It is known that chronic neurodegeneration is associated with an inflammatory response, chiefly mediated by the brain macrophage population, the microglia. However it remains unclear how this microglial response contributes to neurodegeneration and, thus far, non-steroidal anti-inflammatory drugs (NSAIDs) have not proved helpful in patients with dementia [
1]. We have previously shown that the microglial response in the ME7 model of prion disease is characterised by a muted inflammatory phenotype with very limited synthesis of pro-inflammatory cytokines [
2,
3]. However these microglia are primed by disease to respond more robustly to subsequent inflammatory challenges either peripherally or centrally [
4]. One consequence of this is that animals with existing disease show exaggerated sickness behaviour responses to systemic administration of bacterial endotoxin lipopolysaccharide (LPS), used to mimic systemic infection in these animals [
5,
6]. Furthermore, we have shown that cognitive dysfunction [
7] and neuronal death [
4] can both be acutely exacerbated by the superimposition of systemic inflammatory challenge on a background on progressing disease and that disease progression itself can be expedited following systemic inflammatory challenge with LPS [
6] or poly I:C (double stranded RNA analogue used to mimic systemic viral infection) [
8]. There is now growing evidence from animal models of Alzheimer's disease [
9‐
11], Parkinson's disease [
12,
13], aging [
14,
15], amyotrophic lateral sclerosis [
16], stroke [
17], experimental autoimmune encephalomyelitis [
18] and Wallerian degeneration [
19] that these exacerbating effects of systemic inflammation occur not only in the ME7 model of prion disease but constitute a generic phenomenon whereby systemic inflammation has more severe outcomes in individuals with prior pathology in the CNS (see [
20] for review). Importantly, this phenomenon also appears to occur in the human population: we have now shown in an Alzheimer's disease patient cohort that systemic inflammatory events are associated with more rapid cognitive decline [
21]. Clinically it is well recognised that patients with dementia frequently deteriorate after systemic infections, suffering episodes of delirium and long-term cognitive impairment, but this area remains little studied. Thus, it is now a priority to address mechanisms by which systemic inflammation may bring about these deleterious changes in those brains with pre-existing pathology.
In the current study we addressed the hypothesis that systemic cytokines play a role in this exacerbation of CNS inflammation, heightened sickness behaviour responses and the associated increase in apoptosis in the CNS. We have inoculated animals with the ME7 strain of prion disease or with normal brain homogenate (NBH) and then challenged these animals with LPS (500 μg/kg) in the presence or absence of the synthetic glucocorticoid dexamethasone-21-phosphate to inhibit cytokine synthesis induced by LPS. These animals were assessed on measures of sickness behaviour, systemic and CNS induction of cytokines and on induction of new apoptotic events. We found that while dexamethasone-21-phosphate did inhibit systemic cytokine synthesis and did block the hypothermic response it had no significant effect on activity and did not block CNS synthesis of cytokine mRNA or microglial IL-1β nor prevent acute neurodegeneration induced by LPS.