Role of microglia and toll-like receptor 4 in the pathophysiology of delirium Ryan Jalleh, Keith Koh, Boyoun Choi, Ebony Liu, John Maddison, Mark R. Hutchinson ⇑ Discipline of Physiology, School of Medical Sciences, University of Adelaide, Adelaide, SA 5005, Australia article info Article history: Received 18 June 2012 Accepted 15 August 2012 Available online xxxx abstract Delirium is a serious medical condition that commonly afflicts elderly inpatients. This is especially com- mon in the post-operative setting where it increases mortality, length of hospital stay and health care costs. The exact mechanisms involved in its pathogenesis remain uncertain and there is currently no effective pharmacological therapy for treatment or prevention of delirium. We hypothesize that microg- lia-mediated neuroinflammation via toll-like receptor 4 signalling is a significant contributor to post- operative delirium. Based on our proposed mechanism, three novel pharmacological therapies have been suggested to be effective to prevent or treat delirium. Curcumin, ibudilast and minocycline have been shown to interfere with various steps in the proinflammatory microglial activation intracellular signal- ling pathway, disrupting the subsequent neuroinflammatory cascade. We hypothesize that these drugs could be a novel pharmacotherapy that could significantly improve the outcome of post-operative delir- ious patients. Ó 2012 Elsevier Ltd. All rights reserved. Introduction Delirium is a syndrome characterised by the rapid onset of im- paired attention that fluctuates, together with altered conscious- ness and impaired cognition. There is a wide spectrum of causes such as toxicity, infection, surgery, shock and metabolic distur- bances. It is a significant problem in elderly hospital inpatients with incidence varying from 14% to 56% and hospital mortality rates ranging from 25% to 33% [1,2]. It is estimated that total direct 1-year health care costs attributable to delirium range from $143 billion to $152 billion nationally in the US, which is significant when compared with other conditions such as hip fracture [3]. In addition there is the underestimated toll on the individual and family including longer length of hospital stay, functional decline, higher rates of nursing home placement and caregiver burden. The pathophysiology of delirium has been an issue that has been difficult to grasp and there have been numerous hypotheses attempting to explain why delirium occurs. One of the more prom- inent hypotheses is the cholinergic theory of delirium: a deficit in cholinergic neurotransmitter pathways causes cognitive deficit and an impaired attention span [4–6]. Currently, pharmacological management of delirium is reserved for severe cases [7,8]. The most commonly used drugs are benzodiazepines and the typical or atypical antipsychotics [7]. One randomised controlled trial [9] has shown that haloperidol reduces the severity and duration of delirium. However, the study was underpowered and antipsychot- ics are not without risks. Both typical and atypical antipsychotics have been shown to increase the risk of stroke, ischaemic events and sudden cardiac death even with short term use [7,10,11] and have the potential to worsen delirium [12]. Additionally, antipsy- chotics do not reduce the incidence of delirium [9,13]. Trials of ace- tylcholinesterase drugs (e.g. donepezil) which increase cholinergic activity have also failed to reduce the incidence of delirium or length of stay in hospital [14–16]. Thus, the development of an alternative pharmacological therapy will be of great clinical benefit. The hypothesis Neuroinflammation is one possible mechanism that may con- tribute to delirium. Microglia are reactive immune cells present in the central nervous system that have been shown to interact with neuronal synapses [17,18]. These cells possess toll-like recep- tor 4 (TLR4), which recognises molecules such as pathogen-associ- ated molecular patterns (PAMPs) produced by bacteria [19]. For example, endotoxin, a component of bacterial cell walls, is known to bind to this receptor [17]. In addition to these exogenous li- gands, molecules released by injured cells known as danger-asso- ciated molecular patterns (DAMPs) are endogenous ligands that also bind to microglia [20]. Finally, an exciting novel class of li- gands detected by TLRs are xenobiotics – small molecules not nor- mally found in the host organism. These can range from dietary substances and environmental toxins, to prescribed pharmacother- apies including opioids commonly prescribed for post-operative pain [21,22]. These agents are termed here as xenobiotic-associ- ated molecular patterns (XAMPs). Once these ligands bind to the TLRs, inflammatory mediators are released by the microglia 0306-9877/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.mehy.2012.08.013 ⇑ Corresponding author. Tel.: +61 8 8313 0322; fax: +61 8 8224 0685. E-mail address: mark.hutchinson@adelaide.edu.au (M.R. Hutchinson). Medical Hypotheses xxx (2012) xxx–xxx Contents lists available at SciVerse ScienceDirect Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy Please cite this article in press as: Jalleh R et al. Role of microglia and toll-like receptor 4 in the pathophysiology of delirium. Med Hypotheses (2012), http://dx.doi.org/10.1016/j.mehy.2012.08.013