Docosahexaenoic Acid Promotes Recovery of Motor Function by Neuroprotection and Neuroplasticity Mechanisms

The omega-3 polyunsaturated fatty acid, docosahexaenoic acid (DHA), has been shown to promote recovery of motor function after spinal cord injury. This is likely to be at least partly due to neuroprotective effects of DHA. However, recent studies have shown that DHA also supports neuroplasticity after injury, such as promoting sprouting of spared corticospinal tract (CST) axons. In this chapter, we review the published studies showing that DHA promotes recovery of motor function in rodent models of spinal cord injury (SCI), and consider the available data on the underlying mechanisms. This includes effects on inflammation and on neuronal and oligodendrocyte survival at the injury site, and effects on spared CST axons and serotonergic axons. Current data support the hypothesis that DHA promotes recovery of motor function by both neuroprotection and neuroplasticity mechanisms. The significance of this, and the implications of combining DHA with rehabilitation strategies, will be discussed

The human G93A-SOD1 mutation in a pre-symptomatic rat model of amyotrophic lateral sclerosis increases the vulnerability to a mild spinal cord compression

<p>Abstract</p> <p>Background</p> <p>Traumatic injuries can undermine neurological functions and act as risk factors for the development of irreversible and fatal neurodegenerative disorders like amyotrophic lateral sclerosis (ALS). In this study, we have investigated how a mutation of the superoxide dismutase 1 (SOD1) gene, linked to the development of ALS, modifies the acute response to a gentle mechanical compression of the spinal cord. In a 7-day post-injury time period, we have performed a comparative ontological analysis of the gene expression profiles of injured spinal cords obtained from pre-symptomatic rats over-expressing the G93A-SOD1 gene mutation and from wild type (WT) littermates.</p> <p>Results</p> <p>The steady post-injury functional recovery observed in WT rats was accompanied by the early activation at the epicenter of injury of several growth-promoting signals and by the down-regulation of intermediate neurofilaments and of genes involved in the regulation of ion currents at the 7 day post-injury time point. The poor functional recovery observed in G93A-SOD1 transgenic animals was accompanied by the induction of fewer pro-survival signals, by an early activation of inflammatory markers, of several pro-apoptotic genes involved in cytochrome-C release and by the persistent up-regulation of the heavy neurofilament subunits and of genes involved in membrane excitability. These molecular changes occurred along with a pronounced atrophy of spinal cord motor neurones in the G93A-SOD1 rats compared to WT littermates after compression injury.</p> <p>Conclusions</p> <p>In an experimental paradigm of mild mechanical trauma which causes no major tissue damage, the G93A-SOD1 gene mutation alters the balance between pro-apoptotic and pro-survival molecular signals in the spinal cord tissue from the pre-symptomatic rat, leading to a premature activation of molecular pathways implicated in the natural development of ALS.</p

Lipid Profiles from Dried Blood Spots Reveal Lipidomic Signatures of Newborns Undergoing Mild Therapeutic Hypothermia after Hypoxic-Ischemic Encephalopathy.

Hypoxic-ischemic encephalopathy (HIE) is associated with perinatal brain injury, which may lead to disability or death. As the brain is a lipid-rich organ, various lipid species can be significantly impacted by HIE and these correlate with specific changes to the lipidomic profile in the circulation. Objective: To investigate the peripheral blood lipidomic signature in dried blood spots (DBS) from newborns with HIE. Using univariate analysis, multivariate analysis and sPLS-DA modelling, we show that newborns with moderate-severe HIE (n = 46) who underwent therapeutic hypothermia (TH) displayed a robust peripheral blood lipidomic signature comprising 29 lipid species in four lipid classes; namely phosphatidylcholine (PC), lysophosphatidylcholine (LPC), triglyceride (TG) and sphingomyelin (SM) when compared with newborns with mild HIE (n = 18). In sPLS-DA modelling, the three most discriminant lipid species were TG 50:3, TG 54:5, and PC 36:5. We report a reduction in plasma TG and SM and an increase in plasma PC and LPC species during the course of TH in newborns with moderate-severe HIE, compared to a single specimen from newborns with mild HIE. These findings may guide the research in nutrition-based intervention strategies after HIE in synergy with TH to enhance neuroprotection.NIHR Cambridge Biomedical Research Centre (146281) & Biotechnology and Biological Sciences Research Council (BB/P028195/1

Incremental induction of NMDAR-STP and NMDAR-LTP in the CA1 area of ventral hippocampal slices relies on graded activation of discrete NMDA receptors

N-methyl-D-aspartate receptor (NMDAR)-dependent short- and long-term types of potentiation (STP and LTP, respectively) are frequently studied in the CA1 area of dorsal hippocampal slices (DHS). Far less is known about the NMDAR-dependence of STP and LTP in ventral hippocampal slices (VHS), where both types of potentiation are smaller in their magnitude than in the DHS. Here, we first briefly review our knowledge about the NMDARdependence of STP and LTP, and some other forms of synaptic plasticity. We then show in new experiments, that the decay of NMDAR-STP in VHS, similar to dorsal hippocampal NMDAR-STP, is not time- but activity-dependent. We also demonstrate that the induction of submaximal levels of NMDAR-STP and NMDAR-LTP in VHS differs from the induction of saturated levels of plasticity in terms of their sensitivity to subunit-preferring NMDAR antagonists. These data suggest that activation of distinct NMDAR subtypes in a population of neurons results in an incremental increase in the induction of different phases of potentiation with changing sensitivity to pharmacological agents. Differences in pharmacological sensitivity, which arise due to differences in the levels of agonist-evoked biological response, might explain the disparity of the results concerning NMDAR subunit involvement in the induction of NMDAR-dependent plasticity

Commentary on "Fish Oil-Containing Lipid Emulsions in Adult Parenteral Nutrition: A Review of the Evidence" (https://doi.org/10.1177/0148607117721907).

This is the peer reviewed version of the following article: Adolph, M. , Calder, P. C., Deutz, N. E., Carmona, T. G., Klek, S. , Lev, S. , Mayer, K. , Michael‐Titus, A. T., Pradelli, L. , Puder, M. , Singer, P. and Vlaardingerbroek, H. (2019), Commentary on “Fish Oil–Containing Lipid Emulsions in Adult Parenteral Nutrition: A Review of the Evidence”. Journal of Parenteral and Enteral Nutrition, 43: 454-455. doi:10.1002/jpen.1047, which has been published in final form at https://doi.org/10.1002/jpen.1047. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived VersionsAbbasoglu et al published a narrative review concerning the use of fish oil–containing lipid emulsions in adult parenteral nutrition (PN).1 We wholeheartedly agree with the authors when they state that “high‐quality and adequately powered RCTs are necessary” and “well‐conducted meta‐analyses can be key to demonstrating positive or negative effects.” However, we disagree with other aspects of their review, particularly assertions of a lack of evidence in favor of using fish oil–containing lipid emulsions rather than more traditional lipid formulations

Eicosapentaenoic acid and docosahexaenoic acid reduce interleukin-1β-mediated cartilage degradation

Introduction: In inflammatory joint disease, such as osteoarthritis (OA), there is an increased level of proinflammatory cytokines, such as interleukin (IL)-1β. These cytokines stimulate the production of matrix metalloproteinases (MMPs), which leads to the degradation of the cartilage extracellular matrix and the loss of key structural components such as sulphated glycosaminoglycan (sGAG) and collagen II. The aim of this study was to examine the therapeutic potential of n-3 polyunsaturated fatty acids (PUFAs) in an in vitro model of cartilage inflammation. Methods: Two specific n-3 compounds were tested, namely, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), each at 0.1, 1 and 10 μM. Full thickness bovine cartilage explants, 5 mm in diameter, were cultured for 5 days with or without IL-1β and in the presence or absence of each n-3 compound. The media were replaced every 24 hours and assayed for sGAG content using the 1,9-dimethylmethylene blue (DMB) method. Chondrocyte viability was determined at the end of the culture period using fluorescence microscopy to visualise cells labelled with calcein AM and ethidium homodimer. Results: Treatment with IL-1β (10 ng.ml-1) produced a large increase in sGAG release compared to untreated controls, but with no effect on cell viability, which was maintained above 80% for all treatments. In the absence of IL-1β, both n-3 compounds induced a mild catabolic response with increased loss of sGAG, particularly at 10 μM. By contrast, in the presence of IL-1β, both EPA and DHA at 0.1 and 1 μM significantly reduced IL-1β-mediated sGAG loss. The efficacy of the EPA treatment was maintained at approximately 75% throughout the 5-day period. However, at the same concentrations, the efficacy of DHA, although initially greater, reduced to approximately half that of EPA after 5 days. For both EPA and DHA, the highest dose of 10 μM was less effective. Conclusions: The results support the hypothesis that n-3 compounds are anti-inflammatory through competitive inhibition of the arachidonic acid oxidation pathway. The efficacy of these compounds is likely to be even greater at more physiological levels of IL-1β. Thus we suggest that n-3 PUFAs, particularly EPA, have exciting therapeutic potential for preventing cartilage degradation associated with chronic inflammatory joint disease

Neuronal let-7b-5p acts through the Hippo-YAP pathway in neonatal encephalopathy

Despite increasing knowledge on microRNAs, their role in the pathogenesis of neonatal encephalopathy remains to be elucidated. Herein, we identify let-7b-5p as a significant microRNA in neonates with moderate to severe encephalopathy from dried blood spots using next generation sequencing. Validation studies using Reverse Transcription and quantitative Polymerase Chain Reaction on 45 neonates showed that let-7b-5p expression was increased on day 1 in neonates with moderate to severe encephalopathy with unfavourable outcome when compared to those with mild encephalopathy. Mechanistic studies performed on glucose deprived cell cultures and the cerebral cortex of two animal models of perinatal brain injury, namely hypoxic-ischaemic and intrauterine inflammation models confirm that let-7b-5p is associated with the apoptotic Hippo pathway. Significant reduction in neuronal let-7b-5p expression corresponded with activated Hippo pathway, with increased neuronal/nuclear ratio of Yes Associated Protein (YAP) and increased neuronal cleaved caspase-3 expression in both animal models. Similar results were noted for let-7b-5p and YAP expression in glucose-deprived cell cultures. Reduced nuclear YAP with decreased intracellular let-7b-5p correlated with neuronal apoptosis in conditions of metabolic stress. This finding of the Hippo-YAP association with let-7b needs validation in larger cohorts to further our knowledge on let-7b-5p as a biomarker for neonatal encephalopathy