Why docosahexaenoic acid and aspirin supplementation could be useful in women as a primary prevention therapy against Alzheimer's disease?

Pomponi, Massimiliano; Gambassi, Giovanni; Gioia, Annamaria Di; Masullo, Carlo

doi:10.1016/j.arr.2010.09.003

Cited by 12 publications

(8 citation statements)

References 87 publications

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“…However, interpretation is complicated because COX enzymes can also metabolize docosahexaenoic acid/ eicosapentaenoic acid to the anti-inflammatory resolvins [216]. In this regard, it has been suggested that low-dose aspirin, in combination with fish oil, is strongly antiinflammatory because it can allosterically activate COX2, and in the presence of docosahexaenoic acid be protective in AD [217]. As CBD can upregulate PPARγ and COX2 at low micromolar doses, it is possible that CBD could have antiinflammatory affects both via PPARγ and resolvins [18].…”

Section: Cbd Enzyme Targets In Neurodegenerationmentioning

confidence: 99%

Molecular Targets of Cannabidiol in Neurological Disorders

Bih

Chen

Nunn³

et al. 2015

Neurotherapeutics

416

299

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Cannabis has a long history of anecdotal medicinal use and limited licensed medicinal use. Until recently, alleged clinical effects from anecdotal reports and the use of licensed cannabinoid medicines are most likely mediated by tetrahydrocannabinol by virtue of: 1) this cannabinoid being present in the most significant quantities in these preparations; and b) the proportion:potency relationship between tetrahydrocannabinol and other plant cannabinoids derived from cannabis. However, there has recently been considerable interest in the therapeutic potential for the plant cannabinoid, cannabidiol (CBD), in neurological disorders but the current evidence suggests that CBD does not directly interact with the endocannabinoid system except in vitro at supraphysiological concentrations. Thus, as further evidence for CBD's beneficial effects in neurological disease emerges, there remains an urgent need to establish the molecular targets through which it exerts its therapeutic effects. Here, we conducted a systematic search of the extant literature for original articles describing the molecular pharmacology of CBD. We critically appraised the results for the validity of the molecular targets proposed. Thereafter, we considered whether the molecular targets of CBD identified hold therapeutic potential in relevant neurological diseases. The molecular targets identified include numerous classical ion channels, receptors, transporters, and enzymes. Some CBD effects at these targets in in vitro assays only manifest at high concentrations, which may be difficult to achieve in vivo, particularly given CBD's relatively poor bioavailability. Moreover, several targets were asserted through experimental designs that demonstrate only correlation with a given target rather than a causal proof. When the molecular targets of CBD that were physiologically plausible were considered for their potential for exploitation in neurological therapeutics, the results were variable. In some cases, the targets identified had little or no established link to the diseases considered. In others, molecular targets of CBD were entirely consistent with those already actively exploited in relevant, clinically used, neurological treatments. Finally, CBD was found to act upon a number of targets that are linked to neurological therapeutics but that its actions were not consistent withmodulation of such targets that would derive a therapeutically beneficial outcome. Overall, we find that while >65 discrete molecular targets have been reported in the literature for CBD, a relatively limited number represent plausible targets for the drug's action in neurological disorders when judged by the criteria we set. We conclude that CBD is very unlikely to exert effects in neurological diseases through modulation of the endocannabinoid system. Moreover, a number of other molecular targets of CBD reported in the literature are unlikely to be of relevance owing to effects only being observed at supraphysiological concentrations. Of interest and after excludin...

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Section: Cbd Enzyme Targets In Neurodegenerationmentioning

confidence: 99%

Molecular Targets of Cannabidiol in Neurological Disorders

Bih

Chen

Nunn³

et al. 2015

Neurotherapeutics

416

299

View full text Add to dashboard Cite

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“…Combination of NSAIDs and DHA or EPA has been proposed as an efficient strategy to prevent or treat neuroinflammatory pathways associated to neurodegenerative diseases (Pomponi et al, 2011), with no results in humans yet. In vitro, microglia treatment with DHA or aspirin or both reveals that the combination of aspirin and DHA promotes the antioxidant endogenous enzyme gluthatione production, with no potentiation on proinflammatory cytokine production (Pettit et al, 2013).…”

Section: Pharmacological Strategy To Promote Endogenous Spm Producmentioning

confidence: 99%

Anti-Inflammatory Effects of Omega-3 Fatty Acids in the Brain: Physiological Mechanisms and Relevance to Pharmacology

Layé¹,

Nadjar²,

Joffre³

et al. 2017

Pharmacol Rev

299

170

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Classically, polyunsaturated fatty acids (PUFA) were largely thought to be relatively inert structural components of brain, largely important for the formation of cellular membranes. Over the past 10 years, a host of bioactive lipid mediators that are enzymatically derived from arachidonic acid, the main n-6 PUFA, and docosahexaenoic acid, the main n-3 PUFA in the brain, known to regulate peripheral immune function, have been detected in the brain and shown to regulate microglia activation. Recent advances have focused on how PUFA regulate the molecular signaling of microglia, especially in the context of neuroinflammation and behavior. Several active drugs regulate brain lipid signaling and provide proof of concept for targeting the brain. Because brain lipid metabolism relies on a complex integration of diet, peripheral metabolism, including the liver and blood, which supply the brain with PUFAs that can be altered by genetics, sex, and aging, there are many pathways that can be disrupted, leading to altered brain lipid homeostasis. Brain lipid signaling pathways are altered in neurologic disorders and may be viable targets for the development of novel therapeutics. In this study, we discuss in particular how n-3 PUFAs and their metabolites regulate microglia phenotype and function to exert their anti-inflammatory and proresolving activities in the brain.

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“…Evidence from RCTs suggests that supplementation does not significantly benefit participants with AD but may improve certain cognitive domains in mild cognitive impairment [61,62,63,64]. The finding that aspirin enhances conversion of DHA to neuroprotective compounds such as neuropotectin D1 may mean that a combination of aspirin and DHA provides further cognitive benefits [65]. The impact of failing to control for DHA levels in the diet of participants in RCTs or epidemiologic studies is also unclear.…”

Section: Nsaids: Evidence From Clinical Trialsmentioning

confidence: 99%

Targeting neuroinflammation in Alzheimer’s disease: evidence for NSAIDs and novel therapeutics

Deardorff

Grossberg

2016

Expert Review of Neurotherapeutics

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There is an increasing recognition of the immune system as an important mediator in the pathogenesis of Alzheimer's disease (AD). As immune system modulators, non-steroidal anti-inflammatory drugs (NSAIDs) garnered initial enthusiasm from pre-clinical and epidemiologic studies as agents to reduce the risk of AD. Areas covered: This article will examine the evidence for the use of NSAIDs in AD by discussing the proposed mechanism of action, results from epidemiologic studies, and data from randomized controlled trials. In addition, a survey of several novel approaches to targeting inflammatory pathways currently in pre-clinical and clinical phases of development is presented. These agents primarily act to modulate microglial functioning, enhance amyloid-β phagocytosis, suppress potentially harmful pro-inflammatory responses, or enhance systemic immunity. Expert commentary: While long-term use of NSAIDs is associated with a reduced incidence of AD in epidemiologic studies, randomized controlled trials have not replicated these findings. Thus, NSAID use cannot currently be recommended either for primary prevention or treatment of AD. However, the available evidence does suggest that cognitively normal patients taking long-term courses of NSAIDs for other indications likely have a decreased risk of AD, which represents an important finding given the high prevalence of NSAID use among older adults.

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Why docosahexaenoic acid and aspirin supplementation could be useful in women as a primary prevention therapy against Alzheimer's disease?

Cited by 12 publications

References 87 publications

Molecular Targets of Cannabidiol in Neurological Disorders

Molecular Targets of Cannabidiol in Neurological Disorders

Anti-Inflammatory Effects of Omega-3 Fatty Acids in the Brain: Physiological Mechanisms and Relevance to Pharmacology

Targeting neuroinflammation in Alzheimer’s disease: evidence for NSAIDs and novel therapeutics

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