Oxidative stress and inflammation are a major driver of cell dysfunction and can cause chronic disease. Inflammation and oxidative stress are now thought to contribute significantly to brain diseases and cognitive degeneration. In particular, oxidative stress can disrupt cellular signalling and cause lipid peroxidation which can lead to the death of neurones in the brain. Certain long chain fatty acids may be protective of brain degeneration because they are able to inhibit inflammation that can be a cause of oxidative stress. For this reason the omega-3 fatty acid in fish oil, eicosapentaenoic acid (EPA, C20:5 (n-3)), has been researched for its anti-inflammatory activity. Eicosapentaenoic acid accumulates in the cell membranes of neurones (and other cells) where its acts as a pool of precursors to a series of short lives signal molecules called the series 3 eicosanoids (including prostaglandins) and series 5 leukotrienes, which are synthesised through the cyclooxygenase and lipoxygenase enzymes systems, respectively.
The series 3 eicosanoids and series 5 leukotrienes produced by EPA are actually mildly pro-inflammatory. However they have particular anti-inflammatory effects because they can block the formation of highly pro-inflammatory series 2 eicosanoids and series 4 leukotrienes synthesised from omega-6 fatty acids. Series 3 eicosanoids are formed when phospholipase A2 cleaves EPA from its phospholipid in the cell membrane. Cyclooxygenase (COX) and lipoxygenase (LOX) then synthesises a range of eicosanoids including thromboxanes, leukotrienes and prostaglandins that regulate inflammation. The same COX and LOX enzymes also convert arachidonic acid (AA, C20:4 (n-6)) to series 2 pro-inflammatory eicosanoids, but this is inhibited competitively by the synthesis of series 3 eicosanoids. Alpha-linolenic acid (ALA, C18:3 (n-3)), EPA’s parent compound, also competitively inhibits AA synthesis through competition for the delta 5-desaturase enzymes in the essential fatty acid synthesis pathway.
Docosahexaenoic acid (DHA, C22:6 (n-3)) is also present in fish oils and can be synthesised from ALA. Traditionally DHA has been considered important simply as a precursor of EPA, a reaction that can occur through catalysis by an elongase enzyme and delta 4-desaturase enzyme. In this way DHA forms a pool of precursor molecules for EPA and series 3 eicosanoid synthesis and is thus anti-inflammatory. However, discovery of novel alternative synthesis pathways for both EPA and DHA suggests that these compounds may be converted into other compounds that have particular protective effects on neurones in the brain. Such products are termed non-classic eicosanoids. For example, DHA can be synthesised to neuroprotectin D1, a compound that may have particular effects at attenuating oxidative stress in neurones, thus protecting them from death. This is interesting because DHA is known to accumulate particularly in the neurones of the brain, suggesting a role for it in brain function.
Other compounds that are synthesised from EPA and DHA include a range of different resolvins. The resolvins were the first non-classical eicosanoids to be discovered and they may be important during the resolution phase of inflammation. As they are synthesised during cell to cell interactions they are also called the resolution interaction products. Resolvins can be synthesised from both EPA (E series) and DHA (D series). Docosatrienes are synthesised from DHA and are conjugate trienes. The docosatrienes help regulate immunity and are neuroprotective. Neuroprotective docosatrienes are termed the protectins (docosatrienes and protectins are interchangeable terminologies), of which protectin D1 is an example. DHA can also be metabolised to inflammation regulating maresins, which are also classified as docosatrienes. Interestingly aspirin may cause the synthesis of isomers of the resolvins and docosatrienes which may explain some of its anti-inflammatory effects.
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