Neurorestorative Targets of Dietary Long-Chain Omega-3 Fatty Acids in Neurological Injury

Abstract

Long-chain omega-3 polyunsaturated fatty acids (LC-O3PUFAs) exhibit therapeutic potential for the treatment and prevention of the neurological deficits associated with spinal cord injury (SCI). However, the mechanisms implicated in these protective responses remain unclear. The objective of the present functional metabolomics study was to identify and define the dominant metabolic pathways targeted by dietary LC-O3PUFAs. Sprague-Dawley rats were fed rodent purified chows containing menhaden fish oil-derived LC-O3PUFAs for 8 weeks before being subjected to sham or spinal cord contusion surgeries. We show, through untargeted metabolomics, that dietary LC-O3PUFAs regulate important biochemical signatures associated with amino acid metabolism and free radical scavenging in both the injured and sham-operated spinal cord. Of particular significance, the spinal cord metabolome of animals fed with LC-O3PUFAs exhibited reduced glucose levels (−48%) and polar uncharged/hydrophobic amino acids (<−20%) while showing significant increases in the levels of antioxidant/anti-inflammatory amino acids and peptides metabolites, including β-alanine (+24%), carnosine (+33%), homocarnosine (+27%), kynurenine (+88%), when compared to animals receiving control diets (p < 0.05). Further, we found that dietary LC-O3PUFAs impacted the levels of neurotransmitters and the mitochondrial metabolism, as evidenced by significant increases in the levels of N-acetylglutamate (+43%) and acetyl-CoA levels (+27%), respectively. Interestingly, this dietary intervention resulted in a global correction of the pro-oxidant metabolic profile that characterized the SCI-mediated sensorimotor dysfunction. In summary, the significant benefits of metabolic homeostasis and increased antioxidant defenses unlock important neurorestorative pathways of dietary LC-O3PUFAs against SCI.

Protective effect of docosahexaenoic acid on lipotoxicity‐mediated cell death in Schwann cells: Implication of PI3K/AKT and mTORC2 pathways

“…DHA also reduced apoptosis by inhibiting caspase-3 activation, and the cleavage of PARP1 and lamin-B under PA conditions (Almaguel et al, 2009(Almaguel et al, , 2010. In a series of studies using an in vivo rat spinal injury model, we recently reported that acute parenteral administration of DHA prior to injury and a diet rich in menhaden fish oil-derived omega-3 fatty acids improved the conduction and locomotor function of rats after spinal cord injury (SCI; Figueroa & De Leon, 2014;Figueroa et al, 2012;Figueroa, Cordero, Llan, & De Leon, 2013). These studies show that DHA pretreatment increased the percentage of white matter sparing resulting in axonal preservation.…”

Fatty Acid Binding Protein 5 Modulates Docosahexaenoic Acid-Induced Recovery in Rats Undergoing Spinal Cord Injury

“…A cohort of animals was fed custom AIN-93Gbased diets that were prepared with alterations to the n-3 FA source as described previously. 4,8 Please refer to Tables 1 and 2 for a detailed description of the composition of the diets. Animals received the diets for 8 weeks before injury and for an additional week post-SCI.…”

“…We used standard unbiased metabolic profiling to detect and determine the spinal cord lipid levels, as previously described by our group 4,8,15 and others. 7,[36][37][38][39] Briefly, animals were deeply anesthetized and transcardially perfused with ice-cold phosphatebuffered saline (PBS).…”

“…1 Whereas secondary injury processes, such as excitotoxicity, ischemia, inflammation, demyelination, and apoptosis, are deleterious, injury to the spinal cord also initiates a number of endogenous restorative responses. [2][3][4] Among them, 1) angiogenesis, 2) remyelination, 3) transcriptional upregulation of proregenerative genes and 4) neurotrophic factors, 5) axonal regeneration, 6) activation of endogenous antioxidant defenses, and 7) accumulation of prorestorative fatty acids are well-described spontaneous repair responses post-SCI. Although limited and fragmented, these processes provide a striking example of the spinal cord inherent capacity for tissue repair.…”

“…[5][6][7][8] Our laboratory and others have shown that administration of DHA has polytarget actions and is capable of attenuating secondary damage while promoting functional recovery post-SCI. [9][10][11][12][13][14] DHA confers strong prophylaxis against functional impairments when supplied before SCI 4,8,13,15,16 ; however, the molecular target underlying these repair responses still remains elusive.…”