Effect of proinflammatory activation on the neurosupportive functions of astrocytes

  • Megan Steele

Western Sydney University thesis: Doctoral thesis

Abstract

A complex relationship exists between astrocytes and neurons involving astrocytic uptake of glucose and glutathione (GSH) precursors (cysteine, glycine and glutamate) and the release of lactate and GSH, which are taken up by neurons, either directly or after extracellular degradation. This metabolic exchange between astrocytes and neurons is vital to normal neuronal functions including GSH-dependent cellular antioxidant defence. It is therefore hypothesised that a breakdown in astroglial-neuronal interaction, due to chronically activated astrocytes altering their metabolic phenotype, might lead to neurons becoming energetically challenged and vulnerable to neurodegeneration, as observed in Alzheimer"s disease (AD). This thesis examined the affect of proinflammatory activation on two key neurosupportive functions of astrocytes: (1) the supply of GSH and its degradation products and (2) the uptake of glucose and release of lactate. A large portion of the project related to establishment of the conditions of inflammatory activation in U373 cells and the development and validation of a high pressure liquid chromatography (HPLC) method required for the determination of GSH and related thiol compounds. Based on the premise that astrocytes are key modulators in the progression of oxidative stress associated neurodegenerative diseases, thirteen herbal extracts purported to possess anti-ageing or cognitive-enhancing properties by traditional Chinese medicine were tested for their cytoprotective ability in hydrogen peroxide-challenged U373 cells. Findings from this thesis suggest that inflammation activated astrocytes might contribute to neurodegenerative processes through the upregulation of neurotoxic activities (i.e. release of cytokines such as IL-6 and neurotoxic compounds such as homocysteine) as well as decreases in neurosupportive functions (i.e. provision of substrates for GSH synthesis and energy metabolism). The results presented strongly support the hypothesis that reactive astrocytes play a key role in disease progression. Furthermore, a multi-compound, multi-targeted approach is proposed for the prevention and treatment of AD and drugs capable of restoring astrocytic function or supplementation of astrocyte-derived neuronal nutrients may be especially important.
Date of Award2011
Original languageEnglish

Keywords

  • astrocytes
  • neurons
  • lactates
  • glucose
  • metabolism
  • neurodegenerative diseases
  • Alzheimer's disease
  • nervous system
  • degeneration

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