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      Repetitive and Prolonged Omega-3 Fatty Acid Treatment after Traumatic Brain Injury Enhances Long-Term Tissue Restoration and Cognitive Recovery

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          Abstract

          <p class="first" id="d2922762e200">Traumatic brain injury (TBI) is one of the most disabling clinical conditions that could lead to neurocognitive disorders in survivors. Our group and others previously reported that prophylactic enrichment of dietary omega-3 polyunsaturated fatty acids (n-3 PUFAs) markedly ameliorate cognitive deficits after TBI. However, it remains unclear whether a clinically relevant therapeutic regimen with n-3 PUFAs administered after TBI would still offer significant improvement of long-term cognitive recovery. In the present study, we employed the decline of spatial cognitive function as a main outcome after TBI to investigate the therapeutic efficacy of post-TBI n-3 PUFA treatment and the underlying mechanisms. Mice were subjected to sham operation or controlled cortical impact, followed by random assignment to receive the following four treatments: (1) vehicle control; (2) daily intraperitoneal injections of n-3 PUFAs for 2 weeks, beginning 2 h after TBI; (3) fish oil dietary supplementation throughout the study, beginning 1 day after TBI; or (4) combination of treatments (2) and (3). Spatial cognitive deficits and chronic brain tissue loss, as well as endogenous brain repair processes such as neurogenesis, angiogenesis, and oligodendrogenesis, were evaluated up to 35 days after TBI. The results revealed prominent spatial cognitive deficits and massive tissue loss caused by TBI. Among all mice receiving post-TBI n-3 PUFA treatments, the combined treatment of fish oil dietary supplement and n-3 PUFA injections demonstrated a reproducible beneficial effect in attenuating cognitive deficits although without reducing gross tissue loss. Mechanistically, the combined treatment promoted post-TBI restorative processes in the brain, including generation of immature neurons, microvessels, and oligodendrocytes, each of which was significantly correlated with the improved cognitive recovery. These results indicated that repetitive and prolonged n-3 PUFA treatments after TBI are capable of enhancing brain remodeling and could be developed as a potential therapy to treat TBI victims in the clinic. </p>

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          Most cited references 45

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          Neurorestorative therapies for stroke: underlying mechanisms and translation to the clinic.

          Restorative cell-based and pharmacological therapies for experimental stroke substantially improve functional outcome. These therapies target several types of parenchymal cells (including neural stem cells, cerebral endothelial cells, astrocytes, oligodendrocytes, and neurons), leading to enhancement of endogenous neurogenesis, angiogenesis, axonal sprouting, and synaptogenesis in the ischaemic brain. Interaction between these restorative events probably underpins the improvement in functional outcome. This Review provides examples of cell-based and pharmacological restorative treatments for stroke that stimulate brain plasticity and functional recovery. The molecular pathways activated by these therapies, which induce remodelling of the injured brain via angiogenesis, neurogenesis, and axonal and dendritic plasticity, are discussed. The ease of treating intact brain tissue to stimulate functional benefit in restorative therapy compared with treating injured brain tissue in neuroprotective therapy might more readily help with translation of restorative therapy from the laboratory to the clinic.
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            Dietary omega-3 fatty acids normalize BDNF levels, reduce oxidative damage, and counteract learning disability after traumatic brain injury in rats.

            Omega-3 fatty acids (i.e., docosahexaenoic acid; DHA) regulate signal transduction and gene expression, and protect neurons from death. In this study we examined the capacity of dietary omega3 fatty acids supplementation to help the brain to cope with the effects of traumatic injury. Rats were fed a regular diet or an experimental diet supplemented with omega-3 fatty acids, for 4 weeks before a mild fluid percussion injury (FPI) was performed. FPI increased oxidative stress, and impaired learning ability in the Morris water maze. This type of lesion also reduced levels of brain-derived neurotrophic factor (BDNF), synapsin I, and cAMP responsive element-binding protein (CREB). It is known that BDNF facilitates synaptic transmission and learning ability by modulating synapsin I and CREB. Supplementation of omega-3 fatty acids in the diet counteracted all of the studied effects of FPI, that is, normalized levels of BDNF and associated synapsin I and CREB, reduced oxidative damage, and counteracted learning disability. The reduction of oxidative stress indicates a benevolent effect of this diet on mechanisms that maintain neuronal function and plasticity. These results imply that omega-3 enriched dietary supplements can provide protection against reduced plasticity and impaired learning ability after traumatic brain injury.
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              HDAC inhibition prevents white matter injury by modulating microglia/macrophage polarization through the GSK3β/PTEN/Akt axis.

              Severe traumatic brain injury (TBI) elicits destruction of both gray and white matter, which is exacerbated by secondary proinflammatory responses. Although white matter injury (WMI) is strongly correlated with poor neurological status, the maintenance of white matter integrity is poorly understood, and no current therapies protect both gray and white matter. One candidate approach that may fulfill this role is inhibition of class I/II histone deacetylases (HDACs). Here we demonstrate that the HDAC inhibitor Scriptaid protects white matter up to 35 d after TBI, as shown by reductions in abnormally dephosphorylated neurofilament protein, increases in myelin basic protein, anatomic preservation of myelinated axons, and improved nerve conduction. Furthermore, Scriptaid shifted microglia/macrophage polarization toward the protective M2 phenotype and mitigated inflammation. In primary cocultures of microglia and oligodendrocytes, Scriptaid increased expression of microglial glycogen synthase kinase 3 beta (GSK3β), which phosphorylated and inactivated phosphatase and tensin homologue (PTEN), thereby enhancing phosphatidylinositide 3-kinases (PI3K)/Akt signaling and polarizing microglia toward M2. The increase in GSK3β in microglia and their phenotypic switch to M2 was associated with increased preservation of neighboring oligodendrocytes. These findings are consistent with recent findings that microglial phenotypic switching modulates white matter repair and axonal remyelination and highlight a previously unexplored role for HDAC activity in this process. Furthermore, the functions of GSK3β may be more subtle than previously thought, in that GSK3β can modulate microglial functions via the PTEN/PI3K/Akt signaling pathway and preserve white matter homeostasis. Thus, inhibition of HDACs in microglia is a potential future therapy in TBI and other neurological conditions with white matter destruction.
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                Author and article information

                Journal
                Cell Transplantation
                Cell Transplant
                Cognizant, LLC
                0963-6897
                1555-3892
                April 2017
                April 2017
                April 2017
                April 2017
                : 26
                : 4
                : 555-569
                Affiliations
                [1 ] Department of Neurosurgery, General Hospital of PLA, Beijing, P.R. China
                [2 ] Pittsburgh Institute of Brain Disorders and Recovery and Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA
                [3 ] State Key Laboratory of Medical Neurobiology and Institute of Brain Sciences, Fudan University, Shanghai, P.R. China
                Article
                10.3727/096368916X693842
                5531869
                27938482
                © 2017

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