Omega-3 fatty acids and traumatic brain injury

National Institute On Alcohol Abuse And Alcoholism

Investigators

Linked publications, trials & patents

Abstract

Previously, we have established that the brain DHA status can positively affect the behavioral and histologic outcome in a clinically relevant traumatic brain injury (TBI) model using the repetitive Closed-Head Impact Model of Engineered Rotational Acceleration (rCHIMERA) where mice received daily impact for three consecutive days. Subsequently, we found that intraperitoneal injection of synaptamide (5 mg/kg), an endogenous metabolite of DHA, immediately after each CHIMERA impact, significantly reduced glia cell activation in the corpus callosum, CA1 and optic tract from day 1 to 3.5 months post-injury in wild-type but not in GPR110 KO mice. After establishing that rCHIMERA causes optic tract injury and visual dysfunction, we demonstrated the neuroprotective role of GPR110 activation in repetitive mild TBI using visual evoke potential (VEP) as a functional outcome. GPR110 ligands, synaptamide (5 mg/kg, i.p) and its stable analogue A8 (1 mg/kg, i.p) injected after each impact, improved long-term (at 3.5 months after injury) histological and functional consequences of rCHIMERA in wild type but not in GPR110 KO mice. Our findings suggested the translational potential of DHA and these GPR110 ligands in repetitive mild TBI, particularly A8 as it is stable and provides the neuroprotective effects at a lower dose. During this review period, we initiated the investigation on the TBI biomarker discovery in collaboration with The University of Pennsylvania by analyzing DHA and/or DHA metabolites, particularly synaptamide, in human plasma samples from a clinical trial on traumatic brain injury in relation to recovery outcome. As part of our preliminary tests, we found that two cycles of freeze-thaw on a subset of these samples resulted in no significant difference in lipid metabolites analyzed, including but not limited to free AA and DHA, hydroxylated derivatives of AA and DHA, synaptamide, anandamide, PGE2/D2, and thromboxane B2. We also found little difference between serum and plasma lipid metabolites, with the exception of thromboxane B2, 11-HETE, 15-HETE, and especially 12-HETE. These metabolites were detected at a significantly higher level in the serum compared to the plasma, presumably due to the coagulation process during the preparation of human serum samples. Based on these preliminary results, we will analyze human plasma samples from TBI patients collected by The University of Pennsylvania.