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The Role of Anti-Inflammatory Drugs in the Prevention and Treatment of Alzheimer's Disease
Annual Review of Medicine, 1996
▪ Risk factor intervention is a useful strategy for prevention of poorly understood diseases. Fifteen studies have examined the relation of glucocorticoid and nonsteroid antiinflammatory treatments and onset or progression of Alzheimer's disease (AD). Fourteen of these studies suggest that such treatments (especially nonsteroidal agents) prevent or ameliorate symptoms of AD. Abundant circumstantial evidence implicates inflammation in the pathogenesis of AD. Inhibition of cyclooxygenases, the central action of nonsteroidal antiinflammatory drugs (but not a prominent effect of steroids), limits inflammation, but it may also alter neural metabolic pathways, resulting in cell death from excitotoxicity or oxidative stress. Randomized controlled trials are needed to determine whether steroids, nonsteroidal antiinflammatory drugs, or both can prevent or treat the symptoms of AD.
An update on the efficacy of non-steroidal anti-inflammatory drugs in Alzheimer's disease
Expert Opinion on Investigational Drugs, 2009
Several epidemiological studies suggest that long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) may protect against Alzheimer's disease (AD), especially for patients carrying one or more ε4 allele of the apolipoprotein E. The biological mechanism of this protection is not completely understood and may involve inhibition of COX activity, inhibition of β-amyloid 1-42 (Aβ42) production and aggregation, inhibition of β-secretase activity, activation of PPAR-γ or stimulation of neurotrophin synthesis. Unfortunately, long-term, placebo-controlled clinical trials with both non-selective and COX-2 selective NSAIDs in AD patients produced negative results. A secondary prevention study with rofecoxib in patients with mild cognitive impairment and a primary prevention study with naproxen and celecoxib in elderly subjects with a family history of AD were also negative. All these failures have diminished the hope that NSAIDs could be beneficial in the treatment of AD. It is hypothesized that the chronic use of NSAIDs may be beneficial only in the normal brain by inhibiting the production of Aβ42. Once the Aβ deposition process has started, NSAIDs are no longer effective and may even be detrimental because of their inhibiting activity on activated microglia of the AD brain, which mediates Aβ clearance and activates compensatory hippocampal neurogenesis.
Current Alzheimer Research, 2011
Alzheimer's disease (AD) is the most common form of neurodegenerative dementias worldwide. Amyloiddeposition, neurofibrillary tangle formation and Neuroinflammation are the major pathogenetic mechanisms that in concert lead to memory dysfunction and decline of cognition. To date, there is no curative treatment for AD. Epidemiological analysis support the notion that sustained intake of non-steroidal anti-inflammatory drugs (NSAIDs) reduce the risk and delay the onset of AD. In contrast, therapeutic studies testing NSAID efficacy in AD patients have not yielded positive results. This suggests that either the investigated drugs have not addressed the mechanism of action required for mediating beneficial effects or that NSAIDs are effective at stages way before clinical onset of symptoms. The NSAIDs concerned are pleiotrophic in nature and interact with more than one pathomechanism. Therefore evidence for more than one neuroprotective action of NSAIDs has been put forward and it seems likely that some of the drugs act at multiple levels through more than one molecular mechanism. Some, even may not only be beneficial, but negative actions may be overruled by protective effects. Within these mechanisms, modulation of-secretase activity, the activation of the peroxisome proliferator-activated receptor-, binding to prostaglandin receptors or interactions at the blood-brain barrier may account for the observed protection from AD. This article reviews the current knowledge and views on the above mechanisms and critically discusses current obstacles and the potential as future AD therapeutics.
The potential role of non-steroidal anti-inflammatory drugs in treating Alzheimer’s disease
Expert Opinion on Investigational Drugs, 2004
The potential role of non-steroidal anti-inflammatory drugs in treating Alzheimer's disease 2 Expert Opin. Investig. Drugs (2004) 13(11) 40 amino acids (Aβ40) but the C-terminal-extended species made of 42 residues is also produced (Aβ42). This longer form is more prone to aggregate into fibrils and Aβ42 makes up the major component of amyloid plaques. Plaques are in equilibrium with soluble monomers and oligomers. They may not be the sole contributor to neuronal death, as there is evidence that soluble amyloid is also potentially neurotoxic [4]. 2. The use of non-steroidal anti-inflammatory drugs and the risk of Alzheimer's disease Epidemiological studies have documented a reduced prevalence of Alzheimer's disease among users of non-steroidal anti-inflammatory drugs (NSAIDs). The protective effects of NSAIDs seem to be linked to the duration of treatment. A population-based cohort study of 6989 subjects found a relative Alzheimer's disease risk of 0.95 in subjects with short-term use of NSAIDs, 0.83 in those with intermediate-term use and 0.2 in those with long-term use [5]. Pooled data from nine studies involving 14,654 subjects confirmed that the protective effects depend on the duration of NSAID use with relative risks of 0.95 among short-term (< 1 month), 0.83 among intermediate-term (< 24 months) and 0.27 among long-term (> 24 months) users [6]. The type of NSAID used also appears to affect the magnitude of the protective effect. In a recent cohort study of 1301 dementia-free subjects at baseline and followed up for 6 years, no subjects who used non-aspirin NSAIDs for around 3 years developed Alzheimer's disease 3 years later [7]. More specifically, the re-analysis of the Rotterdam study indicates that risk decrease is restricted to NSAIDs that lower Aβ42 (ibuprofen, sulindac, flurbiprofen, indomethacin and diclofenac) [8]. In a cross-sectional retrospective study involving 2708 community-dwelling elderly patients, a significantly decreased risk of cognitive impairment was found for patients using non-aspirin NSAIDs [9]. The lowest adjusted odd ratio for a single non-aspirin NSAID drug was observed for diclofenac (0.2). However, a further pooled analysis [10]
Cyclooxygenase inhibitors: a novel direction for Alzheimer's management
Pharmacological reports : PR
Research in Alzheimer's disease (AD) currently includes various cellular, molecular, genetic, clinical and therapeutic approaches. The cytopathological significance of oxidative damage has been studied in neurons of AD patients. Many epidemiological studies suggest that use of non-steroidal anti-inflammatory drugs (NSAIDs) delay or slow the clinical expression of AD, and anti-oxidant properties of NSAIDs have also been previously described. Therefore, in this study we examined the role of various cyclooxygenase (COX)-1 and COX-2 inhibitors (NSAIDs) in a rat model of aluminum-induced oxidative stress to mimic AD-like conditions. We found that the animals receiving aluminum treatment for one month (4.2 mg/kg, ip) had highly elevated levels of reactive oxygen species (expressed as malondialdehyde--MDA). Moreover, treatment with the COX-2 inhibitor, rofecoxib (0.83 mg/kg, po), was able to significantly reduce this oxidative stress (p<0.05 when compared to aluminum treatment alone...
Journal of Neurochemistry, 2004
5 The abbreviations used are: VSMC, vascular smooth mucle cells; NSAIDs, non-steroidal anti-inflammatory drugs; SOCE, store-operated Ca 2+ entry; VOCE, voltage-operated Ca 2+ entry; CRAC, Ca 2+ -release activated current; RBL, rat basophilic leukemia; 2-APB, 2-aminoethoxydiphenyl borate; [Ca 2+ ]cyt, cytosolic Ca 2+ concentration; [Ca 2+ ]mit, mitochondrial Ca 2+ concentration. http://www.jbc.org/cgi/
Role of Traditional Nonsteroidal Anti-inflammatory Drugs in Alzheimer’s Disease
American Journal of Alzheimer's Disease & Other Dementiasr, 2014
The role of nonsteroidal anti-inflammatory drugs (NSAIDs) in prevention of Alzheimer’s disease (AD) has been evaluated in many studies. We performed a meta-analysis to summarize the existing evidence on the relation between use of classical NSAIDs and AD. Randomized controlled trials (RCTs) evaluating the role of classical NSAIDs in AD was searched using different search engines. The RCTs in patients who had the degree of AD measured on Mini-Mental State Examination (MMSE) or AD Assessment Scale-Cognitive subscale (ADAS-cog) were included in the study. The RCTs and data (AD scores) were independently assessed by 2 reviewers, and data were included in meta-analysis only after a common consensus was reached. The pooled results from the ADAS-cog and MMSE scores failed to show any difference between the treatment and the placebo groups as opposed to findings from some observational studies. However, in view of heterogeneity of results, there is a need to conduct more RCTs to arrive at c...
Review on Evaluating the Role of Nsaids for the Treatment of Alzheimer's Disease
International Journal of Applied Pharmaceutics, 2021
Recently, several studies have been reported that nonsteroidal anti-inflammatory drugs can fight against neurodegenerative disorders by various mechanisms. Currently, available therapies of neurodegenerative disorders (NDs) provide only symptomatic relief. This is the point at which we need an alternative that acts on the root cause of disease. Parkinson’s disease and Alzheimer’s disease are the two NDs concentrated here. Since the drug profile is already known, drug repurposing is a promising technique in research, thereby reducing the cost and period effectively. Epidemiological studies on various nonsteroidal anti-inflammatory drugs (NSAIDs) showed good results, but when it came to clinical studies the results are found to be poor. Hence, it can be concluded that NSAIDs provide its neuroprotective activity on its long-term use only, as the brain accessibility of this kind of drug is poor due to its lower lipophilicity.
CNS & Neurological Disorders - Drug Targets, 2011
Epidemiological studies suggest that systemic use of non-steroidal anti-inflammatory drugs (NSAIDs) can prevent or retard the development of Alzheimer's disease (AD). However, clinical trials investigating the effects of NSAIDs on AD progression have yielded mixed or inconclusive results. The aim of this review is to distinguish the role of inflammation and the molecular targets of NSAIDs in the different stages of AD pathology. AD brains are characterized by extracellular deposits of-amyloid protein and intraneuronal accumulation of hyperphosphorylated tau protein. Already in the early stages of AD pathology-amyloid protein deposits are associated with inflammatory proteins and microglia, the brain resident macrophages. Recently, two genome-wide association studies identified new genes that are associated with an increased risk of developing AD. These genes include CLU and CR1 which encode for clusterin and complement receptor 1 respectively. Both genes are involved in the regulation of inflammation. This strongly indicates that inflammation plays a central role in the aetiology of AD. In this review we will show that the primary targets of NSAIDs are involved in a pathological stage that precedes the clinical appearance of AD. The early, preclinical involvement of inflammation in AD explains why patients with clinical signs of AD do not benefit from anti-inflammatory treatment and suggests that NSAIDs, rather than having a direct therapeutic effect, may have preventive effects.