||Following major surgery, many patients experience problems that originate from the brain, such as postoperative cognitive dysfunction and postoperative delirium. The cerebral dysfunction is most likely influenced by a wide variety of factors, such as advanced age, specifics of surgical and anaesthetic techniques, ischemia/reperfusion injury, cerebral hypoxia, and neuroinflammation. We hypothesize that loss of integrity of the blood brain barrier by ROS and systemic inflammation, followed by the initiation of neuroinflammation, is the central mechanism in the development of cerebral dysfunction. We hypothesize that age and changes in dopaminergic pathways may be important additional modulators of neuroinflammation due to major surgery. Optimization of anaesthetic techniques offers immediate improvement in perioperative care. In addition, we investigate the efficacy of increasing brain H2S levels on postoperative neuroinflammation.
Research question: What mechanisms are involved in the development of neuroinflammation and cerebral dysfunction following major surgery and how can this be prevented ?
We propose 4 aims in order to investigate the thesis question:
1. Relate perioperative brain microcirculation, neuroinflammatory and brain damage markers and cognitive performance decline in patients.
2. Investigate the efficacy of perioperative pharmacological modulation of systemic and neuroinflammation in humans and mice.
3. Measure the effect of age on the CBS/H2S pathway and neuroinflammation after major surgery in mice.
4. Assess the efficacy of the CBS/H2S pathway activation in limiting major surgery induced neuroinflammation in mice.