Omega-3 fatty acids and traumatic brain injury

National Institute On Alcohol Abuse And Alcoholism

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Abstract

Previously, we have shown that the brain DHA status can positively affect the behavioral and histologic outcome in a clinically relevant head injury model using the repetitive Closed-Head Impact Model of Engineered Rotational Acceleration (rCHIMERA) received daily for three consecutive days. As the DHA status is closely linked to the production of synaptamide, an endogenous ligand to GPR110, observed neuroprotective effects of DHA may be contributed by synaptamides biological effects. During the last review period, we found that intraperitoneal injection of synaptamide (5 mg/kg) 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. We also established that rCHIMERA causes optic tract injury and visual dysfunction. During this review period, we continued to investigate the neuroprotective role of GPR110 activation in TBI using visual evoke potential (VEP) as a functional outcome. rCHIMERA increased the expression of GPR110 in the mouse brain within 1 h. GPR110 ligands, synaptamide and its stable analogue A8, were tested for long-term histological and functional consequences of rCHIMERA in wild-type and GPR110 KO mice. Synaptamide and A8 dose-dependently increased the cAMP production in cultured microglia and suppressed the acute production of pro-inflammatory cytokine TNF-alpha in mouse brain after rCHIMERA injury. Synaptamide (5 mg/kg, i.p) and A8 (1 mg/kg, i.p) injected after each impact similarly improved visual function at 3.5 months after injury. The axonal damage in optic tract of injured mice visualized by silver staining was also significantly less when treated with synaptamide or A8. These effects were observed only in wild-type but not in GPR110 KO mice, indicating that the protective effect of these ligands is GPR110-dependent. The current data suggest the translational potential of these GPR110 ligands in repetitive mild TBI, particularly A8 as it is stable and provides the neuroprotective effects at a lower dose.