The Role of Inflammation In Post-Operative Cognitive Dysfunction

Abstract

Post-operative cognitive dysfunction (POCD) is a common complication occurring mainly to elderly patients after surgery. The highest incidence of POCD is observed in orthopaedic and cardiac procedures. The background of this thesis is based on the evidence that hippocampal interleukin 1 beta (IL-1β) plays a major role in inflammation and memory performance. Localised IL-1β dysregulation in the hippocampus can be triggered by elevated systemic cytokines resulting from peripheral infective challenge; the underlying immune-to-CNS communication triggers glial activation, sickness behaviour and memory impairment. The aim of this work was to investigate a possible causative relationship between anaesthesia, aseptic surgical trauma, systemic and hippocampal inflammation and memory function in mice. The first part of the work was dedicated to the development of an appropriate model of orthopaedic surgery, which allowed me to show that surgery under anaesthesia, but not anaesthesia alone, causes inflammatory-mediated, hippocampal-dependent, cognitive dysfunction. Post-operative elevated plasma cytokines, assessed by ELISA, and clone expansion of inflammatory cells, such as monocytes (evidenced by flow cytometry techniques), were associated with memory impairment, increased IL-1β expression and reactive microgliosis (evidenced by immunohistochemistry), but not astrogliosis (assessed with western blotting), in the hippocampus. Results from behavioural tests such as fear conditioning showed that blocking inflammation with minocycline prevents these post-surgical changes. Likewise, antagonism of IL-1β receptors mitigated hippocampal-dependent memory dysfunction. Experiments to rule out a possible infection were also performed, and excluded that the results could depend upon contamination of the wounds in the animal model. Also, age and gender were explored as possible risk factors. These findings support the existence of a surgery-induced IL-1β-mediated inflammatory mechanism that is followed by reactive microgliosis in the hippocampus and underlies memory impairment. This mechanism appears to be dependent on gender and can be attenuated by some anaesthetics, but it is worse in older age.