Abstract
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.
Highlights
Traumatic brain injury (TBI) is a leading cause of death and disability[1,2,3] and survivors suffer from cognitive and psychological disorders
All groups showed a decrease in TBI-induced impairment over 70 days, but a significant improvement was observed in cortical impact injury (CCI) FortasynÒ Connect (FC)-treated animals as early as the third day post-trauma, compared to the CCI-control diet group
Focal contusion TBI, such as that induced in CCI, creates cavitation at the injury epicentre
Summary
Traumatic brain injury (TBI) is a leading cause of death and disability[1,2,3] and survivors suffer from cognitive and psychological disorders. The deficits post-TBI result from multiple neurochemical and metabolic events,[4] leading to neuronal loss, dendritic, axonal, and synaptic changes,[5] and white matter abnormalities.[6,7,8] TBI increases the risk of neurodegenerative diseases such as Alzheimer’s disease (AD)[9] and Parkinson’s disease.[10]. Experimental and human TBI observations report significant synaptic alterations.[11,12,13,14,15] Brain connectivity is disrupted in TBI patients and this is related to cognitive dysfunction.[16,17] Phospholipids (PLs) are key to the structure of membranes, and TBI triggers significant changes in PL.
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