Neuro-inflammation following Human Traumatic Brain Injury

Head injury is an important health issue as it is the commonest cause of death in those aged under 40 years in the developed world. The treatments that are used in patients with severe head injury are largely supportive. Studies in animals have shown us that inflammation in the brain after it is injured can make the injury worse. This study will look at the levels of inflammatory molecules, called cytokines, in the brain and see if blocking these molecules‘ action reduces the damage to nerve cells.
The study will be carried out in the Division of Neurosurgery in the University of Cambridge. We will use a monitoring technique called microdialysis to enable us to measure the levels of cytokines in the brains of patients with severe head injuries. We will go on to see if the levels of these cytokines are associated with activation of inflammatory cells within the brain called microglia.
We will also test to see whether these cytokines are toxic to human nerve cells (neurons) when these cells are grown outside the body.

Traumatic Brain Injury (head injury, TBI) is a common cause of death and disability in both the developed and developing world. The potentially damaging role of cerebral inflammation following TBI has been demonstrated in many animal models. However, this data is yet to be replicated in humans. In particular, the interleukin-1 family of cytokines has been heavily implicated in potentiating neuronal injury. Our aim is to characterise the cytokine response following human TBI using cerebral microdialysis, a technique for sampling the brain extracellular space.
The first objective will be to develop a robust microdialysis methodology for the recovery of cytokines. Initially, this has taken the form of in vitro testing of the microdialysis catheters already employed in clinical use to determine the relative recovery for each cytokine of interest and to investigate the effect of albumin in the perfusate on relative recovery. The two types of perfusate will then be compared directly in vivo using paired catheters in the same patient.
The microdialysis methodology from these initial studies will be used in an observational study of the temporal course of cytokine expression following human TBI focusing on the following cytokines IL-1?, IL-1?, IL-1receptor antagonist, IL-6, IL-8 and TNF-?.
The next objective will be to carry out a randomised interventional study using IL-1receptor antagonist in human patients following severe TBI. The primary outcome will be safety however we will also incorporate cerebral microdialysis to determine whether the drug crosses the blood brain barrier and whether it alters the pattern of cytokine expression.
We also intend to elucidate the relationship between cytokine expression and microglial activation using a combined PET-microdialysis study, using the PK11195 ligand. It is hypothesised that activated microglia are the source of cytokine expression following trauma.
Finally, we will test the putative neurotoxic effects of the microdialysate recovered from the human brain following TBI on human neuronal cell culture. Our objective is to develop an in vitro neurotoxicity assay that can then be utilised to investigate which, if any, of the components of the microdialysate is toxic to neurons.
Taken together these studies will further our understanding of the molecular mediators of injury following human TBI by replicating and furthering many of the findings from animal models. In addition, attenuating the inflammatory response following TBI may provide a novel therapeutic approach for the treatment of human TBI.