Abstract: 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. Omega-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.
Abstract: 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.
Abstract: Alzheimer’s disease is the most common form of dementia in the elderly and is a progressive neurodegenerative disorder characterised by a decline in cognitive function and also profound alterations in mood and behaviour. The pathology of the disease is characterised by the presence in the brain of extracellular amyloid peptide deposits and intracellular neurofibrillary tangles. Although many hypotheses have been put forward for the aetiology of the disease, increased inflammation and oxidative stress appear key features contributing to the pathology. The omega-3 polyunsaturated fats, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have well characterised effects on inflammation and may have neuroprotective effects in a number of neurodegenerative conditions including Alzheimer’s disease. The aims of this article are to review the neuroprotective effects of EPA and DHA in Alzheimer’s disease, with special emphasis on their role in modulating oxidative stress and inflammation and also examine their potential as therapeutic agents.
Abstract: Retinoic acid receptors (RARs), retinoid X receptors (RXRs), and peroxisome proliferator-activated receptors (PPARs) are transcription factors involved in many cellular processes, such as learning and memory. RAR and RXR mRNA levels decrease with ageing, and the decreases can be reversed by retinoic acid treatment, which also alleviates age-related memory deficits. The omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have neuroprotective effects in the aged brain and are endogenous ligands of RXR and PPAR. We investigated whether dietary EPA and DHA supplementation reverses age-related declines in protein levels of these receptors in rat forebrain. Two studies were conducted comparing adult and old rats. In the first, old rats were fed standard or EPA/DHA-enriched (270 mg/kg/day, EPA to DHA ratio 1.5:1) diets for 12 weeks. Analysis by Western blot revealed significant decreases in RARalpha, RXRalpha, RXRbeta, and PPARgamma in the forebrain with ageing, which were reversed by supplementation. Immunohistochemical analysis of the hippocampus showed significant age-related decreases in RARalpha and RXRbeta expression in CA1 and the dentate gyrus, which were restored by supplementation. Decreases in hippocampal doublecortin expression were also partially alleviated, suggesting a positive effect on neurogenesis. We also investigated the effects of DHA supplementation (300 mg/kg/day for 12 weeks) on RARalpha, RXRalpha, and RXRbeta expression in the prefrontal cortex, striatum, and hippocampus. Overall, DHA supplementation appeared to increase receptor expression compared with the untreated old group. These observations illustrate additional mechanisms that might underlie the neuroprotective effects of omega-3 fatty acids in ageing. (c) 2010 Wiley-Liss, Inc.
Abstract: Polyunsaturated fatty acids (PUFA) of the omega-3 series and omega-6 series modulate neurite outgrowth in immature neurones. However, it has not been determined if their neurotrophic effects persist in adult and aged tissue. We prepared cultures of primary sensory neurones from male and female rat dorsal root ganglia (DRG), isolated at different ages: post-natal day 3 (P3) and day 9 (P9), adult (2-4 months) and aged (18-20 months). Cultures were incubated with the omega-6 PUFA arachidonic acid (AA) and the omega-3 PUFA eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), at 0.8, 4, 8 and 40muM. PUFA increased neurite outgrowth throughout the developmental stages studied. The effects of omega-3 PUFA, in particular DHA, were still prominent in aged tissue. The amplitude of the effects was comparable to that of nerve growth factor (NGF; 50ng/ml) and all-trans-retinoic acid (ATRA; 0.1muM). The effects of PUFA were similar in cells positive or negative for the N52 neurofilament marker. Our results show that omega-3 PUFA have a marked neurite-promoting potential in neurones from adult and aged animals.
Abstract: The central nervous system is highly enriched in long-chain polyunsaturated fatty acid (PUFA) of the omega-6 and omega-3 series. The presence of these fatty acids as structural components of neuronal membranes influences cellular function both directly, through effects on membrane properties, and also by acting as a precursor pool for lipid-derived messengers. An adequate intake of omega-3 PUFA is essential for optimal visual function and neural development. Furthermore, there is increasing evidence that increased intake of the long-chain omega-3 PUFA, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), may confer benefits in a variety of psychiatric and neurological disorders, and in particular neurodegenerative conditions. However, the mechanisms underlying these beneficial effects are still poorly understood. Recent evidence also indicates that in addition to the positive effects seen in chronic neurodegenerative conditions, omega-3 PUFA may also have significant neuroprotective potential in acute neurological injury. Thus, these compounds offer an intriguing prospect as potentially new therapeutic approaches in both chronic and acute conditions. The purpose of this article is to review the current evidence of the neurological benefits of omega-3 PUFA, looking specifically at neurodegenerative conditions and acute neurological injury.
Abstract: Previous studies have shown that omega-3 polyunsaturated fatty acids such as alpha-linolenic acid and docosahexaenoic acid (DHA) are neuroprotective in models of spinal cord injury (SCI) in rodents. However, the mechanism of action underlying these effects has not been elucidated, and the optimum treatment regime remains to be defined. We have therefore carried out a detailed analysis of the effects of DHA in adult rats subject to thoracic compression SCI. Saline or DHA (250 nmol/kg) was administered intravenously (i.v.) 30 min after compression. After injury, the saline group received a standard control diet for 1 or 6 weeks, whereas DHA-injected animals received either a control or a DHA-enriched diet (400 mg/kg/day) for 1 or 6 weeks. Other groups received a DHA-enriched diet only for 1 week following injury, or received acute DHA (250 nmol/kg; i.v.) treatment delayed up to 3 h after injury. We also assessed oxidative stress and the inflammatory reaction at the injury site, neuronal and oligodendrocyte survival and axonal damage and the locomotor recovery. At 24 h, lipid peroxidation, protein oxidation, RNA/DNA oxidation and the induction of cyclooxygenase-2 were all significantly reduced by i.v. DHA administration. At 1 week and 6 weeks, macrophage recruitment was reduced and neuronal and oligodendrocyte survival was substantially increased. Axonal injury was reduced at 6 weeks. Locomotor recovery was improved from day 4, and sustained up to 6 weeks. Rats treated with a DHA-enriched diet in addition to the acute DHA injection were not significantly different from the acute DHA-treated animals at 1 week, but at 6 weeks showed additional improvements in both functional and histological outcomes. DHA treatment was ineffective if the acute injection was delayed until 3 h post-injury, or if the DHA was administered for 1 week solely by diet. Our results in a clinically relevant model of SCI show that significant neuroprotection can be obtained by combining an initial acute i.v. injection of DHA with a sustained dietary supplementation. Given that the safety and tolerability of preparations enriched in omega-3 fatty acids is already well-documented, such a combined DHA treatment regime deserves consideration as a very promising approach to SCI management.
Abstract: Ageing is associated with a decrease in the brain content of omega-3 polyunsaturated fatty acids (PUFA), such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and with decreased neuroplasticity. The glutamate receptor subunits GluR2 and NR2B play a significant role in forebrain synaptic plasticity. We investigated GluR2 and NR2B in the aged prefrontal cortex, hippocampus and striatum, and tested if treatment with a preparation containing EPA and DHA can reverse age-related changes. The study compared adult and old (3-4 and 24-26 month) rats, and the latter were fed a standard diet or a diet supplemented for 12 weeks with omega-3 PUFA at 270mg/kg/day (ratio EPA to DHA 1.5:1). Ageing was associated with decreases in the GluR2 and NR2B subunits in all structures. These decreases were fully reversed by omega-3 PUFA supplementation. Age-related changes in the phospholipid PUFA content were also seen. Decreases in DHA were mostly corrected by supplementation. This study supports the neuroprotective effect of omega-3 fatty acids in brain ageing, and illustrates specific mechanisms underlying this effect.
Abstract: Spinal cord injury (SCI) is a cause of major neurological disability, and no satisfactory treatment is currently available. Evidence suggests that polyunsaturated fatty acids (PUFAs) could target some of the pathological mechanisms that underlie damage after SCI. We examined the effects of treatment with PUFAs after lateral spinal cord hemisection in the rat. The omega-3 PUFAs alpha-linolenic acid and docosahexaenoic acid (DHA) injected 30 min after injury induced significantly improved locomotor performance and neuroprotection, including decreased lesion size and apoptosis and increased neuronal and oligodendrocyte survival. Evidence showing a decrease in RNA/DNA oxidation suggests that the neuroprotective effect of omega-3 PUFAs involved a significant antioxidant function. In contrast, animals treated with arachidonic acid, an omega-6 PUFA, had a significantly worse outcome than controls. We confirmed the neuroprotective effect of omega-3 PUFAs by examining the effects of DHA treatment after spinal cord compression injury. Results indicated that DHA administered 30 min after spinal cord compression not only greatly increased survival of neurons but also resulted in significantly better locomotor performance for up to 6 weeks after injury.This report shows a striking difference in efficacy between the effects of treatment with omega-3 and omega-6 PUFAs on the outcome of SCI, with omega-3 PUFAs being neuroprotective and omega-6 PUFAs having a damaging effect. Given the proven clinical safety of omega-3 PUFAs, our observations show that these PUFAs have significant therapeutic potential in SCI. In contrast, the use of preparations enriched in omega-6 PUFAs after injury could worsen outcome after SCI.
Abstract: The aims of this preliminary study were to:
(1) Compare FRAXTM (excluding BMD) with FRAXTM (including calcaneal QUS T-Score) predictions for fracture risk
(2) Assess the ability of each to predict actual fracture over the long-term (10 years)
Osteoporosis remains a major public health concern and accurate assessment of the associated bone fracture risk should enable appropriate targeting of vulnerable individuals with interventions intended to reduce this risk. Fracture risk may be predicted using simple non-invasive screening techniques that ensure patient safety at relatively low cost such as quantitative ultrasound (QUS) or the WHO fracture risk assessment tool, FRAXTM, an algorithm of hip and other major osteoporotic fracture risk over 10 years (Kanis et al. 2008)
One hundred and eighty Caucasian females, aged 40 to 79 at baseline (BMI range 18-34 Kg/m2), were randomly selected from a cohort of 900 subjects screened using calcaneal QUS (McCue Cubaclinical). Relevant patient details were retrospectively entered into the FRAXTM assessment tool, either with or without BMD calcaneal QUS T-score, and indices of fracture risk were compared. Subjects completed a follow up questionnaire to ascertain details of any fracture and level of trauma within the subsequent 10 years, and fragility fractures were abstracted. FRAXâ„¢ scores were classified into low, medium and high risk based on FRAXâ„¢ criteria and the results analysed by Chi-squared statistic.
The FRAXâ„¢ scores were significantly different when calculated with and without BMD (P<0.05), and although not significant the Chi-squared analysis indicated a far closer relationship between fragility fracture and high risk with BMD (P=0.08 vs. P=0.93). Furthermore, ten year follow up (mean 10.1 years) revealed that 26 of the 180 subjects sustained fragility fractures, 9 of which were predicted by FRAXTM without BMD (18%) and 13 by FRAXTM with BMD (28%). There were two spine fractures which were in the high risk category for both techniques, of the 17 wrist fractures 5 were in the high risk category for FRAXâ„¢ and 8 for FRAXâ„¢ (with BMD), the hip fracture was predicted by both techniques as was one of the two elbow fractures.
It should be noted that the predictive ability of the techniques may have been confounded by increased interim use of HRT and other osteoporosis treatments taken following the initial screen, as has been noted by us and others (Barr et al. 2010; Hinkley et al. 2009). However, based on our data it appears that the addition of calcaneal QUS T-score improves the ability of FRAXâ„¢ to predict fragility fractures in women.
Barr RJ, Stewart A, Torgerson DJ, Reid DM (2010) Osteoporos Int, 21, 561-568
Hinkley HJ, Bird D, Drysdale IPD (2009) A09001873, ASBMR 31st Annual Meeting, Denver USA
Kanis JA , Johnell O, Oden H, Johansson GH, McCloskey E (2008) Osteoporos Int, 19, 385-397
Abstract: It has been frequently suggested that vegans may have inadequate calcium and vitamin D intakes due to the lack of dairy products in their diet and insufficient calcium and vitamin D rich foods that could effectively substitute for these. This low dietary intake may subsequently have a negative effect on their bone mineral density (BMD). The aim of this study was to assess the long-term effects of changing to a vegan diet on BMD.
The BMD of 9 new mature female vegans was assessed using calcaneal QUS (McCue Cubaclinical). The subjects had a mean age of 33.3 years (S.D. 10.3 years) at baseline. All the subjects had adopted a vegan diet within 18 months (mean 11 months) of the initial screening. Following this initial assessment the subjects were then re-assessed at an annual vegan fair (May/June) to monitor changes in BMD.
Interim analysis at 3 years revealed a significant decrease of 7.8% in the mean left calcaneal scores (P<0.05). This trend was also seen with the right calcaneal scores, although it was not statistically significant (mean decrease 7.1%). Interestingly, at 4 years analysis of a subset of these scores revealed a partial restoration in mean BMD scores, such that the values were no longer significantly different from the baseline scores.
The results of this study suggest that when initially changing to a vegan diet there is an apparent initial detrimental effect on BMD; however, this effect appears transient in nature as restoration of BMD is achieved within a fairly short time-frame. It should be noted that due to the small sample size these results can only be considered exploratory in nature and this work is part of an ongoing longitudinal same-subject study.
