MEDIATORS OF INFLAMMATION IN ACUTE NEUROTOXICITY

UoM administered thesis: Phd

  • Authors:
  • Emily Robinson

Abstract

Neuroinflammation is a major feature of most neurodegenerative conditions, and can leadto the exacerbation of neuronal injury. Inflammatory challenges in the central nervoussystem (CNS) have been shown to activate peripheral immune cells, which subsequentlyinfiltrate into the brain. Concurrently, resident inflammatory cells in the CNS, such asmicroglia, become activated and release inflammatory mediators, including cytokines.The pro-inflammatory cytokine interleukin-1 (IL-1) is a key mediator of neuronal injury.Although two IL-1 agonists exist, IL-1alpha and IL-1β, the majority of research has focussedon the contribution of IL-1β to neuronal injury. Excitotoxic cell death in the rat brain,induced by striatal injection of the glutamate agonist AMPA, is exacerbated by coadministrationof recombinant IL-1β. To identify possible mediators which facilitate theexacerbation of neuronal injury by IL-1 this study investigated the early peripheral andcentral mediators of inflammation in response to AMPA + IL-1β.Neutrophil infiltration and increased neuronal activity were found to be present at 4h post-AMPA + IL-1β injection, which lead to the induction of microglial IL-1alpha in the ipsilateralcortex, in the absence of any IL-1β expression. To target the peripheral neutrophil responsean intervention study was performed to inhibit peripheral TNFalpha, which is thought tomobilise neutrophils. No significant effect of pre-treatment with etanercept, a TNFalphainhibitor, was observed on neuronal injury produced in response to AMPA + IL-1β, thougha slight trend for protection was seen. To target the central IL-1alpha response after AMPA +IL-1β treatment an anti-IL-1alpha antibody was injected directly into the cerebral cortex, butthis had no effect on AMPA + IL-1β induced cell death. Therefore, using a reductionist invitro approach in organotypic slice cultures haemin, an inducer of endogenous IL-1alpha, wasused to investigate IL-1alpha mediated cell death. Haemin induced cell death was shown to beIL-1 dependent and preliminary studies using IL-1alphaKO mice indicated that IL-1alpha maypartially mediate this effect. This suggests that in the AMPA + IL-1β paradigm IL-1alpha is thedominant IL-1 isoform early after AMPA + IL-1β treatment, which can trigger subsequentneuronal cell death, as a result of the additive effects of neutrophil infiltration and highneuronal activity in the cortex. This study highlights the potential therapeutic value ofinhibiting IL-1alpha expression early following acute neuronal injury.

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Original languageEnglish
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Award date1 Aug 2013