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Unesterified docosahexaenoic acid is protective in neuroinflammation.

ABSTRACT: Docosahexaenoic acid (22:6n-3) is the major brain n-3 polyunsaturated fatty acid and it is possible that docosahexaenoic acid is anti-inflammatory in the brain as it is known to be in other tissues. Using a combination of models including the fat-1 transgenic mouse, chronic dietary n-3 polyunsaturated fatty acid modulation in transgenic and wild-type mice, and acute direct brain infusion, we demonstrated that unesterified docosahexaenoic acid attenuates neuroinflammation initiated by intracerebroventricular lipopolysaccharide. Hippocampal neuroinflammation was assessed by gene expression and immunohistochemistry. Furthermore, docosahexaenoic acid protected against lipopolysaccharide-induced neuronal loss. Acute intracerebroventricular infusion of unesterified docosahexaenoic acid or its 12/15-lipoxygenase product and precursor to protectins and resolvins, 17S-hydroperoxy-docosahexaenoic acid, mimics anti-neuroinflammatory aspects of chronically increased unesterified docosahexaenoic acid. LC-MS/MS revealed that neuroprotectin D1 and several other docosahexaenoic acid-derived specialized pro-resolving mediators are present in the hippocampus. Acute intracerebroventricular infusion of 17S-hydroperoxy-docosahexaenoic acid increases hippocampal neuroprotectin D1 levels concomitant to attenuating neuroinflammation. These results show that unesterified docosahexaenoic acid is protective in a lipopolysaccharide-initiated mouse model of acute neuroinflammation, at least in part, via its conversion to specialized pro-resolving mediators; these docosahexaenoic acid stores may provide novel targets for the prevention and treatment(s) of neurological disorders with a neuroinflammatory component. Our study shows that chronically increased brain unesterified DHA levels, but not solely phospholipid DHA levels, attenuate neuroinflammation. Similar attenuations occur with acute increases in brain unesterified DHA or 17S-HpDHA levels, highlighting the importance of an available pool of precursor unesterified DHA for the production of enzymatically derived specialized pro-resolving mediators that are critical in the regulation of neuroinflammation.

SUBMITTER: Orr SK

PROVIDER: S-EPMC4068707 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Unesterified docosahexaenoic acid is protective in neuroinflammation.

Orr Sarah K SK Palumbo Sara S Bosetti Francesca F Mount Howard T HT Kang Jing X JX Greenwood Carol E CE Ma David W L DW Serhan Charles N CN Bazinet Richard P RP

Journal of neurochemistry 20130828 3

Docosahexaenoic acid (22:6n-3) is the major brain n-3 polyunsaturated fatty acid and it is possible that docosahexaenoic acid is anti-inflammatory in the brain as it is known to be in other tissues. Using a combination of models including the fat-1 transgenic mouse, chronic dietary n-3 polyunsaturated fatty acid modulation in transgenic and wild-type mice, and acute direct brain infusion, we demonstrated that unesterified docosahexaenoic acid attenuates neuroinflammation initiated by intracerebr ...[more]

PMID: 23919613

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Project description:Traumatic brain injury (TBI) is the leading cause of acquired neurologic disability in children, yet specific therapies to treat TBI are lacking. Therapies that decrease the inflammatory response and enhance a reparative immune action may decrease oxidative damage and improve outcomes after TBI. Docosahexaenoic acid (DHA) modulates the immune response to injury in many organs. DHA given in the diet before injury decreased rat pup cognitive impairment, oxidative stress and white matter injury in our developmental TBI model using controlled cortical impact (CCI). Little is known about DHA effects on neuroinflammation in the developing brain. Further, it is not known if DHA given after developmental TBI exerts neuroprotective effects. We hypothesized that acute DHA treatment would decrease oxidative stress and improve cognitive outcome, associated with decreased pro-inflammatory activation of microglia, the brain's resident macrophages. METHODS:17-day-old rat pups received intraperitoneal DHA or vehicle after CCI or SHAM surgery followed by DHA diet or continuation of REG diet to create DHACCI, REGCCI, SHAMDHA and SHAMREG groups. We measured brain nitrates/nitrites (NOx) at post injury day (PID) 1 to assess oxidative stress. We tested memory using Novel Object Recognition (NOR) at PID14. At PID 3 and 7, we measured reactivity of microglial activation markers Iba1, CD68 and CD206 and astrocyte marker GFAP in the injured cortex. At PID3, 7 and 30 we measured mRNA levels of inflammation-related genes and transcription factors in flow-sorted brain cells. RESULTS:DHA decreased oxidative stress at PID1 and pro-inflammatory microglial activation at PID3. CCI increased mRNA levels of two interferon regulatory family transcription factors, blunted by DHA, particularly in microglia-enriched cell populations at PID7. CCI increased mRNA levels of genes associated with "pro- " and "anti-" inflammatory activity at PID3, 7 and 30. Most notably within the microglia-enriched population, DHA blunted increased mRNA levels of pro-inflammatory genes at PID 3 and 7 and of anti-inflammatory genes at PID 30. Particularly in microglia, we observed parallel activation of pro-inflammatory and anti-inflammatory genes. DHA improved performance on NOR at PID14 after CCI. CONCLUSIONS:DHA decreased oxidative stress and histologic and mRNA markers of microglial pro-inflammatory activation in rat pup brain acutely after CCI associated with improved short term cognitive function. DHA administration after CCI has neuroprotective effects, which may result in part from modulation of microglial activation toward a less inflammatory profile in the first week after CCI. Future and ongoing studies will focus on phagocytic function and reactive oxygen species production in microglia and macrophages to test functional effects of DHA on neuroinflammation in our model. Given its favorable safety profile in children, DHA is a promising candidate therapy for pediatric TBI.

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Unesterified docosahexaenoic acid is protective in neuroinflammation.

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Unesterified docosahexaenoic acid is protective in neuroinflammation.

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