RESUMEN
BACKGROUND: Neuroinflammation is thought to contribute to psychiatric and neurological disorders such as major depression and Alzheimer's disease (AD). N-6 polyunsaturated fatty acids (PUFA) and molecules derived from them, including linoleic acid- and arachidonic acid-derived lipid mediators, are known to have pro-inflammatory properties in the periphery; however, this has yet to be tested in the brain. Lowering the consumption of n-6 PUFA is associated with a decreased risk of depression and AD in human observational studies. The purpose of this study was to investigate the inflammation-modulating effects of lowering dietary n-6 PUFA in the mouse hippocampus. METHODS: C57BL/6 male mice were fed either an n-6 PUFA deprived (2% of total fatty acids) or an n-6 PUFA adequate (23% of total fatty acids) diet from weaning to 12 weeks of age. Animals then underwent intracerebroventricular surgery, in which lipopolysaccharide (LPS) was injected into the left lateral ventricle of the brain. Hippocampi were collected at baseline and following LPS administration (1, 3, 7, and 14 days). A microarray (n = 3 per group) was used to identify candidate genes and results were validated by real-time PCR in a separate cohort of animals (n = 5-8 per group). RESULTS: Mice administered with LPS had significantly increased Gene Ontology categories associated with inflammation and immune responses. These effects were independent of changes in gene expression in any diet group. Results were validated for the effect of LPS treatment on astrocyte, cytokine, and chemokine markers, as well as some results of the diets on Ifrd2 and Mfsd2a expression. CONCLUSIONS: LPS administration increases pro-inflammatory and lipid-metabolizing gene expression in the mouse hippocampus. An n-6 PUFA deprived diet modulated inflammatory gene expression by both increasing and decreasing inflammatory gene expression, without impairing the resolution of neuroinflammation following LPS administration.
Asunto(s)
Dieta con Restricción de Grasas , Ácidos Grasos Omega-6 , Expresión Génica/efectos de los fármacos , Hipocampo/efectos de los fármacos , Inflamación/metabolismo , Metabolismo de los Lípidos/efectos de los fármacos , Lipopolisacáridos/farmacología , Animales , Hipocampo/metabolismo , Inflamación/genética , Metabolismo de los Lípidos/genética , Masculino , RatonesRESUMEN
BACKGROUND: Eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA) recommendations are frequently stated at 500 mg/d; however, adherence to these recommendations would result in a large global commercial EPA/DHA production deficit. Previously, our laboratory demonstrated that acute DHA intake in rats can increase the capacity for synthesis-secretion of n-3 (ω-3) polyunsaturated fatty acids (PUFAs). OBJECTIVE: We aimed to investigate the utility of a dietary DHA cycling strategy that employs 2 wk of repeated DHA feeding for a total of 3 cycles over 12 wk. METHODS: Male Long-Evans rats were fed a 10% fat diet by weight comprised of either 1) a 2-wk, 2% α-linolenic acid (ALA, DHA-ALA group 18:3n-3) diet followed by a 2-wk, 2% DHA + 2% ALA diet over 3 consecutive 4-wk periods ("DHA cycling," DHA-ALA group); 2) a 2% DHA + 2% ALA diet (DHA group) for 12 wk; or 3) a 2% ALA-only diet (ALA group) for 12 wk. At 15 wk old, blood and tissue fatty acid concentrations and liver mRNA expression and 13C-DHA natural abundances were determined. RESULTS: DHA concentrations in plasma, erythrocytes, and whole blood between the DHA-ALA group and the DHA groups were not different (P ≥ 0.05), but were 72-110% higher (P < 0.05) than in the ALA group. Similarly, DHA concentrations in liver, heart, adipose, and brain were not different (P ≥ 0.05) between the DHA-fed groups, but were at least 62%, 72%, 320%, and 68% higher (P < 0.05) than in the ALA group in liver, heart, adipose, and skeletal muscle, respectively. Compound-specific isotope analysis indicated that 310% more liver DHA in the DHA-ALA group compared with the DHA group is derived from dietary ALA, and this was accompanied by a 123% and 93% higher expression of elongation of very long-chain (Elovl)2 and Elovl5, respectively, in the DHA-ALA group compared with the ALA group. CONCLUSIONS: DHA cycling requires half the dietary DHA while achieving equal blood and tissue DHA concentrations in rats. Implementation of such dietary strategies in humans could reduce the gap between global dietary n-3 PUFA recommendations and commercial production.
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Ácidos Docosahexaenoicos/farmacología , Ácido alfa-Linolénico/metabolismo , Tejido Adiposo/química , Animales , Química Encefálica , Ácidos Docosahexaenoicos/administración & dosificación , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Eritrocitos , Ácidos Grasos/química , Ácidos Grasos/metabolismo , Vacuna contra la Parotiditis/química , Músculo Esquelético/química , Miocardio/química , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Long-EvansRESUMEN
Multiple sclerosis is a demyelinating and inflammatory disease. Myelin is enriched in lipids, and more specifically, oleic acid. The goal of this study was to evaluate the concentration of oleic acid following demyelination and remyelination in the cuprizone model, test if these changes occurred in specific lipid species, and whether differences in the cuprizone model correlate with changes observed in post-mortem human brains. Eight-week-old C57Bl/6 mice were fed a 0.2% cuprizone diet for 5 weeks and some animals allowed to recover for 11 days. Demyelination, inflammation, and lipid concentrations were measured in the corpus callosum. Standard fatty acid techniques and liquid chromatography combined with tandem mass spectrometry were performed to measure concentrations of fatty acids in total brain lipids and a panel of lipid species within the phosphatidylcholine (PC). Similar measurements were conducted in post-mortem brain tissues of multiple sclerosis patients and were compared to healthy controls. Five weeks of cuprizone administration resulted in demyelination followed by significant remyelination after 11 days of recovery. Compared to control, oleic acid was decreased after 5 weeks of cuprizone treatment and increased during the recovery phase. This decrease in oleic acid was associated with a specific decrease in the PC 36:1 pool. Similar results were observed in human post-mortem brains. Decreases in myelin content in the cuprizone model were accompanied by decreases in oleic acid concentration and is associated with PC 36:1 suggesting that specific lipids could be a potential biomarker for myelin degeneration. The biological relevance of oleic acid for disease progression remains to be verified.
Asunto(s)
Quelantes , Cuprizona , Enfermedades Desmielinizantes/inducido químicamente , Enfermedades Desmielinizantes/tratamiento farmacológico , Esclerosis Múltiple/patología , Fosfatidilcolinas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Animales , Encéfalo/patología , Cuerpo Calloso/efectos de los fármacos , Cuerpo Calloso/metabolismo , Femenino , Humanos , Metabolismo de los Lípidos/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Vaina de Mielina/efectos de los fármacos , Ácido Oléico/metabolismo , Fosfatidilcolinas/administración & dosificación , Cambios Post MortemRESUMEN
BACKGROUND: Neuroinflammation is a recognized hallmark of Alzheimer's disease, along with accumulation of amyloid-ß plaques, neurofibrillary tangles and synaptic loss. n-3 polyunsaturated fatty acids (PUFA) and molecules derived from them, including eicosapentaenoic acid-derived eicosanoids and docosahexaenoic acid-derived docosanoids, are known to have both anti-inflammatory and pro-resolving properties, while human observational data links consumption of these fatty acids to a decreased risk of Alzheimer's disease. Few studies have examined the neuroinflammation-modulating effects of n-3 PUFA feeding in an Alzheimer's disease-related model, and none have investigated whether these effects are mediated by changes in brain eicosanoids and docosanoids. Here, we use both a fat-1 transgenic mouse and a fish oil feeding model to study the impact of increasing tissue n-3 PUFA on neuroinflammation and the production of pro-inflammatory and pro-resolving lipid mediators. METHODS: Fat-1 mice, transgenic animals that can convert n-6 to n-3 PUFA, and their wildtype littermates were fed diets containing either fish oil (high n-3 PUFA) or safflower oil (negligible n-3 PUFA) from weaning to 12â¯weeks. Animals then underwent intracerebroventricular infusion of either amyloid-ß 1-40 or a control peptide. Hippocampi were collected from non-surgery and surgery animals 10â¯days after infusion. Microarray was used to measure enrichment of inflammation-associated gene categories and expression of genes involved in the synthesis of lipid mediators. Results were validated by real-time PCR in a separate cohort of animals. Lipid mediators were measured via liquid chromatography tandem mass spectrometry. RESULTS: Fat-1 and wildtype mice fed fish oil had higher total hippocampal DHA than wildtype mice fed the safflower oil diet. The safflower-fed mice, but not the fat-1 or fish oil-fed mice, had significantly increased expression in gene ontology categories associated with inflammation in response to amyloid-ß infusion. These effects were independent of changes in the expression of genes involved in the synthesis of eicosanoids or docosanoids in any group. Gene expression was replicated upon validation in the wildtype safflower and fish oil-fed, but not the fat-1 mice. Protectin, maresin and D and E series resolvins were not detected in any sample. There were no major differences in levels of other eicosanoids or docosanoids between any of the groups in response to amyloid-ß infusion. CONCLUSIONS: Fish oil feeding decreases neuroinflammatory gene expression in response to amyloid-ß. Neither amyloid-ß infusion or increasing brain DHA affects the brain concentrations of specialized pro-resolving mediators in this model, or the concentrations of most other eicosanoids and docosanoids.
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Enfermedad de Alzheimer/metabolismo , Encéfalo/efectos de los fármacos , Eicosanoides/metabolismo , Ácidos Erucicos/metabolismo , Aceites de Pescado/farmacología , Expresión Génica/efectos de los fármacos , Inflamación/metabolismo , Animales , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Inflamación/genética , Ratones , Ratones TransgénicosRESUMEN
The field of lipidomics has evolved vastly since its creation 15 years ago. Advancements in mass spectrometry have allowed for the identification of hundreds of intact lipids and lipid mediators. However, because of the release of fatty acids from the phospholipid membrane in the brain caused by ischemia, identifying the neurolipidome has been challenging. Microwave fixation has been shown to reduce the ischemia-induced release of several lipid mediators. Therefore, this study aimed to develop a method combining high-resolution tandem mass spectrometry (MS/MS), high-energy head-focused microwave fixation and statistical modeling, allowing for the measurement of intact lipids and lipid mediators in order to eliminate the ischemia-induced release of fatty acids and identify the rat neurolipidome. In this study, we demonstrated the ischemia-induced production of bioactive lipid mediators, and the reduction in variability using microwave fixation in combination with liquid chromatography (LC)-MS/MS. We have also illustrated for the first time that microwave fixation eliminates the alterations in intact lipid species following ischemia. While many phospholipid species were unchanged by ischemia, other intact lipid classes, such as diacylglycerol, were lower in concentration following microwave fixation compared to ischemia.
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Isquemia Encefálica/fisiopatología , Metabolismo de los Lípidos , Neuronas/metabolismo , Transducción de Señal , Animales , Isquemia Encefálica/metabolismo , Ceramidas/metabolismo , Diglicéridos/metabolismo , Ácidos Grasos/metabolismo , Inflamación/inducido químicamente , Inflamación/fisiopatología , Lipopolisacáridos/farmacología , Masculino , Microondas , Fosfolípidos/metabolismo , Ratas , Ratas Long-EvansRESUMEN
BACKGROUND: Neuroinflammation is a proposed mechanism by which Alzheimer's disease (AD) pathology potentiates neuronal death and cognitive decline. Consumption of omega-3 polyunsaturated fatty acids (PUFA) is associated with a decreased risk of AD in human observational studies and exerts protective effects on cognition and pathology in animal models. These fatty acids and molecules derived from them are known to have anti-inflammatory and pro-resolving properties, presenting a potential mechanism for these protective effects. METHODS: Here, we explore this mechanism using fat-1 transgenic mice and their wild type littermates weaned onto either a fish oil diet (high in n-3 PUFA) or a safflower oil diet (negligible n-3 PUFA). The fat-1 mouse carries a transgene that enables it to convert omega-6 to omega-3 PUFA. At 12 weeks of age, mice underwent intracerebroventricular (icv) infusion of amyloid-ß 1-40. Brains were collected between 1 and 28 days post-icv, and hippocampal microglia, astrocytes, and degenerating neurons were quantified by immunohistochemistry with epifluorescence microscopy, while microglia morphology was assessed with confocal microscopy and skeleton analysis. RESULTS: Fat-1 mice fed with the safflower oil diet and wild type mice fed with the fish oil diet had higher brain DHA in comparison with the wild type mice fed with the safflower oil diet. Relative to the wild type mice fed with the safflower oil diet, fat-1 mice exhibited a lower peak in the number of labelled microglia, wild type mice fed with fish oil had fewer degenerating neurons, and both exhibited alterations in microglia morphology at 10 days post-surgery. There were no differences in astrocyte number at any time point and no differences in the time course of microglia or astrocyte activation following infusion of amyloid-ß 1-40. CONCLUSIONS: Increasing brain DHA, through either dietary or transgenic means, decreases some elements of the inflammatory response to amyloid-ß in a mouse model of AD. This supports the hypothesis that omega-3 PUFA may be protective against AD by modulating the immune response to amyloid-ß.
RESUMEN
Docosahexaenoic acid (DHA) is an omega-3 polyunsaturated fatty acid (n-3 PUFA) that has been shown to raise seizure thresholds in the maximal pentylenetetrazole model following acute subcutaneous (s.c.) administration in rats. Following s.c. administration, however, the dose-response relationship for DHA has shown an inverted U-pattern. The purposes of the present experiment were as follows: (1) to determine the pattern of serum unesterified concentrations resulting from the intravenous (i.v.) infusions of various doses of DHA, (2) to determine the time course of these concentrations following the discontinuation of the infusions, and (3) to determine whether seizure protection in the maximal PTZ model would correlate with serum unesterified DHA levels. Animals received 5-minute i.v. infusions of saline or 25, 50, 100, or 200mg/kg of DHA via a cannula inserted into one of the tail veins. Blood was collected during and after the infusions by means of a second cannula inserted into the other tail vein (Experiment 1). A separate group of animals received saline or 12.5-, 25-, 50-, 100-, or 200 mg/kg DHA i.v. via a cannula inserted into one of the tail veins and were then seizure-tested in the maximal PTZ model either during infusion or after the discontinuation of the infusions. Slow infusions of DHA increased serum unesterified DHA concentrations in a dose-dependent manner, with the 200-mg/kg dose increasing the concentration approximately 260-fold compared with saline-infused animals. Following discontinuation of the infusions, serum concentrations rapidly dropped toward baseline, with half-lives of approximately 40 and 11s for the 25-mg/kg dose and 100-mg/kg dose, respectively. In the seizure-tested animals, DHA significantly increased latency to seizure onset in a dose-dependent manner. Following the discontinuation of infusion, seizure latency rapidly decreased toward baseline. Overall, our study suggests that i.v. infusion of unesterified DHA results in transient anticonvulsant effects which parallel unesterified DHA serum concentrations.
Asunto(s)
Ácidos Docosahexaenoicos/administración & dosificación , Ácidos Docosahexaenoicos/sangre , Pentilenotetrazol/toxicidad , Convulsiones/sangre , Convulsiones/tratamiento farmacológico , Animales , Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/sangre , Relación Dosis-Respuesta a Droga , Infusiones Intravenosas , Masculino , Ratas , Ratas Wistar , Convulsiones/inducido químicamente , Factores de TiempoRESUMEN
Docosahexaenoic acid (DHA) is important for brain function, however, the exact amount required for the brain is not agreed upon. While it is believed that the synthesis rate of DHA from α-linolenic acid (ALA) is low, how this synthesis rate compares with the amount of DHA required to maintain brain DHA levels is unknown. The objective of this work was to assess whether DHA synthesis from ALA is sufficient for the brain. To test this, rats consumed a diet low in n-3 PUFAs, or a diet containing ALA or DHA for 15 weeks. Over the 15 weeks, whole body and brain DHA accretion was measured, while at the end of the study, whole body DHA synthesis rates, brain gene expression, and DHA uptake rates were measured. Despite large differences in body DHA accretion, there was no difference in brain DHA accretion between rats fed ALA and DHA. In rats fed ALA, DHA synthesis and accretion was 100-fold higher than brain DHA accretion of rats fed DHA. Also, ALA-fed rats synthesized approximately 3-fold more DHA than the DHA uptake rate into the brain. This work indicates that DHA synthesis from ALA may be sufficient to supply the brain.
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Encéfalo/metabolismo , Ácidos Docosahexaenoicos/biosíntesis , Ácido alfa-Linolénico/metabolismo , Administración Oral , Animales , Volumen Sanguíneo , Dieta , Ácidos Docosahexaenoicos/administración & dosificación , Ácidos Docosahexaenoicos/farmacocinética , Ácidos Grasos Insaturados/metabolismo , Metabolismo de los Lípidos , Masculino , Especificidad de Órganos , Ratas , Ratas Long-Evans , TranscriptomaRESUMEN
Docosahexaenoic acid (DHA) is an omega-3 polyunsaturated fatty acid (n-3 PUFA) which has been shown to raise seizure thresholds following acute administration in rats. The aims of the present experiment were the following: 1) to test whether subchronic DHA administration raises seizure threshold in the maximal pentylenetetrazol (PTZ) model 24h following the last injection and 2) to determine whether the increase in seizure threshold is correlated with an increase in serum and/or brain DHA. Animals received daily intraperitoneal (i.p.) injections of 50mg/kg of DHA, DHA ethyl ester (DHA EE), or volume-matched vehicle (albumin/saline) for 14days. On day 15, one subset of animals was seizure tested in the maximal PTZ model (Experiment 1). In a separate (non-seizure tested) subset of animals, blood was collected, and brains were excised following high-energy, head-focused microwave fixation. Lipid analysis was performed on serum and brain (Experiment 2). For data analysis, the DHA and DHA EE groups were combined since they did not differ significantly from each other. In the maximal PTZ model, DHA significantly increased seizure latency by approximately 3-fold as compared to vehicle-injected animals. This increase in seizure latency was associated with an increase in serum unesterified DHA. Total brain DHA and brain unesterified DHA concentrations, however, did not differ significantly in the treatment and control groups. An increase in serum unesterified DHA concentration reflecting increased flux of DHA to the brain appears to explain changes in seizure threshold, independent of changes in brain DHA concentrations.
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Ácidos Docosahexaenoicos/uso terapéutico , Convulsiones/tratamiento farmacológico , Animales , Ácidos Docosahexaenoicos/administración & dosificación , Ácidos Docosahexaenoicos/sangre , Inyecciones Intraperitoneales , Masculino , Pentilenotetrazol , Ratas , Ratas Wistar , Convulsiones/sangre , Convulsiones/inducido químicamenteRESUMEN
Brain eicosapentaenoic acid (EPA) levels are 250- to 300-fold lower than docosahexaenoic acid (DHA), at least partly, because EPA is rapidly ß-oxidized and lost from brain phospholipids. Therefore, we examined if ß-oxidation was necessary for maintaining low EPA levels by inhibiting ß-oxidation with methyl palmoxirate (MEP). Furthermore, because other metabolic differences between DHA and EPA may also contribute to their vastly different levels, this study aimed to quantify the incorporation and turnover of DHA and EPA into brain phospholipids. Fifteen-week-old rats were subjected to vehicle or MEP prior to a 5 min intravenous infusion of (14)C-palmitate, (14)C-DHA, or (14)C-EPA. MEP reduced the radioactivity of brain aqueous fractions for (14)C-palmitate-, (14)C-EPA-, and (14)C-DHA-infused rats by 74, 54, and 23%, respectively; while it increased the net rate of incorporation of plasma unesterified palmitate into choline glycerophospholipids and phosphatidylinositol and EPA into ethanolamine glycerophospholipids and phosphatidylserine. MEP also increased the synthesis of n-3 docosapentaenoic acid (n-3 DPA) from EPA. Moreover, the recycling of EPA into brain phospholipids was 154-fold lower than DHA. Therefore, the low levels of EPA in the brain are maintained by multiple redundant pathways including ß-oxidation, decreased incorporation from plasma unesterified FA pool, elongation/desaturation to n-3 DPA, and lower recycling within brain phospholipids.
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Encéfalo/metabolismo , Ácido Eicosapentaenoico/metabolismo , Fosfolípidos/metabolismo , Animales , Ácido Eicosapentaenoico/sangre , Esterificación , Cinética , Masculino , Oxidación-Reducción , Fosfolípidos/sangre , Ratas , Ratas Sprague-Dawley , Agua/químicaRESUMEN
Complex partial seizures, which typically originate in limbic structures such as the amygdala, are often resistant to antiseizure medications. Our goal was to investigate the effects of chronic dietary supplementation with n-3 polyunsaturated fatty acids (PUFAs) derived from fish oil on seizure thresholds in the amygdala, as well as on blood and brain PUFA levels. The acute effects of injected n-3 PUFAs--eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)--were also tested in the maximal pentylenetetrazol (PTZ) seizure model. In amygdala-implanted subjects, fish oil supplementation significantly increased amygdaloid afterdischarge thresholds, as compared with controls at 3, 5, and 7 months after the start of supplementation. Fish oil supplementation also increased serum EPA and DHA concentrations. DHA concentration in the pyriform-amygdala area increased in the fish-oil treated group by 17-34%, but this effect did not reach statistical significance (P=0.065). DHA significantly increased the latency to seizure onset in the PTZ seizure model, whereas EPA had no significant effect. These observations suggest that chronic dietary fish oil supplementation can raise focal amygdaloid seizure thresholds and that this effect is likely mediated by DHA rather than by EPA.
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Amígdala del Cerebelo/fisiopatología , Epilepsia Parcial Compleja/dietoterapia , Epilepsia Parcial Compleja/patología , Aceites de Pescado/administración & dosificación , Amígdala del Cerebelo/efectos de los fármacos , Animales , Peso Corporal/efectos de los fármacos , Peso Corporal/fisiología , Convulsivantes/toxicidad , Modelos Animales de Enfermedad , Ácidos Docosahexaenoicos/administración & dosificación , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Ingestión de Alimentos/efectos de los fármacos , Ingestión de Alimentos/fisiología , Electrodos Implantados , Electroencefalografía , Epilepsia Parcial Compleja/inducido químicamente , Ácidos Grasos/metabolismo , Ácidos Grasos Omega-3/administración & dosificación , Estudios de Seguimiento , Masculino , Pentilenotetrazol/toxicidad , Ratas , Ratas Wistar , Factores de TiempoRESUMEN
BACKGROUND: To compare a treat-to-target (T2T) approach and routine care (RC) in adults with active to severely active rheumatoid arthritis (RA) initiating subcutaneous abatacept. METHODS: A 12-month cluster-randomized trial in active RA patients treated with abatacept was conducted. Physicians were randomized to RC or T2T with a primary endpoint of achieving sustained Clinical Disease Activity Index (CDAI) low disease activity (LDA) at two consecutive assessments approximately 3 months apart. Additional outcomes included Simple Disease Activity Index (SDAI), Disease Activity Score 28-CRP (DAS28-CRP), Routine Assessment of Patient Index Data 3 (RAPID3), and the Health Assessment Questionnaire-Disability Index (HAQ-DI). Time to achieve therapeutic endpoints was assessed with survival analysis. RESULTS: Among the 284 enrolled patients, 130 were in the T2T group and 154 in RC. Primary endpoint was achieved by 36.9% and 40.3% of patients in T2T and RC groups, respectively. No significant between-group differences were observed in the odds of achieving secondary outcomes, except for a higher likelihood of CDAI LDA in the T2T group vs. RC (odds ratio [95% confidence interval]: 1.33 [1.03-1.71], p = 0.0263). Compared with RC, patients in the T2T group achieved SDAI remission significantly faster (Kaplan-Meier-estimated mean [standard error]: 14.0 [0.6] vs. 19.3 [0.8] months, p = 0.0428) with a trend toward faster achievement of CDAI LDA/remission, DAS28-CRP remission, and HAQ-DI minimum clinically important difference. CONCLUSIONS: Patients managed per T2T and those under RC experienced significant improvements in RA disease activity at 12 months of abatacept treatment. T2T was associated with higher odds of CDAI LDA and a shorter time to achieving therapeutic endpoints. TRIAL REGISTRATION: Name of the registry: ClinicalTrials.gov. TRIAL REGISTRATIONS: NCT03274141 . Date of registration: September 6, 2017.
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Artritis Reumatoide , Adulto , Humanos , Abatacept/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Estimación de Kaplan-Meier , Diferencia Mínima Clínicamente Importante , Oportunidad RelativaRESUMEN
Resolution of inflammation in the periphery was once thought to be a passive process, but new research now suggests it is an active process mediated by specialized pro-resolving lipid mediators (SPM) derived from omega-3 polyunsaturated fatty acids (n-3 PUFA). However, this has yet to be illustrated in neuroinflammation. The purpose of this study was to measure resolution of neuroinflammation and to test whether increasing brain docosahexaenoic acid (DHA) affects the resolution of neuroinflammation. C57Bl/6 mice, fat-1 mice and their wildtype littermates, fed either fish oil or safflower oil, received lipopolysaccharide (LPS) in the left lateral ventricle. Animals were then euthanized at various time points for immunohistochemistry, gene expression, and lipidomic analyses. Peak microglial activation was observed at 5 days post-surgery and the resolution index was 10 days. Of the approximately 350 genes significantly changed over the 28 days post LPS injection, 130 were uniquely changed at 3 days post injection. No changes were observed in the bioactive mediator pools. However, a few lysophospholipid species were decreased at 24hr post surgery. When brain DHA is increased, microglial cell density did not resolve faster and did not alter gene expression. In conclusion, resolution of neuroinflammation appears to be independent of SPM. Increasing brain DHA had no effect in this model.
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Encéfalo/metabolismo , Ácidos Docosahexaenoicos/metabolismo , Aceites de Pescado/administración & dosificación , Lipopolisacáridos/toxicidad , Aceite de Cártamo/administración & dosificación , Animales , Encéfalo/efectos de los fármacos , Inflamación/inducido químicamente , Inflamación/dietoterapia , Inflamación/metabolismo , Inyecciones Intraventriculares , Lipopolisacáridos/administración & dosificación , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BLRESUMEN
N-acylethanolamines (NAEs) are lipid signaling mediators, which can be synthesized from dietary fatty acids via n-acylphosphatidylethanolamine-phospholipase D (NAPE-PLD) and in turn influence physiological outcomes; however, the roles of NAPE-PLD upon dietary fatty acid modulation are not fully understood. Presently, we examine if NAPE-PLD is necessary to increase NAEs in response to dietary fatty acid manipulation. Post-weaning male wild-type (C57Bl/6), NAPE-PLD (-/+) and NAPE-PLD (-/-) mice received isocaloric fat diets containing either beef tallow, corn oil, canola oil or fish oil (10% wt/wt from fat) for 9 weeks. Brain docosahexaenoic acid (DHA) levels were higher (P<.01) in NAPE-PLD (-/+) (10.01±0.31 µmol/g) and NAPE-PLD (-/-) (10.89±0.61 µmol/g) than wild-type (7.72±0.61 µmol/g) consuming fish oil. In NAPE-PLD (-/-) mice, brain docosahexaenoylethanolamide (DHEA) levels were higher (P<.01) after fish oil feeding suggesting that NAPE-PLD was not necessary for DHEA synthesis. Liver and jejunum arachidonoylethanolamide, 1,2-arachidonoylglycerol and DHEA levels reflected their corresponding fatty acid precursors suggesting that alternate pathways are involved in NAE synthesis. NAPE-PLD (-/-) mice had lower oleoylethanolamide levels in the jejunum and a leaner phenotype compared to wild-type mice. Overall, these results demonstrate that dietary fatty acid can augment tissue NAEs in the absence of NAPE-PLD.
Asunto(s)
Etanolaminas/metabolismo , Ácidos Grasos/farmacología , Fosfolipasa D/genética , Animales , Distribución de la Grasa Corporal , Peso Corporal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Dieta , Ácidos Grasos/metabolismo , Femenino , Aceites de Pescado/química , Aceites de Pescado/farmacología , Yeyuno/efectos de los fármacos , Yeyuno/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Fosfolipasa D/metabolismoRESUMEN
Background: Brain concentrations of omega-3 docosahexaenoic acid (DHA, 22:6n-3) have been reported to positively correlate with seizure thresholds in rodent seizure models. It is not known whether brain DHA depletion, achieved by chronic dietary omega-3 polyunsaturated fatty acid (PUFA) deficiency, lowers seizure thresholds in rats. Objective: The present study tested the hypothesis that lowering brain DHA concentration with chronic dietary n-3 PUFA deprivation in rats will reduce seizure thresholds, and that compared to injected oleic acid (OA), injected DHA will raise seizure thresholds in rats maintained on n-3 PUFA adequate and deficient diets. Methods: Rats (60 days old) were surgically implanted with electrodes in the amygdala, and subsequently randomized to the AIN-93G diet containing adequate levels of n-3 PUFA derived from soybean oil or an n-3 PUFA-deficient diet derived from coconut and safflower oil. The rats were maintained on the diets for 37 weeks. Afterdischarge seizure thresholds (ADTs) were measured every 4-6 weeks by electrically stimulating the amygdala. Between weeks 35 and 37, ADTs were assessed within 1 h of subcutaneous OA or DHA injection (600 mg/kg). Seizure thresholds were also measured in a parallel group of non-implanted rats subjected to the maximal pentylenetetrazol (PTZ, 110 mg/kg) seizure test. PUFA composition was measured in the pyriform-amygdala complex of another group of non-implanted rats sacrificed at 16 and 32 weeks. Results: Dietary n-3 PUFA deprivation did not significantly alter amygdaloid seizure thresholds or latency to PTZ-induced seizures. Acute injection of OA did not alter amygdaloid ADTs of rats on the n-3 PUFA adequate or deficient diets, whereas acute injection of DHA significantly increased amygdaloid ADTs in rats on the n-3 PUFA adequate control diet as compared to rats on the n-3 PUFA deficient diet (P < 0.05). Pyriform-amygdala DHA percent composition did not significantly differ between the groups, while n-6 docosapentaenoic acid, a marker of n-3 PUFA deficiency, was significantly increased by 2.9-fold at 32 weeks. Conclusion: Chronic dietary n-3 PUFA deficiency does not alter seizure thresholds in rats, but may prevent the anti-seizure effects of DHA.
RESUMEN
Dietary docosahexaenoic acid (DHA, 22:6n-3) not only increases blood and tissue levels of DHA, but also eicosapentaenoic acid (EPA, 20:5n-3). It is generally believed that this increase is due to DHA retroconversion to EPA, however, a slower conversion of α-linolenic acid (ALA, 18:3n-3) derived EPA to downstream metabolic products (i.e. slower turnover of EPA) is equally plausible. In this study, 21-day old Long Evans rats were weaned onto an ALA only or DHA + ALA diet for 12 weeks. Afterwards, livers were collected and the natural abundance 13C-enrichment was determined by compound specific isotope analysis (CSIA) of liver EPA by isotope ratio mass-spectrometry and compared to dietary ALA and DHA 13C-enrichment. Isotopic signatures (per mil, ) for liver EPA were not different (p > 0.05) between the ALA only diet (-25.89 ± 0.39 , mean ± SEM) and the DHA + ALA diet (-26.26 ± 0.40 ), suggesting the relative contribution from dietary ALA and DHA to liver EPA did not change. However, with DHA feeding estimates of absolute EPA contribution from ALA increased 4.4-fold (147 ± 22 to 788 ± 153 nmol/g) compared to 3.2-fold from DHA (91 ± 14 to 382 ± 13 nmol/g), respectively. In conclusion, CSIA of liver EPA in rats following 12-weeks of dietary DHA suggests that retroconversion of DHA to EPA is a relatively small contributor to increases in EPA, and that this increase in EPA is largely coming from elongation/desaturation of ALA.
RESUMEN
Several studies have found decreased levels of ω-3 polyunsaturated fatty acids in the brain and blood of schizophrenia patients. Furthermore, dietary ω-3 supplements may improve schizophrenia symptoms and delay the onset of first-episode psychosis. We used an animal model of NMDA receptor hypofunction, NR1KD mice, to understand whether changes in glutamate neurotransmission could lead to changes in brain and serum fatty acids. We further asked whether dietary manipulations of ω-3, either depletion or supplementation, would affect schizophrenia-relevant behaviors of NR1KD mice. We discovered that NR1KD mice have elevated brain levels of ω-6 fatty acids regardless of their diet. While ω-3 supplementation did not improve any of the NR1KD behavioral abnormalities, ω-3 depletion exacerbated their deficits in executive function. Omega-3 depletion also caused extreme mortality among male mutant mice, with 75% mortality rate by 12 weeks of age. Our studies show that alterations in NMDAR function alter serum and brain lipid composition and make the brain more vulnerable to dietary ω-3 deprivation.
RESUMEN
Maternal docosahexaenoic acid (DHA, 22:6n-3) supplies the developing fetus during pregnancy; however, the mechanisms are unclear. We utilized pregnant rats to determine rates of DHA accretion, tissue unesterified DHA uptake and whole-body DHA synthesis-secretion. Female rats maintained on a DHA-free, 2% α-linolenic acid diet were either:1) sacrificed at 56 days for baseline measures, 2) mated and sacrificed at 14-18 days of pregnancy or 3) or sacrificed at 14-18 days as age-matched virgin controls. Maternal brain, adipose, liver and whole body fatty acid concentrations was determined for balance analysis, and kinetic modeling was used to determine brain and liver plasma unesterified DHA uptake and whole-body DHA synthesis-secretion rates. Total liver DHA was significantly higher in pregnant (95±5 µmol) versus non-pregnant (49±5) rats with no differences in whole-body DHA synthesis-secretion rates. However, liver uptake of plasma unesterified DHA was 3.8-fold higher in pregnant animals compared to non-pregnant controls, and periuterine adipose DHA was lower in pregnant (0.89±0.09 µmol/g) versus non-pregnant (1.26±0.06) rats. In conclusion, higher liver DHA accretion during pregnancy appears to be driven by higher unesterified DHA uptake, potentially via DHA mobilization from periuterine adipose for delivery to the fetus during the brain growth spurt.
Asunto(s)
Ácidos Docosahexaenoicos/metabolismo , Ácidos Docosahexaenoicos/farmacocinética , Hígado/metabolismo , Fenómenos Fisiologicos de la Nutrición Prenatal , Tejido Adiposo/metabolismo , Animales , Animales Recién Nacidos , Peso Corporal , Encéfalo/metabolismo , Ácidos Docosahexaenoicos/sangre , Ingestión de Alimentos , Ácidos Grasos/sangre , Femenino , Embarazo , Ratas Long-Evans , Distribución Tisular , Ácido alfa-Linolénico/metabolismo , Ácido alfa-Linolénico/farmacocinéticaRESUMEN
Maternal delivery of docosahexaenoic acid (DHA, 22:6n-3) to the developing fetus via the placenta is required for fetal neurodevelopment, and is the only mechanism by which DHA can be accreted in the fetus. The aim of the current study was to utilize a balance model of DHA accretion combined with kinetic measures of serum unesterified DHA uptake to better understand the mechanism by which maternal DHA is delivered to the fetus via the placenta. Female rats maintained on a 2% α-linolenic acid diet free of DHA for 56 days were mated, and for balance analysis, sacrificed at 18 days of pregnancy, and fetus, placenta and maternal carcass fatty acid concentration were determined. For tissue DHA uptake, pregnant dams (14-18 days) were infused for 5 min with radiolabeled 14C-DHA and kinetic modeling was used to determine fetal and placental serum unesterified DHA uptake rates. DHA accretion rates in the fetus were determined to be 38 ± 2 nmol/d/g, 859 ± 100 nmol/d/litter and 74 ± 3 nmol/d/pup, which are all higher (P < 0.05) than the fetal serum unesterified DHA uptake rates of 16 ± 6 nmol/d/g, 239 ± 145 nmol/d/litter and 14 ± 8 nmol/d/pup. No differences (p > 0.05) in placental DHA accretion rates versus serum unesterified DHA uptake rates were observed as values varied only 6-35% between studies. No differences in placental accretion and uptake rates suggests that serum unesterified DHA is a significant pool for the maternal-placental transfer of DHA, and lower fetal DHA uptake compared to accretion supports remodeling of placental DHA for delivery to the fetus.
Asunto(s)
Ácidos Docosahexaenoicos/metabolismo , Feto/metabolismo , Intercambio Materno-Fetal , Placenta/metabolismo , Animales , Dieta , Femenino , Embarazo , Ratas , Ratas Long-EvansRESUMEN
Neuroinflammation is a characteristic of a multitude of neurological and psychiatric disorders. Modulating inflammatory pathways offers a potential therapeutic target in these disorders. Omega-3 polyunsaturated fatty acids have anti-inflammatory and pro-resolving properties in the periphery, however, their effect on neuroinflammation is less studied. This review summarizes 61 animal studies that tested the effect of omega-3 polyunsaturated fatty acids on neuroinflammatory outcomes in vivo in various models including stroke, spinal cord injury, aging, Alzheimer's disease, Parkinson's disease, lipopolysaccharide and IL-1ß injections, diabetes, neuropathic pain, traumatic brain injury, depression, surgically induced cognitive decline, whole body irradiation, amyotrophic lateral sclerosis, N-methyl-D-aspartate-induced excitotoxicity and lupus. The evidence presented in this review suggests anti-neuroinflammatory properties of omega-3 polyunsaturated fatty acids, however, it is not clear by which mechanism omega-3 polyunsaturated fatty acids exert their effect. Future research should aim to isolate the effect of omega-3 polyunsaturated fatty acids on neuroinflammatory signaling in vivo and elucidate the mechanisms underlying these effects.