Targeting Cytokine Systems to Achieve Neuroprotection: Experimental Models of Seizures and Neurodegeneration

Balosso, Silvia (2009). Targeting Cytokine Systems to Achieve Neuroprotection: Experimental Models of Seizures and Neurodegeneration. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.0000f270

Abstract

This study investigated whether IL-1β and TNF-α have a role in the pathophysiology of seizures by altering neuronal excitability and cell survival and also probed new targets to achieve an effective anticonvulsive action.

The first set of experiments evaluated if acute and spontaneous seizures can be effectively inhibited by blocking the brain production of IL-1β using a selective inhibitor of caspase-1, the key enzyme specifically involved in the production of the releasable and biologically active form of IL-1β. Caspase-1 inhibition significantly reduced the number and the total time spent in seizures, indicating that this treatment represents an effective and novel anticonvulsive strategy.

The second set of experiments investigated the intracellular pathway involved in the IL-1β proconvulsant actions which appear to occur via a novel non-transcriptional pathway: namely, the IL-1β-mediated activation of neutral-sphingomyelinase, the production of ceramide and the subsequent phosphorylation of Src-family of tyrosine kinases and the target receptor protein NR2B subunit of the NMDA receptor, resulting in the potentiation of NMDA function. This fast post-translational effect of IL-1β represents a novel and non-conventional pathway by which inflammatory molecules produced in epileptic tissue can affect neurotransmission.

Then, this work demonstrated that a brief pro-inflammatory stimulus, characterized by the activation of microglia and subsequent lasting release of critical concentrations of IL-1β, primes neuronal vulnerability to a subsequent excitotoxic insult, highlighting one mechanism by which a pre-existent pro-inflammatory state may increase hippocampal neuronal susceptibility to the excitotoxic damage associated with seizures. Thus, pharmacological approaches specifically targeted to block the overproduction of IL-1β and its functions in diseased conditions may represent new, nonconventional strategies for the treatment of seizure disorders, which are refractory to classical anticonvulsant treatments.

The second part of this thesis demonstrated that TNF-α significantly decreases epileptic activity by specifically acting on neuronal p75 receptors. The actions of TNF-α on neuronal excitability strictly depend on whether p55 or p75 receptors are preferentially involved and appear to be mediated also by changes in the assembly of glutamate receptor subunits. These novel functional glia-neuronal interactions add important insights into the mechanism of ictogenesis and seizure-associated neuronal cell death, highlighting innovative pharmacological strategies to block the activation of cytokine-mediated signalling in diseased conditions.

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