Non-Steroidal Anti-Inflammatory Drugs and Cognitive Function: Are Prostaglandins at the Heart of Cognitive Impairment in Dementia and Delirium ?

Abstract

Studies of non-steroidal anti-inflammatory drugs (NSAIDs) in rheumatoid arthritis imply that inflammation is important in the development of Alzheimer’s disease (AD). However, these drugs have not alleviated the symptoms of AD in those who have already developed dementia. This suggests that the primary mediator targeted by these drugs, PGE2, is not actively suppressing memory function in AD. Amyloid-β oligomers appear to be important for the mild cognitive changes seen in AD transgenic mice, yet amyloid immunotherapy has also proven unsuccessful in clinical trials. Collectively, these findings indicate that NSAIDs may target a prodromal process in mice that has already passed in those diagnosed with AD, and that synaptic and neuronal loss are key determinants of cognitive dysfunction in AD. While the role of inflammation has not yet become clear, inflammatory processes definitely have a negative impact on cognitive function during episodes of delirium during dementia. Delirium is an acute and profound impairment of cognitive function frequently occurring in aged and demented patients exposed to systemic inflammatory insults, which is now recognised to contribute to long-term cognitive decline. Recent work in animal models is beginning to shed light on the interactions between systemic inflammation and CNS pathology in these acute exacerbations of dementia. This review will assess the role of prostaglandin synthesis in the memory impairments observed in dementia and delirium and will examine the relative contribution of amyloid, synaptic and neuronal loss. We will also discuss how understanding the role of inflammatory mediators in delirious episodes will have major implications for ameliorating the rate of decline in the demented population.

Subacute ibuprofen treatment rescues the synaptic and cognitive deficits in advanced-aged mice

“…While subacute ibuprofen treatment improves memory and synaptic plasticity in amyloid AD mouse models (Kotilinek, et al, 2008, Van Dam, et al, 2010), to our knowledge, this is a first report showing the protective effects of ibuprofen against cognitive decline in aged wild-type mice. Ibuprofen is one of the classical types of NSAIDs, which suppresses the prostaglandin biogenesis from arachidonic acid by inhibiting functions of cyclooxygenase (COX)-1 and COX-2 (Cunningham and Skelly, 2012). Chronic inflammation occurs in the hippocampus of aged rats.…”

“…Sulindac treatment also attenuated an age-related decrease in the NR1 and NR2B NMDA receptor subunits, which are associated with PSD-95 at the post-synaptic cleft (Mesches, et al, 2004). Since prostaglandins trigger diverse inflammatory cascades in the brain (Cunningham and Skelly, 2012), subacute ibuprofen treatment may also rescue aging-related cognitive declines by preventing the prostaglandin-mediated neuroinflammation via COX-2 inhibition. However, COX-2 is controversially required to mediate the consolidation of hippocampal-dependent memory in rats (Teather, et al, 2002).…”

Pro-Resolving Lipid Mediators Improve Neuronal Survival and Increase Aβ42 Phagocytosis

“…Interventions based on inhibition of inflammation in AD patients have in most cases not been successful [27]. In addition, long-term use of NSAIDs may induce gastrointestinal and cardiovascular side effects [28]. Therefore, there is call for a novel strategy, not based on classical anti-inflammatory treatment, and therapeutic strategies based on resolving the inflammatory state in AD are therefore of interest.…”

Predictive Factors for Agitation Severity of Hyperactive Delirium in Terminally Ill Cancer Patients in a General Hospital Using Ordered Logistic Regression Analysis

“…7,8,27,28 On the other hand, the antiinflammatory effects were effective for the prevention of cognitive impairment even in chronic situations. 29 In the current study, NSAIDs were identified as a predictive factor for agitation severity of delirium in terminally ill cancer patients. The reason might be because NSAIDs are usually used in patients with uncontrollable pain 30 and fever.…”