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 PUFA modulation in transgenic and wildtype 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. Further, 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. LCMS/MS revealed that neuroprotectin D1 and several other docosahexaenoic acid-derived specialized pro-resolving mediators are present in the hippocampus. Acute icv infusion of 17S-hydroperoxydocosahexaenoic 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.

Post-Myocardial Infarction Depression

“…Another study found that PUFA omega-3 had a similar effect on depression as the SSRI antidepressant fluoxetine, while the combination (EPA and fluoxetine) resulted in a superior effect than either of them alone (Jazayeri et al 2008). The influence of PUFA omega-3 on psychiatric disorders has yielded mechanistic hypotheses, one of which involves the anti-inflammatory properties of fatty acids, in accordance with the fact that increased cytokine levels are associated with depression (Orr and Bazinet 2008;Kiecolt-Glaser 2010). A second hypothesis, based on PUFA omega-3 depletion studies, involves a modulation of monoaminergic neurotransmission (Chalon 2006) since a profound PUFA omega-3 deficiency is able to alter several neurotransmission systems such as dopaminergic and serotonergic.…”

N-3 PUFAs and neuroinflammatory processes in cognitive disorders

“…In particular EPA, DHA and their bioactive mediators have potent antiinflammatory and pro-resolving properties in the periphery D103, page 3 of 10 Dossier Q. Leyrolle et al: OCL 2016, 23(1) D103 (Serhan and Chiang, 2013) and in the brain (Bazinet and Laye, 2014;Laye, 2010;Orr and Bazinet, 2008;Rapoport, 2008). Loss of these regulatory processes can result in excessive, inappropriate or on-going inflammation that can cause irreparable damage to host tissues, including the brain.…”

“…Short-term exposure to dietary EPA reduced IL-1-induced spatial memory deficit and anxiolytic behavior (Song et al, 2004(Song et al, , 2008 and improved LPS and Aβ-induced inhibition of LTP in both adult and aged rats . Furthermore, DHA and NPD1 infusion in the brain is acutely protective toward brain cytokine production and microglia activation (Lukiw et al, 2005;Orr et al, 2013). In addition, DHA increase in the brain protects from the effect of bacterial endotoxin-induced synaptic plasticity impairment and ageing (Delpech et al, 2015a(Delpech et al, , 2015cLabrousse et al, 2012).…”

“…In addition, along with the decreased level and activity of the enzyme delta 6-desaturase (Yehuda et al, 2005), the higher cholesterol content in the ageing neuronal membrane decreases membrane fluidity of the BBB (Yehuda et al, 2002). Both in vivo and in vitro studies have reported antiinflammatory activities of DHA in the brain especially in microglia (Laye, 2010;Orr and Bazinet, 2008). At the cellular level, brain DHA modulates several proinflammatory signalling pathways in microglia such as TLR signalling and nucleotide-binding oligomerization domain protein (NOD) signalling (De Smedt-Peyrusse et al, 2008;Liu et al, 2012), inhibits JUNK , and reduces or blocks NF-kB signalling (De Smedt-Peyrusse et al, 2008;Orr et al, 2013).…”

“…Both in vivo and in vitro studies have reported antiinflammatory activities of DHA in the brain especially in microglia (Laye, 2010;Orr and Bazinet, 2008). At the cellular level, brain DHA modulates several proinflammatory signalling pathways in microglia such as TLR signalling and nucleotide-binding oligomerization domain protein (NOD) signalling (De Smedt-Peyrusse et al, 2008;Liu et al, 2012), inhibits JUNK , and reduces or blocks NF-kB signalling (De Smedt-Peyrusse et al, 2008;Orr et al, 2013). The inhibitory effect of DHA on proinflammatory signalling pathway could be mediated by both non-genomic and genomic effect.…”