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Title: Interactions of microglia and neurons in an inflammatory environment
Author: Golde, S.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2004
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This thesis examines in vitro and in vivo under which circumstances activated microglia can be damaging to surrounding cells. Neurotoxic mediators secreted by microglia are characterized and intraneuronal pathways leading to cell death are investigated. Additionally, the question of whether microglial activation can be modulated to protect neurons is addressed. Finally it is investigated whether microglia can damage neurons and possibly axons and oligodendrocytes by similar mechanisms in vivo. Using a co-culture system of embryonal rat primary neurons and rat microglia it is demonstrated that inducible nitric oxide synthase (iNOS)-derived nitric oxide (NO) alone is responsible for neuronal death from interferon-g (IFNg) + lipopolysaccharide (LPS)-activated microglia. Neurons remain sensitive to NO irrespective of maturation state but NO causes neuronal death by two distinct mechanisms: NO acts directly upon immature neurons but indirectly, by eliciting excitotoxicity, on more mature neurons expressing NMDA receptors. The glucocorticoid dexamethasone completely protects neurons from toxicity of co-cultured activated microglia by downregulating NO-production. Dexamethasone lowers iNOS protein and mRNA concentrations in microglia, but does not affect the proteasome-dependent degradation of iNOS. Injection of IFNg + LPS into rat cortex causes widespread activation of microglia and specific iNOS upregulation. This results in early axonal injury which correlates well with the degree of inflammation, but is unchanged by inhibition of iNOS or blockage of NMDA receptors. Surprisingly, 7 days after injection of IFNg + LPS no permanent damage to axons, neurons and oligodendrocytes can be identified, indicating that microglial activation and iNOS expression do not necessarily cause brain damage. Most likely, the duration of inflammation and the concentration of microglial toxins, such as NO, are critical.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available