Eicosapentaenoic acid and arachidonic acid: collaboration and not antagonism is the key to biological understanding

Horrobin, David F.; Jenkins, K. J.; Bennett, C.N.; Christie, William W.

doi:10.1054/plef.2001.0338

Cited by 77 publications

(41 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The detrimental influence of EPA on A␤ levels is consistent with the harmful effects of EPA reported in literature (35)(36)(37). Interestingly, both AA and EPA are the typical stereotypes of omega-6 and omega-3 types of FAs, respectively but in the present investigation, their effects on A␤ levels are comparable.…”

Section: Journal Of Biological Chemistry 6105supporting

confidence: 92%

“…Therefore, it is not surprising that C13 in both FAs are in correspondingly similar positions (39). This also explains why EPA instead being precursor of DHA does not decrease A␤ levels (35)(36)(37). Clearly, the preferred acyl configurations are very different for EPA and DHA, which further justifies that specific geometrical aspects must be invoked to explain the effects of PUFA (chain) on A␤ levels.…”

Section: Journal Of Biological Chemistry 6105mentioning

confidence: 96%

See 1 more Smart Citation

Structural Insight into the Differential Effects of Omega-3 and Omega-6 Fatty Acids on the Production of Aβ Peptides and Amyloid Plaques

Amtul

Uhrig

Rozmahel

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

Several studies have shown the protective effects of dietary enrichment of various lipids in several late-onset animal models of Alzheimer Disease (AD); however, none of the studies has determined which structure within a lipid determines its detrimental or beneficial effects on AD. High-sensitivity enzyme-linked immunosorbent assay (ELISA) shows that saturated fatty acids (SFAs), upstream omega-3 FAs, and arachidonic acid (AA) resulted in significantly higher secretion of both A␤ 40 and 42 peptides compared with long chain downstream omega-3 and monounsaturated FAs (MUFA). Their distinct detrimental action is believed to be due to a structural template found in their fatty acyl chains that lack SFAs, upstream omega-3 FAs, and AA. Immunoblotting experiments and use of APP-C99-transfected COS-7 cells suggest that FAdriven altered production of A␤ is mediated through ␥-secretase cleavage of APP. An early-onset AD transgenic mouse model expressing the double-mutant form of human amyloid precursor protein (APP); Swedish (K670N/M671L) and Indiana (V717F), corroborated in vitro findings by showing lower levels of A␤ and amyloid plaques in the brain, when they were fed a low fat diet enriched in DHA. Our work contributes to the clarification of aspects of structure-activity relationships. Alzheimer Disease (AD)2 is a currently incurable progressive neurological disease that affects higher brain functions, ultimately leading to dementia and death (1). The molecular key event triggering the harmful cascade in AD is generally considered to be increased soluble oligomeric A␤, or more specifically A␤42 levels (2-4). Whereas A␤ generation depends on several factors, the prime event in A␤ generation is cleavage of APP-C99 by ␥-secretase. This is because it is the last essential step in A␤40 versus A␤42 generation, and it is also this cleavage for which most mechanistic information linking lipid homeostasis with A␤ production is available (5, 6).Several studies have shown the protective effects of various lipids on several parameters of AD; however, none of the studies has determined which structure within a lipid decides its detrimental or beneficial effects on A␤ production or the A␤40/42 ratio. Using an AD-cell culture model we identified the parameters, which may define whether a lipid or FA will affect A␤ production. A simple structure-activity relationship (SAR) study was performed in an attempt to examine the following factors: chain length, saturation, position of unsaturation (either at omega-3, -6, -7, or -9 carbon), and orientation (cis, trans) of double bonds as well as the effects of natural and synthetic/conjugated lipids. Based on our in vitro data, we designed a diet high in DHA but low in all deleterious fats and cholesterol, and showed for the first time in an early-onset robust mouse model of AD (which represents individuals who are at high risk of developing early-onset AD due to genetic mutations), that the protective structural template built-in the acyl chain of DHA indeed improves AD-type neuropathology...

show abstract

Section: Journal Of Biological Chemistry 6105supporting

confidence: 92%

Section: Journal Of Biological Chemistry 6105mentioning

confidence: 96%

Structural Insight into the Differential Effects of Omega-3 and Omega-6 Fatty Acids on the Production of Aβ Peptides and Amyloid Plaques

Amtul

Uhrig

Rozmahel

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…they are antagonistic to AA function, such experiments normally involve administration of fairly high doses. At lower doses (Ͻ0.1% total lipids), EPA leads to increased AA abundance in both experimental animals and human subjects (reviewed in Horrobin et al 2002). Such fi ndings are consistent with reports that lower doses of EPA can be more effi cacious than high doses in the treatment of mental health disorders .…”

Section: Molecular Mechanismssupporting

confidence: 82%

Article Commentary: The Emerging Role of Eicosapentaenoic Acid as an Important Psychoactive Natural Product: Some Answers but a Lot more Questions

Ross

2008

Lipid�Insights

View full text Add to dashboard Cite

Omega-3 polyunsaturated fatty acids play important roles in both the structure and communication processes of cells. Dietary defi ciences of these fatty acids have been implicated in cardiac dysfunction, cancer and mood disorders. In the latter, clinical trials have strongly suggested that not all types of omega-3 PUFA are equally effi cacious. In particular eicosapentaenoic acid (EPA) appears to be the most useful in ameliorating the symptoms of major depressive disorder. The mechanism by which omega-3 PUFA have these effects, and why EPA is apparently more effective in this role than the much more abundant brain lipid docosahexaenoic acid, is unclear. The available data do suggest various biologically plausible mechanisms all of which are amenable to study using straightforward experimental approaches. To progress further, a better understanding of how EPA and other omega-3 PUFA effect neurophysiological and neurosignalling processes is required.

show abstract

“…We speculated that E-EPA would show neuroprotective properties in vivo by maintaining neuronal integrity, protecting the brain against excitotoxicity, and support antioxidative defense. We chose E-EPA because previous controlled studies in schizophrenia have shown some benefits (Emsley et al, 2002(Emsley et al, , 2006Horrobin et al, 2002;Peet, 2003Peet, , 2001Peet and Horrobin, 2002a, b), and because treatment response has been associated with an increase in EPA (Arvindakshan et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Ethyl-Eicosapentaenoic Acid in First-Episode Psychosis. A 1H-MRS Study

Berger

Wood

Wellard

et al. 2008

Neuropsychopharmacol

107

View full text Add to dashboard Cite

Ethyl-eicosapentaenoic acid (E-EPA) is an omega-3 fatty acid that has been used in a range of neuropsychiatric conditions with some benefits. However, its mechanism of action is unknown. Here, we investigate its effects on in vivo brain metabolism in first-episode psychosis (FEP). Proton magnetic resonance spectroscopy at 3 T was performed in the temporal lobes of 24 FEP patients before and after 12 weeks of treatment in the context of a larger double-blind, placebo-controlled E-EPA augmentation study. Treatment group effects for glutathione (F1,12 ¼ 6.1, p ¼ 0.03), and a hemisphere-by-group interaction for glutamine/glutamate (F1,20 ¼ 4.4, p ¼ 0.049) were found. Glutathione increased bilaterally and glutamate/glutamine increased in the left hemisphere following E-EPA administration. Improvement in negative symptoms correlated with metabolic brain changes, particularly glutathione (r ¼ À0.57). These results suggest that E-EPA augmentation alters glutathione availability and modulates the glutamine/glutamate cycle in early psychosis, with some of the metabolic brain changes being correlated with negative symptom improvement. Larger confirmatory studies of these postulated metabolic brain effects of E-EPA are warranted.

show abstract

Eicosapentaenoic acid and arachidonic acid: collaboration and not antagonism is the key to biological understanding

Cited by 77 publications

References 36 publications

Structural Insight into the Differential Effects of Omega-3 and Omega-6 Fatty Acids on the Production of Aβ Peptides and Amyloid Plaques

Structural Insight into the Differential Effects of Omega-3 and Omega-6 Fatty Acids on the Production of Aβ Peptides and Amyloid Plaques

Article Commentary: The Emerging Role of Eicosapentaenoic Acid as an Important Psychoactive Natural Product: Some Answers but a Lot more Questions

Ethyl-Eicosapentaenoic Acid in First-Episode Psychosis. A 1H-MRS Study

Contact Info

Product

Resources

About