Evaluating the relationship between the nutrient intake of lactating women and their breast milk nutritional profile: a systematic review and narrative synthesis.

Maternal diet influences breast milk nutritional profile; however, it is unclear which nutrients and contaminants are particularly responsive to short- and long-term changes in maternal intake, and the impact of specific exclusion diets, such as vegan or vegetarian. This study systematically reviewed the literature on the effects of maternal nutrient intake, including exclusion diets, on both the nutrient and contaminant content of breast milk. The electronic databases, PubMed, CENTRAL, Web of Science and CINALH were systematically searched until 4 June 2023, with additionally searches of reference lists (PROSPERO, CRD42020221577). The quality of the studies was examined using Cochrane Risk of Bias tool and Newcastle-Ottawa scale. Eighty-eight studies (n 6577) met the search criteria. Due to high heterogeneity, meta-analysis was not possible. There was strong evidence of response to maternal intakes for DHA and EPA, vitamins A, E and K, iodine and Se in breast milk composition, some evidence of response for α-linolenic acid, B vitamins, vitamin C and D, ovalbumin, tyrosine and contaminants, and insufficient evidence to identify the effects arachidonic acid, Cu, Fe, Zn and choline. The paucity of evidence and high heterogeneity among studies reflects the need for more high-quality trials. However, this review identified the importance of maternal intake in the nutritional content of breast milk for a wide range of nutrients and supports the recommendation for supplementation of DHA and vitamin B12 for those on restrictive diets.

Docosahexaenoic Acid Explains the Unexplained in Visual Transduction.

In George Wald's Nobel Prize acceptance speech for "discoveries concerning the primary physiological and chemical visual processes in the eye", he noted that events after the activation of rhodopsin are too slow to explain visual reception. Photoreceptor membrane phosphoglycerides contain near-saturation amounts of the omega-3 fatty acid docosahexaenoic acid (DHA). The visual response to a photon is a retinal cis-trans isomerization. The trans-state is lower in energy; hence, a quantum of energy is released equivalent to the sum of the photon and cis-trans difference. We hypothesize that DHA traps this energy, and the resulting hyperpolarization extracts the energized electron, which depolarizes the membrane and carries a function of the photon's energy (wavelength) to the brain. There, it contributes to the creation of the vivid images of our world that we see in our consciousness. This proposed revision to the visual process provides an explanation for these previously unresolved issues around the speed of information transfer and the purity of conservation of a photon's wavelength and supports observations of the unique and indispensable role of DHA in the visual process.

Long-chain omega-3 polyunsaturated fatty acids are reduced in neonates with substantial brain injury undergoing therapeutic hypothermia after hypoxic-ischemic encephalopathy.

Hypoxic-ischemic encephalopathy (HIE) is a major cause of neonatal morbidity and mortality. Although therapeutic hypothermia is an effective treatment, substantial chronic neurological impairment often persists. The long-chain omega-3 polyunsaturated fatty acids (PUFAs), docosahexaenoic (DHA) and eicosapentaenoic (EPA) acids, offer therapeutic potential in the post-acute phase. To understand how PUFAs are affected by HIE and therapeutic hypothermia we quantified for the first time the effects of HIE and therapeutic hypothermia on blood PUFA levels and lipid peroxidation. In a cross-sectional approach, blood samples from newborns with moderate to severe HIE, who underwent therapeutic hypothermia (sHIE group) were compared to samples from newborns with mild HIE, who did not receive therapeutic hypothermia, and controls. The sHIE group was stratified into cerebral MRI predictive of good (n = 10), or poor outcomes (n = 10; nine developed cerebral palsy). Cell pellets were analyzed for fatty acid content, and plasma for lipid peroxidation products, thiobarbituric acid reactive substances and 4-hydroxy-2-nonenal. Omega-3 Index (% DHA + EPA) was similar between control and HIE groups; however, with therapeutic hypothermia there were significantly lower levels in poor vs. good prognosis sHIE groups. Estimated Δ-6 desaturase activity was significantly lower in sHIE compared to mild HIE and control groups, and linoleic acid significantly increased in the sHIE group with good prognosis. Reduced long-chain omega-3 PUFAs was associated with poor outcome after HIE and therapeutic hypothermia, potentially due to decreased biosynthesis and tissue incorporation. We speculate a potential role for long-chain omega-3 PUFA interventions in addition to existing treatments to improve neurologic outcomes in sHIE.

Effects of long-chain omega-3 polyunsaturated fatty acids on reducing anxiety and/or depression in adults; A systematic review and meta-analysis of randomised controlled trials.

The omega-3 polyunsaturated fatty acids (PUFAs) eicosapentaenoic- (EPA), docosahexaenoic- (DHA) and docosapentaenoic acid (DPAn-3) are promising therapeutic options in reducing the severity of anxious and depressive symptoms. However, meta-analyses of randomised controlled trials (RCTs) yield mixed findings. This systematic review and meta-analysis reviewed the evidence and assessed the efficacy of EPA, DHA and DPAn-3 in reducing the severity of anxiety and depression with specific consideration to methodological complications unique to the field e.g., dose and ratio of omega-3 PUFAs and placebo composition. Random-effects meta-analysis of ten RCTs comprising 1426 participants revealed statistically significant reduction in depression severity with EPA-enriched interventions at proportions ≥ 60% of total EPA + DHA (SMD: -0.36; 95% CI: -0.68, -0.05; p = 0.02) (I2 = 86%) and EPA doses between ≥ 1 g/day and < 2 g/day (SMD: -0.43; 95% CI: -0.79, -0.07; p = 0.02) (I2 = 88%); however, EPA doses ≥ 2 g/day were not associated with significant therapeutic effects (SMD: -0.20; 95% CI: -0.48, 0.07; p = 0.14). Only one study reported significant reduction in anxiety severity with 2.1 g/day EPA (85.6% of total EPA + DHA), therefore meta-analysis was not possible. No trials administering DPAn-3 were identified. Visual examination of the funnel plot revealed asymmetry, suggesting publication bias and heterogeneity amongst the trials. These results support the therapeutic potential of EPA in depression at proportions ≥ 60% of total EPA + DHA and doses ≥ 1 g/day and < 2 g/day. The observed publication bias and heterogeneity amongst the trials reflect the need for more high-quality trials in this area with consideration to the unique nature of omega-3 PUFAs research, to more fully elucidate the therapeutic potential of EPA, DHA and DPAn-3.

The effects of multi-nutrient formulas containing a combination of n-3 PUFA and B vitamins on cognition in the older adult: a systematic review and meta-analysis.

There is now evidence to suggest that there may be an interaction between B vitamins and n-3 PUFA, with suggestions that increasing intake of both nutrients simultaneously may benefit cognition in older adults. The aim of this systematic review was to investigate whether supplementation with a combination of n-3 PUFA and B vitamins can prevent cognitive decline in older adults. Randomised controlled trials conducted in older adults that measured cognitive function were retrieved. The included trials provided a combination of n-3 PUFA and B vitamins alone, or in combination with other nutrients. Trials that provided n-3 PUFA alone and also measured B vitamin status or provided B vitamin supplementation alone and measured n-3 PUFA status were also included. The databases searched were The Cochrane Library, EMBASE, CINAHL, Scopus and MEDLINE. A total of 14 papers were included in the analysis (n 4913; age: 60-70 years; follow-up 24 weeks to 4 years). The meta-analysis results found a significant benefit of nutrient formulas, which included both n-3 PUFA and B vitamins alongside other nutrients, v. placebo on global cognition assessed using composite scores from a neuropsychological test battery (G = 0·23, P = 0·002), global cognition using single measures of cognition (G = 0·28, P = 0·004) and episodic memory (G = 0·32, P = 0·001). The results indicate that providing a combination of n-3 PUFA and B vitamins as part of a multi-nutrient formula benefits cognition in older adults v. a placebo, and the potential for an interaction between these key nutrients should be considered in future experimental work.

Polyunsaturated fatty acids and fatty acid-derived lipid mediators: Recent advances in the understanding of their biosynthesis, structures, and functions.

Polyunsaturated fatty acids (PUFAs) are structural components of membrane phospholipids, and influence cellular function via effects on membrane properties, and also by acting as a precursor pool for lipid mediators. These lipid mediators are formed via activation of pathways involving at least one step of dioxygen-dependent oxidation, and are consequently called oxylipins. Their biosynthesis can be either enzymatically-dependent, utilising the promiscuous cyclooxygenase, lipoxygenase, or cytochrome P450 mixed function oxidase pathways, or nonenzymatic via free radical-catalyzed pathways. The oxylipins include the classical eicosanoids, comprising prostaglandins, thromboxanes, and leukotrienes, and also more recently identified lipid mediators. With the advent of new technologies there is growing interest in identifying these different lipid mediators and characterising their roles in health and disease. This review brings together contributions from some of those at the forefront of research into lipid mediators, who provide brief introductions and summaries of current understanding of the structure and functions of the main classes of nonclassical oxylipins. The topics covered include omega-3 and omega-6 PUFA biosynthesis pathways, focusing on the roles of the different fatty acid desaturase enzymes, oxidized linoleic acid metabolites, omega-3 PUFA-derived specialized pro-resolving mediators, elovanoids, nonenzymatically oxidized PUFAs, and fatty acid esters of hydroxy fatty acids.

The effects of a high eicosapentaenoic acid multinutrient supplement on measures of stress, anxiety and depression in young adults: Study protocol for NutriMOOD, a randomised double-blind placebo-controlled trial.

Anxiety disorders affect nearly 20% of young adults aged 18-29 years. First-line treatment for anxiety disorders comprises pharmacotherapy and Cognitive Behavioural Therapy, options often criticised for their low efficacy and safety. In contrast, fish-oil-based supplements comprising omega-3 polyunsaturated fatty acids and supporting nutrients are gaining recognition as safe and effective alternatives. Here we present the protocol for a randomised, double-blind, placebo-controlled trial investigating the effects of a high eicosapentaenoic acid multinutrient supplement on validated measures of anxiety and depression in healthy university students experiencing non-clinical levels of anxiety and depression. The primary outcome is improvement in anxiety compared to the placebo group assessed via the Generalised Anxiety Disorder Assessment-7 scale. The participants will be randomised to active treatment comprising a daily dose of 1125 mg eicosapentaenoic acid, 441 mg docosahexaenoic acid, 330 mg magnesium and 7.5 mg vitamin E, or placebo, for 24 weeks, and will complete validated questionnaires and tablet-based tasks sensitive to mood at baseline and end of intervention. Circulating fatty acids and key biomarkers will also be assessed. The students will be genotyped for polymorphisms thought to influence the relationship between long-chain omega-3 polyunsaturated fatty acids and affect. Trial registration; ClinicalTrials.gov, NCT04844034.

A new ketogenic formulation improves functional outcome and reduces tissue loss following traumatic brain injury in adult mice.

Rationale: Traumatic brain injury (TBI) leads to neurological impairment, with no satisfactory treatments available. Classical ketogenic diets (KD), which reduce reliance on carbohydrates and provide ketones as fuel, have neuroprotective potential, but their high fat content reduces compliance, and experimental evidence suggests they protect juvenile brain against TBI, but not adult brain, which would strongly limit their applicability in TBI. Methods: We designed a new-KD with a fat to carbohydrate plus protein ratio of 2:1, containing medium chain triglycerides (MCT), docosahexaenoic acid (DHA), low glycaemic index carbohydrates, fibres and the ketogenic amino acid leucine, and evaluated its neuroprotective potential in adult TBI. Adult male C57BL6 mice were injured by controlled cortical impact (CCI) and assessed for 70 days, during which they received a control diet or the new-KD. Results: The new-KD, that markedly increased plasma Beta-hydroxybutyrate (ß-HB), significantly attenuated sensorimotor deficits and corrected spatial memory deficit. The lesion size, perilesional inflammation and oxidation were markedly reduced. Oligodendrocyte loss appeared to be significantly reduced. TBI activated the mTOR pathway and the new-KD enhanced this increase and increased histone acetylation and methylation. Conclusion: The behavioural improvement and tissue protection provide proof of principle that this new formulation has therapeutic potential in adult TBI.

Effects of a high-DHA multi-nutrient supplement and exercise on mobility and cognition in older women (MOBILE): a randomised semi-blinded placebo-controlled study.

There is a complex interplay between mobility and cognition in older adults. We have previously shown that a high-DHA multi-nutrient supplement improves habitual walking speed, verbal memory and psychomotor response latency in older women. Exercise also improves mobility and cognition in older adults, and n-3 fatty acids and exercise share a range of overlapping biological effects. This study examined for the first time the effects of the high-DHA multi-nutrient supplement and aerobic exercise on mobility and cognition in older women. Women (mean age 67 (sd 8) years) were assigned to the following groups: multi-nutrient (1 g DHA, 160 mg EPA, 240 mg Ginkgo biloba, 60 mg phosphatidylserine, 20 mg d-α tocopherol, 1 mg folic acid and 20 µg vitamin B12 per d, n 13), multi-nutrient and exercise (spin class twice per week, n 14), exercise and placebo (n 12) or placebo (n 12). The multi-nutrient was given for 24 weeks and exercise for 12 weeks. No treatment effects were observed for the primary outcome, habitual walking speed. Improvements in verbal memory and executive function were seen for all treatments groups v. placebo (all, P < 0·05). Significant improvements in self-reported emotional well-being were seen with multi-nutrient and exercise groups v. placebo (P = 0·03). The results suggest that the high-DHA multi-nutrient supplement produces similar improvements in cognitive function to aerobic exercise, offering the intriguing prospect that supplementation may be able to mitigate some of the effects of low physical activity on cognitive function in the elderly.

Long-Chain Polyunsaturated Fatty Acids and Lipid Peroxidation Products in Donor Human Milk in the United Kingdom: Results From the LIMIT 2-Centre Cross-Sectional Study.

BACKGROUND: Donor human milk (DHM) is used as alternative to maternal milk to feed preterm infants; however, it may provide less long-chain (LC) polyunsaturated fatty acids (PUFAs) and more oxidized lipids, which may be detrimental to preterm infant health and development. Levels have not been reported for DHM in the United Kingdom. METHODS: DHM (n = 19) from 2 neonatal units, preterm milk from a neonatal unit (n = 10), and term milk from the community (n = 11) were analyzed for fatty acids, malondialdehyde, 4-hydroxy-2-nonenal, and hexanal. STUDY REGISTRATION: NCT03573531. RESULTS: DHM had significantly lower absolute LCPUFA content than term (P < .001) and significantly lower ω-3 PUFAs than preterm milk (P < .05), although relative LCPUFA composition did not differ. Exclusive DHM feeding leads to significantly lower fat (3.7 vs 6.7 g/d) and LCPUFA (docosahexaenoic acid [DHA]: 10.6 vs 16.8 mg/d; arachidonic acid [ARA]: 17.4 vs 25.2 mg/d) intake than recommended by the European Society for Pediatric Gastroenterology, Hepatology and Nutrition, and provides 17.3% and 43.1% of the in utero accreted ARA and DHA. DHM had the highest proportion of lipid peroxidation. CONCLUSIONS: This study confirms that DHM in the United Kingdom has insufficient LCPUFAs for preterm infants. It demonstrates for the first time that DHM has the highest level of lipid peroxidation, compared with preterm or term milk. This has important implications for preterm infant nutrition, as exclusive DHM feeding might not be suitable long term and may contribute to the development of major preterm neonatal morbidities.

The effects of storage conditions on long-chain polyunsaturated fatty acids, lipid mediators, and antioxidants in donor human milk - A review.

Donor human milk (DHM) is the recommended alternative, if maternal milk is unavailable. However, current human milk banking practices may negatively affect the nutritional quality of DHM. This review summarises the effects of these practices on polyunsaturated fatty acids, lipid mediators and antioxidants of human milk. Overall, there is considerable variation in the reported effects, and further research is needed, particularly with lipid mediators and antioxidants. However, to preserve nutritional quality, DHM should be protected from light exposure and storage at 4 °C minimised, to prevent decreases in vitamin C and endocannabinoids and increases in free fatty acids and lipid peroxidation products. Storage at -20 °C prior to pasteurisation should also be minimised, to prevent free fatty increases and total fat and endocannabinoid decreases. Storage ≤-70 °C is preferable wherever possible, although post-pasteurisation storage at -20 °C for three months appears safe for free fatty acids, lipid peroxidation products, and total fat content.

Combining a high DHA multi-nutrient supplement with aerobic exercise: Protocol for a randomised controlled study assessing mobility and cognitive function in older women.

There is a complex interplay between cognition and gait in older people, with declines in gait speed coexisting with, or preceding cognitive decline. Omega-3 fatty acids, B vitamins, vitamin E, phosphatidylserine, and Ginkgo Biloba show promise in preserving mobility and cognitive function in older adults. Exercise benefits mobility and there is evidence suggesting positive interactions between exercise and omega-3 fatty acids on physical and cognitive function in older adults. Non-frail or pre-frail females aged ≥60 years are included in a randomized placebo controlled study. Intervention groups are: high DHA multi-nutrient supplement and exercise, placebo supplement and exercise, high DHA multi-nutrient supplement, and placebo supplement. Dietary supplementation is 24 weeks. The exercise intervention, two cycle ergometer classes per week, is for the final 12 weeks. The primary outcome is habitual walking speed, secondary outcomes include gait variables under single and dual task, five times sit to stand, verbal and spatial memory, executive function, interference control and health related quality of life. Blood fatty acids, serum homocysteine, dietary intake, physical activity, and verbal intelligence are measured to assess compliance and control for confounding factors. The study is registered at www.clinicaltrials.gov (NCT03228550).

Brain Phospholipid Precursors Administered Post-Injury Reduce Tissue Damage and Improve Neurological Outcome in Experimental Traumatic Brain Injury.

Traumatic brain injury (TBI) leads to cellular loss, destabilization of membranes, disruption of synapses and altered brain connectivity, and increased risk of neurodegenerative disease. A significant and long-lasting decrease in phospholipids (PLs), essential membrane constituents, has recently been reported in plasma and brain tissue, in human and experimental TBI. We hypothesized that supporting PL synthesis post-injury could improve outcome post-TBI. We tested this hypothesis using a multi-nutrient combination designed to support the biosynthesis of PLs and available for clinical use. The multi-nutrient, Fortasyn® Connect (FC), contains polyunsaturated omega-3 fatty acids, choline, uridine, vitamins, cofactors required for PL biosynthesis, and has been shown to have significant beneficial effects in early Alzheimer's disease. Male C57BL/6 mice received a controlled cortical impact injury and then were fed a control diet or a diet enriched with FC for 70 days. FC led to a significantly improved sensorimotor outcome and cognition, reduced lesion size and oligodendrocyte loss, and it restored myelin. It reversed the loss of the synaptic protein synaptophysin and decreased levels of the axon growth inhibitor, Nogo-A, thus creating a permissive environment. It decreased microglia activation and the rise in ß-amyloid precursor protein and restored the depressed neurogenesis. The effects of this medical multi-nutrient suggest that support of PL biosynthesis post-TBI, a new treatment paradigm, has significant therapeutic potential in this neurological condition for which there is no satisfactory treatment. The multi-nutrient tested has been used in dementia patients and is safe and well tolerated, which would enable rapid clinical exploration in TBI.

Interplay Between n-3 and n-6 Long-Chain Polyunsaturated Fatty Acids and the Endocannabinoid System in Brain Protection and Repair.

The brain is enriched in arachidonic acid (ARA) and docosahexaenoic acid (DHA), long-chain polyunsaturated fatty acids (LCPUFAs) of the n-6 and n-3 series, respectively. Both are essential for optimal brain development and function. Dietary enrichment with DHA and other long-chain n-3 PUFA, such as eicosapentaenoic acid (EPA), has shown beneficial effects on learning and memory, neuroinflammatory processes, and synaptic plasticity and neurogenesis. ARA, DHA and EPA are precursors to a diverse repertoire of bioactive lipid mediators, including endocannabinoids. The endocannabinoid system comprises cannabinoid receptors, their endogenous ligands, the endocannabinoids, and their biosynthetic and degradation enzymes. Anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are the most widely studied endocannabinoids and are both derived from phospholipid-bound ARA. The endocannabinoid system also has well-established roles in neuroinflammation, synaptic plasticity and neurogenesis, suggesting an overlap in the neuroprotective effects observed with these different classes of lipids. Indeed, growing evidence suggests a complex interplay between n-3 and n-6 LCPUFA and the endocannabinoid system. For example, long-term DHA and EPA supplementation reduces AEA and 2-AG levels, with reciprocal increases in levels of the analogous endocannabinoid-like DHA and EPA-derived molecules. This review summarises current evidence of this interplay and discusses the therapeutic potential for brain protection and repair.

A High Omega-3 Fatty Acid Multinutrient Supplement Benefits Cognition and Mobility in Older Women: A Randomized, Double-blind, Placebo-controlled Pilot Study.

BACKGROUND: Mobility is a key determinant of frailty in older persons, and a variety of dietary factors, such as the omega-3 fatty acid docosahexaenoic acid (DHA), are positively associated with decreased frailty and improved mobility and cognition in older persons. METHODS: The effects of a multinutrient supplement on mobility and cognition were assessed in postmenopausal women (60-84 years). Participants received either Efalex Active 50+ (1g DHA, 160 mg eicosapentaenoic acid, 240 mg Ginkgo biloba, 60 mg phosphatidylserine, 20mg d-α tocopherol, 1mg folic acid, and 20 µg vitamin B12 per day; N = 15) or placebo (N = 12) for 6 months. Mobility was assessed by VICON 9 motion capture camera system synchronized with Kistler force plates, cognitive performance by computerized cognitive function tests, and blood fatty acid levels by pin-prick analysis. RESULTS: Significant effects of treatment were seen in two of the four cognitive tests, with shorter mean latencies in a motor screening task (p < .05) and more words remembered (p < .03), and one of the three primary mobility measures with improved habitual walking speed (p < .05). Compared with the placebo group, supplementation also resulted in significantly higher blood DHA levels (p < .02). CONCLUSIONS: In this pilot study, multinutrient supplementation improved cognition and mobility in able older females at clinically relevant levels, suggesting a potential role in reducing the decline to frailty.

Long-chain omega-3 fatty acids and the brain: a review of the independent and shared effects of EPA, DPA and DHA.

Omega-3 polyunsaturated fatty acids (PUFAs) exhibit neuroprotective properties and represent a potential treatment for a variety of neurodegenerative and neurological disorders. However, traditionally there has been a lack of discrimination between the different omega-3 PUFAs and effects have been broadly accredited to the series as a whole. Evidence for unique effects of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and more recently docosapentaenoic acid (DPA) is growing. For example, beneficial effects in mood disorders have more consistently been reported in clinical trials using EPA; whereas, with neurodegenerative conditions such as Alzheimer's disease, the focus has been on DHA. DHA is quantitatively the most important omega-3 PUFA in the brain, and consequently the most studied, whereas the availability of high purity DPA preparations has been extremely limited until recently, limiting research into its effects. However, there is now a growing body of evidence indicating both independent and shared effects of EPA, DPA and DHA. The purpose of this review is to highlight how a detailed understanding of these effects is essential to improving understanding of their therapeutic potential. The review begins with an overview of omega-3 PUFA biochemistry and metabolism, with particular focus on the central nervous system (CNS), where DHA has unique and indispensable roles in neuronal membranes with levels preserved by multiple mechanisms. This is followed by a review of the different enzyme-derived anti-inflammatory mediators produced from EPA, DPA and DHA. Lastly, the relative protective effects of EPA, DPA and DHA in normal brain aging and the most common neurodegenerative disorders are discussed. With a greater understanding of the individual roles of EPA, DPA and DHA in brain health and repair it is hoped that appropriate dietary recommendations can be established and therapeutic interventions can be more targeted and refined.

The omega-3 fatty acid eicosapentaenoic acid accelerates disease progression in a model of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a progressive fatal neurodegenerative disease characterised by loss of motor neurons that currently has no cure. Omega-3 polyunsaturated fatty acids, such as eicosapentaenoic acid (EPA), have many health benefits including neuroprotective and myoprotective potential. We tested the hypothesis that a high level of dietary EPA could exert beneficial effects in ALS. The dietary exposure to EPA (300 mg/kg/day) in a well-established mouse model of ALS expressing the G93A superoxide dismutase 1 (SOD1) mutation was initiated at a pre-symptomatic or symptomatic stage, and the disease progression was monitored until the end stage. Daily dietary EPA exposure initiated at the disease onset did not significantly alter disease presentation and progression. In contrast, EPA treatment initiated at the pre-symptomatic stage induced a significantly shorter lifespan. In a separate group of animals sacrificed before the end stage, the tissue analysis showed that the vacuolisation detected in G93A-SOD1 mice was significantly increased by exposure to EPA. Although EPA did not alter motor neurone loss, EPA reversed the significant increase in activated microglia and the astrocytic activation seen in G93A-SOD1 mice. The microglia in the spinal cord of G93A-SOD1 mice treated with EPA showed a significant increase in 4-hydroxy-2-hexenal, a highly toxic aldehydic oxidation product of omega-3 fatty acids. These data show that dietary EPA supplementation in ALS has the potential to worsen the condition and accelerate the disease progression. This suggests that great caution should be exerted when considering dietary omega-3 fatty acid supplements in ALS patients.

Transgenic mice with high endogenous omega-3 fatty acids are protected from spinal cord injury.

Omega-3 polyunsaturated fatty acids have been shown to have therapeutic potential in a variety of neurological disorders, including acute traumatic injury of the spinal cord. We addressed the question whether the neuroprotective effect of these compounds after spinal cord injury could also be seen when their level is raised in tissues prophylactically, prior to injury. In this study we used transgenic fat-1 mice to examine whether enriching spinal cord tissue in endogenous omega-3 polyunsaturated fatty acids has an effect on the outcome after compression spinal cord injury. The results demonstrate that after thoracic compression spinal cord injury, fat-1 mice display better locomotor recovery compared with the wild-type mice on a high omega-6 diet (high omega-6 polyunsaturated fatty acids in tissues), and wild-type mice on a normal diet (controls). This is associated with a significant increase in neuronal and oligodendrocyte survival and a decrease in non-phosphorylated neurofilament loss. The protection from spinal cord injury in fat-1 mice was also correlated with a reduction in microglia/macrophage activation and in pro-inflammatory mediators. In vitro experiments in dorsal root ganglia primary sensory neurons further demonstrated that a fat-1 tissue background confers robust neuroprotection against a combined mechanical stretch and hypoxic injury. In conclusion, our studies support the hypothesis that a raised omega-3 polyunsaturated fatty acid level and an altered tissue omega-6/omega-3 ratio prior to injury leads to a much improved outcome after spinal cord injury.

Improved outcome after peripheral nerve injury in mice with increased levels of endogenous ω-3 polyunsaturated fatty acids.

Functional recovery after a peripheral nerve injury (PNI) is often poor. There is a need for therapies that protect neurons against injury and enhance regeneration. ω-3 polyunsaturated fatty acids (PUFAs) have been shown to have therapeutic potential in a variety of neurological disorders, including acute traumatic injury. The objective of this study was to assess the neuroprotective and pro-regenerative potential of ω-3 PUFAs in PNI. We investigated this in mice that express the fat-1 gene encoding for ω-3 fatty acid desaturase, which leads to an increase in endogenous ω-3 PUFAs and a concomitant decrease in ω-6 PUFAs. Dorsal root ganglion (DRG) neurons from wild-type or fat-1 mice were subjected to a mechanical strain or hypoxic injury, and cell death was assessed using ethidium homodimer-1 labeling. The fat-1 background appears to confer robust neuroprotection against both injuries. We then examined the early functional and morphological changes in wild-type and fat-1 mice after a sciatic nerve crush. An accelerated functional recovery 7 d after injury was seen in fat-1 mice when assessed using von Frey filaments and the sciatic nerve functional index. These observations were also mapped to changes in injury-related markers. The injury-induced expression of ATF-3 was decreased in the DRG of fat-1 mice, whereas the axons detected 6 mm distal to the crush were increased. Fat-1 animals also had some protection against muscle atrophy after injury. In conclusion, both in vitro and in vivo experiments support the idea that a higher endogenous ω-3 PUFA could lead to beneficial effects after a PNI.

Methodological issues and inconsistencies in the field of omega-3 fatty acids research.

There is growing interest into researching omega-3 fatty acids; however, there are considerable variations in the methodologies employed. Many studies add oils to animal feed and under ambient conditions omega-3 fatty acids are particularly unstable and prone to autoxidation and peroxidative damage. It is therefore important to take specific precautions with the stock preparations and when preparing the experimental diets. There is a need for clarity in the reporting of methodologies employed, such as how oil preparations are stored and handled, how experimental diets are prepared, the potential effects of adding additional antioxidants, whether there is a clear rationale for the selection of control/placebo diets, which may be situation dependent, and consistency in expressing the experimental doses. The purpose of this article is to highlight some of these issues in the hope of promoting discussion, and potentially developing guidelines as to what represents best practice.