Neuroinflammation underlies many neurodegenerative brain disorders, which is why advances in drugs or dietary factors that reduce it, would represent a significant step forward. The long-chain polyunsaturated fatty acids (LC-PUFAs) arachidonic acid (AA, 20:4n-6) and docosahexaenoic acid (DHA, 22:6n-3) are known to be “essential” for the central nervous system, in part, due to their role in regulating brain immunity. AA and DHA are substrates for cyclooxygenase, lipoxygenase and cytochrome p450 enzymes which convert them into bioactive lipid mediators (i.e. oxylipins), known to modulate inflammation and resolution pathways in the brain. AA is a precursor to both inflammatory and anti-inflammatory lipid mediators, whereas DHA is a precursor to mostly anti-inflammatory and pro-resolving lipid mediators. Other omega-3 (n-3) LC-PUFAs such as eicosapentaenoic acid (EPA, 20:5n-3) and n-3 docosapentaenoic acid (22:5n-3) are also known to generate potent pro-resolving lipid mediators via the same oxygenase and cytochrome P450 enzymatic pathways. In this issue of Brain, Behavior, and Immunity, Rey et al. demonstrate that dietary supplementation with LC-PUFAs containing EPA (at 10.6% of total fatty acids) and DHA (at 5.6%) to 21-day old mice for 2 months, prevented bacterial lipopolysaccharide (LPS)-induced elevation in brain cytokines (TNF-α and IL-1β) and pro-inflammatory eicosanoids (thromboxane B2, 8-hydroxyeicasatetraenoic acid), and enriched the brain with pro-resolving AA-derived epoxyeicosatrienoic acids and EPA- and DHA-derived hydroxylated metabolites (Rey et al., 2018). In vitro, some of these pro-resolving compounds are known to suppress microglial activation by downregulating NFκB and other inflammatory signaling pathways (Rey et al., 2016). The design of the Rey et al. study is unique in that both the control and supplemented groups received an n-3 PUFA adequate diet containing 1.1–1.6% (of total fatty acids) alpha-linolenic acid (ALA, 18:3n-3), the precursor to EPA And DHA synthesis by the liver (Domenichiello et al., 2014). Many studies addressing the role of n-3 LC-PUFAs in neuroprotection compared the effects of dietary n-3 LC-PUFAs to n-3 PUFA deficient diets lacking ALA in order to minimize the confounding effects of ALA itself or its conversion into bioactive EPA and DHA by the liver. While these studies were seminal in showing the indispensable role of n-3 LC-PUFAs in neuroprotection (e.g. (Orr et al., 2013)), the study by Rey et al. provides new information showing that dietary EPA and DHA protect against neuroinflammation even when ALA is present in the diet (Rey et al., 2018). This suggests a unique role of EPA and DHA, independent of ALA, in reducing brain inflammation. The effects of increasing dietary ALA levels alongside EPA and DHA supplementation remain to be tested.
Clinically, the evidence is conflicting, however. For instance, in a randomized controlled trial, DHA supplementation at 2 g/day for 18 months, did not confer protection against cognitive and functional decline in patients with Alzheimer’s disease, where persistent neuroinflammation is present (Quinn et al., 2010). It is not clear whether neuroinflammatory markers such as microglial activation were affected by DHA in this study (or others), but likely, a lack of clinical benefit reflects a lack of efficacy in targeting inflammation in the human brain by n-3 LC-PUFA. This could be due to multiple factors including the dietary ALA, EPA and DHA background, or dose, duration and timing of n-3 LC-PUFA administration.
On a parallel promising front, recent evidence suggests that lowering dietary n-6 linoleic acid (LA, 18:2n-6), the precursor to AA, might enhance the anti-inflammatory effects of n-3 LC-PUFAs (Ramsden et al., 2015). LA is a precursor to many pro-inflammatory lipid mediators shown to be toxic in animals (Schuster et al., 2018). In patients with drug-resistant migraine, LA lowering from approximately 7% to 2% energy, combined with 1.5 g of supplemental EPA and DHA per day for 12 weeks, reduced the frequency of chronic headaches and improved quality of life, compared to a low (2% energy) LA diet alone (Ramsden et al., 2015). Notably, both diets contained adequate amounts of ALA (0.6–1.6 % energy). While these findings need to be reproduced in larger studies, they point to the possibility that lowering the dietary LA background, might enhance the anti-inflammatory effects of EPA and DHA. Currently, LA accounts for approximately 7% of calories in the US diet, which is high compared to pre-1930 levels of 2% energy (Blasbalg et al., 2011). Overall, Rey et al. showed that dietary n-3 LC-PUFA supplementation to a diet containing adequate levels of ALA enhanced the brain’s capacity to resolve lipopolysaccharide-induced neuroinflammation. Testing the pro-resolving effects of combining n-3 LC-PUFA supplementation with dietary LA lowering represents the next frontier of scientific inquiry in the field of lipids and inflammatory brain disease. How effective these dietary approaches will be on inflammation related disorders such as migraine and Alzheimer’s disease remains to be seen. (Complete Authors article as published)
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