at inflammation-induced modulation of GluN2 subunit expression and downstream signalling, effects which were rescued by prior treatment with minocycline (Chapter Two). The second study explored the effects of inflammation and minocycline administration on plasma and brain metabolites in mice (Chapter Three). The third study and fourth study investigated the psychological effects (Chapter Four) and biochemical effects (Chapter 5) of an acute dose of minocycline in healthy volunteers. It was revealed that minocycline administration decreased fear misclassification, increased contextual learning, decreased levels of the inflammatory marker CRP, and increased serum lipoprotein. Overall, minocycline was able to ameliorate inflammation-induced changes, suggesting that anti-inflammatory mechanisms are linked to glutamatergic signalling and synaptic transmission which lead to downstream psychotropic effects. However, metabolomic analysis also revealed changes in lipid metabolism and energy-related metabolites that could potentially underlie a separate mechanism for minocycline's actions. Nevertheless, given the association between metabolites, and inflammation, it is possible that these pathways interact.
Supervisor: Burnet, Philip Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available