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, destabilisation of membranes, disruption of synapses and altered brain connectivity, and increased risk of neurodegenerative disease. A significant and long-lasting decrease in phospholipids (PL), essential membrane constituents, has recently been reported in plasma and brain tissue, in human and experimental TBI. We hypothesised that supporting PL synthesis post-injury could improve outcome after TBI. We tested this hypothesis using a multi-nutrient combination designed to support the biosynthesis of phospholipids and available for clinical use. The multi-nutrient Fortasyn® Connect (FC) contains polyunsaturated omega-3 fatty acids, choline, uridine, vitamins, co-factors 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 after 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, is safe and well-tolerated, which would enable rapid clinical exploration in TBI

Vascular endothelial growth factor increases neurogenesis after traumatic brain injury

Activation of endogenous stem cells has been proposed as a novel form of therapy in a variety of neurologic disorders including traumatic brain injury (TBI). Vascular endothelial growth factor (VEGF) is expressed in the brain after TBI and serves as a potent activator of angiogenesis and neurogenesis. In this study, we infused exogenous VEGF into the lateral ventricles of mice for 7 days after TBI using mini-osmotic pumps to evaluate the effects on recovery and functional outcome. The results of our study show that VEGF significantly increases the number of proliferating cells in the subventricular zone and in the perilesion cortex. Fate analysis showed that most newborn cells differentiated into astrocytes and oligodendroglia and only a few cells differentiated into neurons. Functional outcome was significantly better in mice treated with VEGF compared with vehicle-treated animals after TBI. Injury size was significantly smaller at 90 days after TBI in VEGF-treated animals, suggesting additional neuroprotective effects of VEGF. In conclusion, VEGF significantly augments neurogenesis and angiogenesis and reduces lesion volumes after TBI. These changes are associated with significant improvement in recovery rates and functional outcome

Data_Sheet_1_High phenylalanine concentrations induce demyelination and microglial activation in mouse cerebellar organotypic slices.pdf

Phenylketonuria (PKU) is an inborn error of metabolism. Mutations in the enzyme phenylalanine hydroxylase (PAH)-encoding gene lead to a decreased metabolism of the amino acid phenylalanine (Phe). The deficiency in PAH increases Phe levels in blood and brain. Accumulation of Phe can lead to delayed development, psychiatric problems and cognitive impairment. White matter (WM) damage is a neuropathological hallmark of PKU and can be seen even in early detected and treated PKU patients. The mechanisms linking high Phe concentrations to WM abnormalities remain unclear. We tested the effects of high Phe concentrations on myelin in three in vitro models of increasing complexity: two simple cell culture models and one model that preserves local brain tissue architecture, a cerebellar organotypic slice culture prepared from postnatal day (P) 8 CD-1 mice. Various Phe concentrations (0.1–10 mM) and durations of exposure were tested. We found no toxic effect of high Phe in the cell culture models. On the contrary, the treatment promoted the maturation of oligodendrocytes, particularly at the highest, non-physiological Phe concentrations. Exposure of cerebellar organotypic slices to 2.4 mM Phe for 21 days in vitro (DIV), but not 7 or 10 DIV, resulted in a significant decrease in myelin basic protein (MBP), calbindin-stained neurites, and neurites co-stained with MBP. Following exposure to a toxic concentration of Phe, a switch to the control medium for 7 days did not lead to remyelination, while very active remyelination was seen in slices following demyelination with lysolecithin. An enhanced number of microglia, displaying an activated type morphology, was seen after exposure of the slices to 2.4 mM Phe for 10 or 21 DIV. The results suggest that prolonged exposure to high Phe concentrations can induce microglial activation preceding significant disruption of myelin.</p

A Single Injection of Docosahexaenoic Acid Induces a Pro-Resolving Lipid Mediator Profile in the Injured Tissue and a Long-Lasting Reduction in Neurological Deficit after Traumatic Brain Injury in Mice

European Research Council under the European Union’s Horizon 2020 research and innovation program (Grant 677542)Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (Grant 107613/Z/15/Z)Barts Charity (Grant MGU0343)Barts Charity award to the Centre for Trauma Sciences