Systemic activation of caspase-1 dependent interleukins and matrix-metalloproteinases in developmental brain trauma

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Traumatic brain injury (TBI) is a major cause of morbidity in the pediatric population. We have developed an animal model to study TBI in the developing rat brain and described that trauma triggers rapid excitotoxic and delayed apoptotic neuronal death. During the ongoing period of support of this project we explored the role of caspase-1 dependent interleukins and matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9) in infant TBI and found that they are activated following trauma and represent potentially promising therapeutic targets. Blockade of IL-18 action by IL-18 binding protein conferred neuroprotection in infant rats subjected to traumatic brain injury. Also, blockade of MMP action with a metalloproteinase inhibitor confers neuroprotection. In addition, systemic activation of caspase-1 dependent interleukins and MMPs occurs in peripheral organs depending on the severity of the traumatic brain injury. In the continuation period of this project we want to identify the cell types and explore the neurohumoral mechanisms which mediate systemic activation of caspase-1 dependent interleukins and MMPs following infant TBI with focus on the vegetative nervous system. Furthermore we want to determine whether pharmacological inhibition of the systemic inflammatory response following TBI may influence the extent of brain injury.