A Single Injection of Docosahexaenoic Acid Induces a Pro-Resolving Lipid Mediator Profile in the Injured Tissue and a Long-Lasting Reduction in Neurological Deficit after Traumatic Brain Injury in Mice

Thau-Zuchman, Orli; Ingram, R.; Harvey, Georgina G; Cooke, Thomas; Palmas, Francesco; Pallier, Patrick N.; Brook, Joseph; Priestley, John V.; Dalli, Jesmond; Tremoleda, Jordi L.; Michael‐Titus, Adina T.

doi:10.1089/neu.2019.6420

Cited by 34 publications

(23 citation statements)

References 67 publications

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“…In addition to membrane fluidity, PUFAs are associated with cognitive function and memory (Cardoso et al, 2016). Supplementation with DHA/EPA maintains levels of pro-resolving or neuroprotecting mediators (Serhan et al, 2015;Thau-Zuchman et al, 2019), suggesting a protective role of PUFAs in post-mitotic neurons. Oxidation of PUFA by an enzyme or non-enzymatic pathways generates inflammatory and toxic products, and these are increased in AD (Montine and Morrow, 2005;Lukiw and Bazan, 2008;Grimm et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Polyunsaturated Fatty Acid Composition of Cerebrospinal Fluid Fractions Shows Their Contribution to Cognitive Resilience of a Pre-symptomatic Alzheimer’s Disease Cohort

et al. 2020

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Alzheimer's disease (AD) pathology is characterized by an early and prolonged decrease in the amyloid peptide (Aβ) levels concomitant with a later increase in phosphotau concentrations in cerebrospinal fluid (CSF). We propose that changes in lipid metabolism can contribute to the abnormal processing of Aβ 42 in AD. Our aim was to determine if polyunsaturated fatty acid (PUFA) metabolism can differentiate presymptomatic AD from normal aging and symptomatic AD. Using neuropsychology measures and Aβ 42 /T-tau in cerebrospinal fluid (CSF), we classify three groups of elderly study participants: cognitively healthy with normal Aβ 42 /T-tau (CH-NAT), cognitively healthy with pathological Aβ 42 /T-tau (CH-PAT), and AD individuals. We determined the size distribution and the concentration of CSF particles using light scattering and quantified PUFA composition in the nanoparticulate (NP) fraction, supernatant fluid (SF), and unesterified PUFA levels using gas chromatography combined with mass spectrometry. Four PUFAs (C20:2n-6, C20:3n-3, C22:4n-6, C22:5n-3) were enriched in NP of AD compared with CH-NAT. C20:3n-3 levels were higher in the NP fraction from AD compared with CH-PAT. When normalized to the number of NPs in CSF, PUFA levels were significantly higher in CH-NAT and CH-PAT compared with AD. In the SF fractions, only the levels of docosahexaenoic acid (DHA, C22:6n-3) differentiated all three clinical groups. Unesterified DHA was also higher in CH-NAT compared with the other clinical groups. Our studies also show that NP PUFAs in CH participants negatively correlate with CSF Aβ 42 while C20:4n-6, DHA, and n-3 PUFAs in the SF fraction positively correlate with T-tau. The profile of PUFAs in different CSF fractions that correlate with Aβ 42 or with T-tau are different for CH-NAT compared with CH-PAT. These studies show that PUFA metabolism is associated with amyloid and tau processing. Importantly, higher PUFA levels in the cognitively healthy study participants with abnormal Aβ 42 /T-tau suggest that PUFA enhances the cognitive resilience of the pre-symptomatic AD population. We propose that interventions that

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Section: Introductionmentioning

confidence: 99%

Polyunsaturated Fatty Acid Composition of Cerebrospinal Fluid Fractions Shows Their Contribution to Cognitive Resilience of a Pre-symptomatic Alzheimer’s Disease Cohort

et al. 2020

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“…Several recent independent studies have shown that DHA promotes beneficial effects in TBI, resulting in improved functional outcomes, and reduced apoptosis and neuroinflammation [10][11][12]. However, the mechanism underlying these functional changes, in particular with edema, remain poorly understood.…”

Section: Discussionmentioning

confidence: 99%

“…Suppression of TLR4 expression and inhibition of inflammatory mediators such as NF-κB leads to suppression of neuroinflammation. A recent study by Thau-Zuchman and colleagues suggested in their mouse controlled cortical impact model that DHA provides neuroprotection via the upregulation of neuroprotective mediators such as DHA-derived resolvins and protectins, and reduction of neuroinflammatory response [12].…”

Section: Discussionmentioning

confidence: 99%

“…Another study that injected 16 mg/kg DHA at 30 min and subsequent doses at 1, 3 and 5 days post injury showed improved motor and cognitive deficits induced by the TBI [11]. Interestingly, a recent study demonstrated that a single 500 nmol/kg dose of DHA injected intravenously can provide a reduction in TBI-induced lesion size, neuroinflammation, and axonal injury [12]. Although several studies have indicated the mechanism of action of DHA on TBI recovery is via reduction in neuroinflammation and apoptosis, other pathophysiological events can also occur after TBI.…”

Section: Introductionmentioning

confidence: 99%

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DHA Attenuates Cerebral Edema Following Traumatic Brain Injury via the Reduction in Blood–Brain Barrier Permeability

Liu

Chen

et al. 2020

IJMS

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Traumatic brain injury (TBI) could result in edema and cause an increase in intracranial pressure of the brain resulting in mortality and morbidity. Although there is hyperosmolarity therapy available for this pathophysiological event, it remains controversial. Recently, several groups have shown docosahexaenoic acid (DHA) to improve functional and histological outcomes following brain injury based on reduction of neuroinflammation and apoptosis. However, the effect of DHA on blood–brain barrier (BBB) dysfunction after brain injury has not been fully studied. Here, a controlled cortical impact rat model was used to test the effect of a single dose of DHA administered 30 min post injury. Modified neurological severity score (mNSS) and forelimb asymmetry were used to determine the functional outcomes. Neuroimaging and histology were used to characterize the edema and BBB dysfunction. The study showed that DHA-treated TBI rats had better mNSS and forelimb asymmetry score than vehicle-treated TBI rats. Temporal analysis of edema using MRI revealed a significant reduction in edema level with DHA treatment compared to vehicle in TBI rats. Histological analysis using immunoglobulin G (IgG) extravasation showed that there was less extravasation, which corresponded with a reduction in aquaporin 4 and astrocytic metalloprotease 9 expression, and greater endothelial occludin expression in the peri-contusional site of the TBI rat brain treated with DHA in comparison to vehicle treatment. In conclusion, the study shows that DHA can exert its functional improvement by prevention of the edema formation via prevention of BBB dysfunction after TBI.

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“…In other animal models of TBI, RvD1 promotes functional recovery and halts glial activation and neuronal death, and RvE1 modulates the inflammatory response (97,98). Moreover, parenteral or enteral administration of DHA reduces lesion size and axonal injury in rodents with TBI (99)(100)(101). The effect of DHA administration in rats with spinal cord injury has recently been summarized in a systematic review and metaanalysis (102).…”

Section: Trauma Traumatic Brain and Spinal Cord Injurymentioning

confidence: 99%

Lipid Mediators in Critically Ill Patients: A Step Towards Precision Medicine

2020

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A dysregulated response to systemic inflammation is a common pathophysiological feature of most conditions encountered in the intensive care unit (ICU). Recent evidence indicates that a dysregulated inflammatory response is involved in the pathogenesis of various ICU-related disorders associated with high mortality, including sepsis, acute respiratory distress syndrome, cerebral and myocardial ischemia, and acute kidney injury. Moreover, persistent or non-resolving inflammation may lead to the syndrome of persistent critical illness, characterized by acquired immunosuppression, catabolism and poor long-term functional outcomes. Despite decades of research, management of many disorders in the ICU is mostly supportive, and current therapeutic strategies often do not take into account the heterogeneity of the patient population, underlying chronic conditions, nor the individual state of the immune response. Fatty acid-derived lipid mediators are recognized as key players in the generation and resolution of inflammation, and their signature provides specific information on patients’ inflammatory status and immune response. Lipidomics is increasingly recognized as a powerful tool to assess lipid metabolism and the interaction between metabolic changes and the immune system via profiling lipid mediators in clinical studies. Within the concept of precision medicine, understanding and characterizing the individual immune response may allow for better stratification of critically ill patients as well as identification of diagnostic and prognostic biomarkers. In this review, we provide an overview of the role of fatty acid-derived lipid mediators as endogenous regulators of the inflammatory, anti-inflammatory and pro-resolving response and future directions for use of clinical lipidomics to identify lipid mediators as diagnostic and prognostic markers in critical illness.

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A Single Injection of Docosahexaenoic Acid Induces a Pro-Resolving Lipid Mediator Profile in the Injured Tissue and a Long-Lasting Reduction in Neurological Deficit after Traumatic Brain Injury in Mice

Cited by 34 publications

References 67 publications

Polyunsaturated Fatty Acid Composition of Cerebrospinal Fluid Fractions Shows Their Contribution to Cognitive Resilience of a Pre-symptomatic Alzheimer’s Disease Cohort

Polyunsaturated Fatty Acid Composition of Cerebrospinal Fluid Fractions Shows Their Contribution to Cognitive Resilience of a Pre-symptomatic Alzheimer’s Disease Cohort

DHA Attenuates Cerebral Edema Following Traumatic Brain Injury via the Reduction in Blood–Brain Barrier Permeability

Lipid Mediators in Critically Ill Patients: A Step Towards Precision Medicine

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