RESUMEN
Docosapentaenoic acid (DPAn-6, 22:5n-6) is an n-6 polyunsaturated fatty acid (PUFA) whose brain concentration can be increased in rodents by dietary n-3 PUFA deficiency, which may contribute to their behavioral dysfunction. We used our in vivo intravenous infusion method to see if brain DPAn-6 turnover and metabolism also were altered with deprivation. We studied male rats that had been fed for 15 weeks post-weaning an n-3 PUFA adequate diet containing 4.6% alpha-linolenic acid (α-LNA, 18:3n-3) or a deficient diet (0.2% α-LNA), each lacking docosahexaenoic acid (22:6n-3) and arachidonic acid (AA, 20:4n-6). [1-(14)C]DPAn-6 was infused intravenously for 5min in unanesthetized rats, after which the brain underwent high-energy microwaving, and then was analyzed. The n-3 PUFA deficient compared with adequate diet increased DPAn-6 and decreased DHA concentrations in plasma and brain, while minimally changing brain AA concentration. Incorporation rates of unesterified DPAn-6 from plasma into individual brain phospholipids were increased 5.2-7.7 fold, while turnover rates were increased 2.1-4.7 fold. The observations suggest that increased metabolism and brain concentrations of DPAn-6 and its metabolites, together with a reduced brain DHA concentration, contribute to behavioral and functional abnormalities reported with dietary n-3 PUFA deprivation in rodents. (196 words).
Asunto(s)
Encéfalo/metabolismo , Ácidos Grasos Omega-3 , Ácidos Grasos Insaturados/metabolismo , Fosfolípidos/inmunología , Animales , Química Encefálica , Masculino , Ratas , Ratas Endogámicas F344 , Factores de TiempoRESUMEN
Calcium-independent phospholipase A(2) group VIA (iPLA(2)ß) releases docosahexaenoic acid (DHA) from phospholipids in vitro. Mutations in the iPLA(2)ß gene, PLA2G6, are associated with dystonia-parkinsonism and infantile neuroaxonal dystrophy. To understand the role of iPLA(2)ß in brain, we applied our in vivo kinetic method using radiolabeled DHA in 4 to 5-month-old wild type (iPLA(2)ß(+/+)) and knockout (iPLA(2)ß(-/-)) mice, and measured brain DHA kinetics, lipid concentrations, and expression of PLA(2), cyclooxygenase (COX), and lipoxygenase (LOX) enzymes. Compared to iPLA(2)ß(+/+) mice, iPLA(2)ß(-/-) mice showed decreased rates of incorporation of unesterified DHA from plasma into brain phospholipids, reduced concentrations of several fatty acids (including DHA) esterified in ethanolamine- and serine-glycerophospholipids, and increased lysophospholipid fatty acid concentrations. DHA turnover in brain phospholipids did not differ between genotypes. In iPLA(2)ß(-/-) mice, brain levels of iPLA(2)ß mRNA, protein, and activity were decreased, as was the iPLA(2)γ (Group VIB PLA(2)) mRNA level, while levels of secretory sPLA(2)-V mRNA, protein, and activity and cytosolic cPLA(2)-IVA mRNA were increased. Levels of COX-1 protein were decreased in brain, while COX-2 protein and mRNA were increased. Levels of 5-, 12-, and 15-LOX proteins did not differ significantly between genotypes. Thus, a genetic iPLA(2)ß deficiency in mice is associated with reduced DHA metabolism, profound changes in lipid-metabolizing enzyme expression (demonstrating lack of redundancy) and of phospholipid fatty acid content of brain (particularly of DHA), which may be relevant to neurologic abnormalities in humans with PLA2G6 mutations.
Asunto(s)
Encéfalo/metabolismo , Ácidos Docosahexaenoicos/metabolismo , Fosfolipasas A2 Grupo VI , Metabolismo de los Lípidos , Proteínas del Tejido Nervioso/metabolismo , Fosfolípidos/metabolismo , Animales , Encéfalo/patología , Química Encefálica/genética , Ciclooxigenasa 1/biosíntesis , Ciclooxigenasa 1/genética , Ácidos Docosahexaenoicos/genética , Regulación Enzimológica de la Expresión Génica/genética , Humanos , Lipooxigenasa/biosíntesis , Lipooxigenasa/metabolismo , Proteínas de la Membrana/biosíntesis , Proteínas de la Membrana/genética , Ratones , Ratones Noqueados , Mutación , Proteínas del Tejido Nervioso/genética , Fosfolipasas A2 Secretoras/biosíntesis , Fosfolipasas A2 Secretoras/genética , Fosfolípidos/genéticaRESUMEN
The long-chain polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid (EPA, 20:5n-3), docosahexaenoic acid (DHA, 22:6n-3), and arachidonic acid (AA, 20:4n-6), are critical for health. These PUFAs can be synthesized in liver from their plant-derived precursors, α-linolenic acid (α-LNA, 18:3n-3) and linoleic acid (LA, 18:2n-6). Vegetarians and vegans may have suboptimal long-chain n-3 PUFA status, and the extent of the conversion of α-LNA to EPA and DHA by the liver is debatable. We quantified liver conversion of DHA and other n-3 PUFAs from α-LNA in rats fed a DHA-free but α-LNA (n-3 PUFA) adequate diet, and compared results to conversion of LA to AA. [U-(13)C]LA or [U-(13)C]α-LNA was infused intravenously for 2h at a constant rate into unanesthetized rats fed a DHA-free α-LNA adequate diet, and published equations were used to calculate kinetic parameters. The conversion coefficient k(â) of DHA from α-LNA was much higher than for AA from LA (97.2×10(-3) vs. 10.6×10(-3)min(-1)), suggesting that liver elongation-desaturation is more selective for n-3 PUFA biosynthesis on a per molecule basis. The net daily secretion rate of DHA, 20.3µmol/day, exceeded the reported brain DHA consumption rate by 50-fold, suggesting that the liver can maintain brain DHA metabolism with an adequate dietary supply solely of α-LNA. This infusion method could be used in vegetarians or vegans to determine minimal daily requirements of EPA and DHA in humans.
Asunto(s)
Ácido Araquidónico/metabolismo , Grasas Insaturadas en la Dieta/administración & dosificación , Ácidos Docosahexaenoicos/metabolismo , Hígado/metabolismo , Animales , Encéfalo/metabolismo , Dieta Vegetariana/efectos adversos , Ácidos Docosahexaenoicos/administración & dosificación , Ácidos Grasos Omega-3/administración & dosificación , Infusiones Intravenosas , Cinética , Masculino , Necesidades Nutricionales , Ratas , Ratas Endogámicas F344 , Ácido alfa-Linolénico/administración & dosificaciónRESUMEN
Dietary n-6 polyunsaturated fatty acid (PUFA) deprivation in rodents reduces brain arachidonic acid (20:4n-6) concentration and 20:4n-6-preferring cytosolic phospholipase A(2) (cPLA(2) -IVA) and cyclooxygenase (COX)-2 expression, while increasing brain docosahexaenoic acid (DHA, 22:6n-3) concentration and DHA-selective calcium-independent phospholipase A(2) (iPLA(2) )-VIA expression. We hypothesized that these changes are accompanied by up-regulated brain DHA metabolic rates. Using a fatty acid model, brain DHA concentrations and kinetics were measured in unanesthetized male rats fed, for 15 weeks post-weaning, an n-6 PUFA 'adequate' (31.4 wt% linoleic acid) or 'deficient' (2.7 wt% linoleic acid) diet, each lacking 20:4n-6 and DHA. [1-(14) C]DHA was infused intravenously, arterial blood was sampled, and the brain was microwaved at 5 min and analyzed. Rats fed the n-6 PUFA deficient compared with adequate diet had significantly reduced n-6 PUFA concentrations in brain phospholipids but increased eicosapentaenoic acid (EPA, 20:5n-3), docosapentaenoic acid n-3 (DPAn-3, 22:5n-3), and DHA (by 9.4%) concentrations, particularly in ethanolamine glycerophospholipid (EtnGpl). Incorporation rates of unesterified DHA from plasma, which represent DHA metabolic loss from brain, were increased 45% in brain phospholipids, as was DHA turnover. Increased DHA metabolism following dietary n-6 PUFA deprivation may increase brain concentrations of antiinflammatory DHA metabolites, which with a reduced brain n-6 PUFA content, likely promotes neuroprotection and alters neurotransmission.
Asunto(s)
Encéfalo/metabolismo , Grasas de la Dieta/administración & dosificación , Ácidos Docosahexaenoicos/metabolismo , Ácidos Grasos Omega-6/deficiencia , Regulación de la Expresión Génica/fisiología , Acilcoenzima A/metabolismo , Animales , Animales Recién Nacidos , Peso Corporal , Isótopos de Carbono/farmacocinética , Cromatografía de Gases , Cromatografía Líquida de Alta Presión/métodos , Grasas de la Dieta/metabolismo , Ácidos Docosahexaenoicos/farmacocinética , Regulación de la Expresión Génica/efectos de los fármacos , Lípidos/sangre , Ratas , Ratas Endogámicas F344RESUMEN
An up-regulated brain arachidonic acid (AA) cascade and a hyperglutamatergic state characterize bipolar disorder (BD). Lamotrigine (LTG), a mood stabilizer approved for treating BD, is reported to interfere with glutamatergic neurotransmission involving N-methyl-d-aspartate receptors (NMDARs). NMDARs allow extracellular calcium into the cell, thereby stimulating calcium-dependent cytosolic phospholipase A2 (cPLA2) to release AA from membrane phospholipid. We hypothesized that LTG, like other approved mood stabilizers, would reduce NMDAR-mediated AA signalling in rat brain. An acute subconvulsant dose of NMDA (25 mg/kg) or saline was administered intraperitoneally to unanaesthetized rats that had been treated p.o. daily for 42 d with vehicle or a therapeutically relevant dose of LTG (10 mg/kg.d). Regional brain AA incorporation coefficients k* and rates J in, and AA signals, were measured using quantitative autoradiography after intravenous [1-14C]AA infusion, as were other AA cascade markers. In chronic vehicle-treated rats, acute NMDA compared to saline increased k* and J in in widespread regions of the brain, as well as prostaglandin (PG)E2 and thromboxane B2 concentrations. Chronic LTG treatment compared to vehicle reduced brain cyclooxygenase (COX) activity, PGE2 concentration, and DNA-binding activity of the COX-2 transcription factor, NF-κB. Pretreatment with chronic LTG blocked the acute NMDA effects on AA cascade markers. In summary, chronic LTG like other mood stabilizers blocks NMDA-mediated signalling involving the AA metabolic cascade. Since markers of the AA cascade and of NMDAR signalling are up-regulated in the post-mortem BD brain, mood stabilizers generally may be effective in BD by dampening NMDAR signalling and the AA cascade.
Asunto(s)
Ácido Araquidónico/sangre , Encéfalo/efectos de los fármacos , Bloqueadores de los Canales de Calcio/farmacología , Receptores de N-Metil-D-Aspartato/metabolismo , Transducción de Señal/efectos de los fármacos , Triazinas/farmacología , Análisis de Varianza , Animales , Autorradiografía , Peso Corporal/efectos de los fármacos , Encéfalo/metabolismo , Ciclooxigenasa 2/metabolismo , Dinoprostona/metabolismo , Eicosanoides/metabolismo , Agonistas de Aminoácidos Excitadores/farmacología , Lamotrigina , Masculino , N-Metilaspartato/farmacología , FN-kappa B/metabolismo , Unión Proteica/efectos de los fármacos , Ratas , Ratas Endogámicas F344 , Tromboxano B2/metabolismoRESUMEN
Brain lipid metabolism was studied in rats following permanent bilateral common carotid artery ligation (BCCL), a model for chronic cerebral hypoperfusion. Unesterified (free) fatty acids (uFA) and acyl-CoA concentrations were measured 6 h, 24 h, and 7 days after BCCL or sham surgery, in high energy-microwaved brain. In BCCL compared to sham rats, cytosolic phospholipase A(2) (cPLA(2)) immunoreactivity in piriform cortex, and concentrations of total uFA and arachidonoyl-CoA, an intermediate for arachidonic acid reincorporation into phospholipids, were increased only at 6 h. At 24 h, immunoreactivity for secretory phospholipase A(2) (sPLA(2)), which may regulate blood flow, was increased near cortical and hippocampal blood vessels. BCCL did not affect levels of brain IB(4)+ microglia, glial fibrillary acidic protein (GFAP)+ astrocytes, cyclooxygenase-2 (COX-2) immunoreactivity at any time, but increased cPLA(2) immunoreactivity in one region at 6 h. Thus, BCCL affected brain lipid metabolism transiently, likely because of compensatory sPLA(2)-mediated vasodilation, without producing evidence of neuroinflammation.
Asunto(s)
Encéfalo/metabolismo , Arterias Carótidas/patología , Metabolismo de los Lípidos , Animales , Arterias Carótidas/metabolismo , Cromatografía Líquida de Alta Presión , Ácidos Grasos/metabolismo , Inmunohistoquímica , Masculino , Ratas , Ratas Endogámicas WKYRESUMEN
BACKGROUND: Dopamine transporter (DAT) homozygous knockout (DAT(-/-)) mice have a 10-fold higher extracellular (DA) concentration in the caudate-putamen and nucleus accumbens than do wildtype (DAT(+/+)) mice, but show reduced presynaptic DA synthesis and fewer postsynaptic D(2) receptors. One aspect of neurotransmission involves DA binding to postsynaptic D(2)-like receptors coupled to cytosolic phospholipase A(2) (cPLA(2)), which releases the second messenger, arachidonic acid (AA), from synaptic membrane phospholipid. We hypothesized that tonic overactivation of D(2)-like receptors in DAT(-/-) mice due to the excess DA would not increase brain AA signaling, because of compensatory downregulation of postsynaptic DA signaling mechanisms. METHODS: [1-(14)C]AA was infused intravenously for 3 min in unanesthetized DAT(+/+), heterozygous (DAT(+/-)), and DAT(-/-) mice. AA incorporation coefficients k* and rates J(in), markers of AA metabolism and signaling, were imaged in 83 brain regions using quantitative autoradiography; brain cPLA(2)-IV activity also was measured. RESULTS: Neither k* nor J(in) for AA in any brain region, or brain cPLA(2)-IV activity, differed significantly among DAT(-/-), DAT(+/-), and DAT(+/+) mice. CONCLUSIONS: These results differ from reported increases in k* and J(in) for AA, and in brain cPLA(2) expression, in serotonin reuptake transporter (5-HTT) knockout mice, and suggest that postsynaptic dopaminergic neurotransmission mechanisms involving AA are downregulated despite elevated DA in DAT(-/-) mice.
Asunto(s)
Ácido Araquidónico/metabolismo , Encéfalo/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/deficiencia , Transducción de Señal/genética , Análisis de Varianza , Animales , Autorradiografía , Peso Corporal/genética , Encéfalo/enzimología , Mapeo Encefálico , Isótopos de Carbono/metabolismo , Regulación hacia Abajo/genética , Ácidos Grasos/sangre , Masculino , Ratones , Ratones Noqueados , Fosfolipasas A2 , Potasio/metabolismoRESUMEN
Neuroinflammation, caused by 6 days of intracerebroventricular infusion of a low dose of lipopolysaccharide (LPS; 0.5 ng/h), stimulates brain arachidonic acid (AA) metabolism in rats, but 6 weeks of lithium pretreatment reduces this effect. To further understand this action of lithium, we measured concentrations of eicosanoids and docosanoids generated from AA and docosahexaenoic acid (DHA), respectively, in high-energy microwaved rat brain using LC/MS/MS and two doses of LPS. In rats fed a lithium-free diet, low (0.5 ng/h)- or high (250 ng/h)-dose LPS compared with artificial cerebrospinal fluid increased brain unesterified AA and prostaglandin E(2) concentrations and activities of AA-selective Ca(2+)-dependent cytosolic phospholipase A(2) (cPLA(2))-IV and Ca(2+)-dependent secretory sPLA(2). LiCl feeding prevented these increments. Lithium had a significant main effect by increasing brain concentrations of lipoxygenase-derived AA metabolites, 5- hydroxyeicosatetraenoic acid (HETE), 5-oxo-eicosatetranoic acid, and 17-hydroxy-DHA by 1.8-, 4.3- and 1.9-fold compared with control diet. Lithium also increased 15-HETE in high-dose LPS-infused rats. Ca(2+)-independent iPLA(2)-VI activity and unesterified DHA and docosapentaenoic acid (22:5n-3) concentrations were unaffected by LPS or lithium. This study demonstrates, for the first time, that lithium can increase brain 17-hydroxy-DHA formation, indicating a new and potentially important therapeutic action of lithium.
Asunto(s)
Ácido Araquidónico/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Ácidos Docosahexaenoicos/metabolismo , Inflamación/metabolismo , Lipopolisacáridos/farmacología , Litio/farmacología , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Trastorno Bipolar/tratamiento farmacológico , Peso Corporal/efectos de los fármacos , Encéfalo/efectos de la radiación , Cateterismo , Grasas de la Dieta/análisis , Relación Dosis-Respuesta a Droga , Esterificación , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Inflamación/fisiopatología , Litio/uso terapéutico , Masculino , Microondas , Ratas , Factores de TiempoRESUMEN
Few studies have examined effects of feeding animals a diet deficient in n-6 polyunsaturated fatty acids (PUFAs) but with an adequate amount of n-3 PUFAs. To do this, we fed post-weaning male rats a control n-6 and n-3 PUFA adequate diet and an n-6 deficient diet for 15 weeks, and measured stable lipid and fatty acid concentrations in different organs. The deficient diet contained nutritionally essential linoleic acid (LA,18:2n-6) as 2.3% of total fatty acids (10% of the recommended minimum LA requirement for rodents) but no arachidonic acid (AA, 20:4n-6), and an adequate amount (4.8% of total fatty acids) of alpha-linolenic acid (18:3n-3). The deficient compared with adequate diet did not significantly affect body weight, but decreased testis weight by 10%. AA concentration was decreased significantly in serum (-86%), brain (-27%), liver (-68%), heart (-39%), testis (-25%), and epididymal adipose tissue (-77%). Eicosapentaenoic (20:5n-3) and docosahexaenoic acid (22:6n-3) concentrations were increased in all but adipose tissue, and the total monounsaturated fatty acid concentration was increased in all organs. The concentration of 20:3n-9, a marker of LA deficiency, was increased by the deficient diet, and serum concentrations of triacylglycerol, total cholesterol and total phospholipid were reduced. In summary, 15 weeks of dietary n-6 PUFA deficiency with n-3 PUFA adequacy significantly reduced n-6 PUFA concentrations in different organs of male rats, while increasing n-3 PUFA and monounsaturated fatty acid concentrations. This rat model could be used to study metabolic, functional and behavioral effects of dietary n-6 PUFA deficiency.
Asunto(s)
Ácido Araquidónico/metabolismo , Grasas Insaturadas en la Dieta , Ácidos Grasos Omega-3/metabolismo , Ácidos Grasos Omega-6/deficiencia , Alimentación Animal , Animales , Peso Corporal , Encéfalo/metabolismo , Cromatografía de Gases , Lípidos , Masculino , Tamaño de los Órganos , Ratas , Ratas Endogámicas F344 , DesteteRESUMEN
Dietary docosahexaenoic acid (DHA; 22:6n-3) and eicosapentaenoic acid (EPA; 20:5n-3) are considered important for maintaining normal heart and brain function, but little EPA is found in brain, and EPA cannot be elongated to DHA in rat heart due to the absence of elongase-2. Ingested EPA may have to be converted in the liver to DHA for it to be fully effective in brain and heart, but the rate of conversion is not agreed on. This rate was determined in male adult rats fed a standard n-3 PUFA, containing diet by infusing unesterified albumin-bound [U-(13)C]EPA intravenously for 2 h and measuring esterified [(13)C]labeled PUFAs in arterial plasma lipoproteins, as well as the specific activity of unesterified plasma EPA. Whole-body (presumably hepatic) synthesis secretion rates from circulating unesterified EPA, calculated from peak first derivatives of plasma esterified concentration x volume curves, equaled 2.61 micromol/day for docosapentaenoic acid (22:5n-3) and 5.46 micromol/day for DHA. The DHA synthesis rate was 24-fold greater than the reported brain DHA consumption rate in rats. Thus, dietary EPA could help to maintain brain and heart DHA homeostasis because it is converted at a relatively high rate in the liver to circulating DHA.
Asunto(s)
Ácidos Docosahexaenoicos/sangre , Ácidos Docosahexaenoicos/metabolismo , Ácido Eicosapentaenoico/sangre , Ácido Eicosapentaenoico/metabolismo , Animales , Dieta , Ácido Eicosapentaenoico/administración & dosificación , Ácidos Grasos Omega-3/administración & dosificación , Ácidos Grasos Omega-3/sangre , Homeostasis , Masculino , Ratas , Ratas Endogámicas F344RESUMEN
Docosahexaenoic acid (DHA; 22:6n-3) is a critical constituent of the brain, but its metabolism has not been measured in the human brain in vivo. In monkeys, using positron emission tomography (PET), we first showed that intravenously injected [1-(11)C]DHA mostly entered nonbrain organs, with approximately 0.5% entering the brain. Then, using PET and intravenous [1-(11)C]DHA in 14 healthy adult humans, we quantitatively imaged regional rates of incorporation (K*) of DHA. We also imaged regional cerebral blood flow (rCBF) using PET and intravenous [(15)O]water. Values of K* for DHA were higher in gray than white matter regions and correlated significantly with values of rCBF in 12 of 14 subjects despite evidence that rCBF does not directly influence K*. For the entire human brain, the net DHA incorporation rate J(in), the product of K*, and the unesterified plasma DHA concentration equaled 3.8 +/- 1.7 mg/day. This net rate is equivalent to the net rate of DHA consumption by brain and, considering the reported amount of DHA in brain, indicates that the half-life of DHA in the human brain approximates 2.5 years. Thus, PET with [1-(11)C]DHA can be used to quantify regional and global human brain DHA metabolism in relation to health and disease.
Asunto(s)
Encéfalo/metabolismo , Ácidos Docosahexaenoicos/metabolismo , Tomografía de Emisión de Positrones/métodos , Adulto , Animales , Encéfalo/anatomía & histología , Mapeo Encefálico , Radioisótopos de Carbono/metabolismo , Ácidos Docosahexaenoicos/química , Femenino , Haplorrinos , Humanos , Masculino , Persona de Mediana Edad , Radiofármacos/metabolismo , Flujo Sanguíneo Regional , Distribución Tisular , Adulto JovenRESUMEN
The extent to which the adult brain can derive some of its arachidonic acid (AA) through internalized synthesis from linoleic acid (LA) is uncertain. Thus, we determined for plasma-derived LA in vivo rates for brain incorporation, beta-oxidation, and conversion to AA. Adult male unanesthetized rats, reared on a diet enriched in LA but low in AA, were infused intravenously for 5 min with [1-(14)C]LA. Timed arterial samples were collected until the animals were killed at 5 min and the brain was removed after microwaving. Within plasma lipids, >96% of radioactivity was in the form of unchanged [1-(14)C]LA, but [(14)C]AA was insignificant (<0.2%). Eighty-six percent of brain radioactivity at 5 min was present as beta-oxidation products, whereas the remainder was mainly in 'stable' phospholipid or triglyceride as LA or AA (11 and <1%, respectively). Unesterified unlabeled LA rapidly enters brain from plasma, but its incorporation into brain total phospholipid and triglyceride, in the form of synthesized AA, is <1% of the amount that enters the brain. Thus, in rats fed even a diet containing low amounts of AA, the LA that enters brain is largely beta-oxidized, and is not a major source of AA in brain.
Asunto(s)
Ácido Araquidónico/metabolismo , Encéfalo/metabolismo , Ácido Linoleico/metabolismo , Animales , Ácido Araquidónico/sangre , Radioisótopos de Carbono/química , Dieta , Ácido Linoleico/sangre , Masculino , Fosfolípidos/sangre , Fosfolípidos/metabolismo , Ratas , Ratas Endogámicas F344RESUMEN
BACKGROUND: Valproic acid (VPA), used for treating bipolar disorder (BD), is teratogenic by inhibiting histone deacetylase. In unanaesthetized rats, chronic VPA, like other mood stabilizers, reduces arachidonic acid (AA) turnover in brain phospholipids, and inhibits AA activation to AA-CoA by recombinant acyl-CoA synthetase-4 (Acsl-4) in vitro. Valnoctamide (VCD), a non-teratogenic constitutional isomer of VPA amide, reported effective in BD, also inhibits recombinant Acsl-4 in vitro. HYPOTHESIS: VCD like VPA will reduce brain AA turnover in unanaesthetized rats. METHODS: A therapeutically relevant (50mg/kg i.p.) dose of VCD or vehicle was administered daily for 30 days to male rats. AA turnover and related parameters were determined using our kinetic model, following intravenous [1-14C]AA in unanaesthetized rats for 10min, and measuring labeled and unlabeled lipids in plasma and high-energy microwaved brain. RESULTS: VCD, compared with vehicle, increased λ, the ratio of brain AA-CoA to unesterified plasma AA specific activities; and decreased turnover of AA in individual and total brain phospholipids. CONCLUSIONS: VCD's ability like VPA to reduce rat brain AA turnover and inhibit recombinant Acsl-4, and its efficacy in BD, suggest that VCD be further considered as a non-teratogenic VPA substitute for treating BD.
Asunto(s)
Amidas/farmacología , Antimaníacos/farmacología , Ácido Araquidónico/antagonistas & inhibidores , Trastorno Bipolar/tratamiento farmacológico , Encéfalo/efectos de los fármacos , Animales , Masculino , Fosfolípidos/metabolismo , RatasRESUMEN
UNLABELLED: PET with 11C-arachidonic acid (AA) can be used to quantify neural signaling related to phospholipase A2 (PLA2). Animal studies suggest reduction in the activity of this signaling system with age. The aim of this study was to evaluate the effect of healthy aging on brain incorporation of 11C-AA, before and after partial-volume correction (PVC). METHODS: Absolute measurements of cerebral blood flow (CBF) were obtained in 8 young and 7 old healthy subjects (mean age +/- SD, 27 +/- 5 y and 65 +/- 9 y) with bolus injection of 15O-water. About 15 min later, dynamic 60-min 3-dimensional scans were acquired after the injection of 11C-AA. Radioactivity frames of 11C-AA were corrected for head motion and registered to magnetic resonance (MR) images. A 3-segment (3S) and a 2-segment (2S) PVC was applied pixel-by-pixel to the activity frames. For the 3S method, the white matter value was estimated using a new automatic method by extrapolating the activity values of pixels with white matter membership > 0.99. Parametric images of the brain incorporation rate of 11C-AA (K*) and cerebral blood volume (Vb), as well as CBF, were generated and regional gray matter values were obtained. RESULTS: Among cortical areas, there were no significant differences (uncorrected P < 0.05) in K* or Vb absolute values between young and old subjects before or after PVC. A significant reduction of CBF was detected in the frontal cortex of the elderly group. After normalization to the global gray average, K*, Vb, and CBF values revealed significant reductions in the frontal lobe of old subjects; none of these differences were significant after PVC. CONCLUSION: These results confirm previous PET findings that brain function at rest is minimally affected by healthy aging. Proper PVC methodology is of critical importance in accurate quantitative assessment of PET physiologic measures.
Asunto(s)
Envejecimiento/fisiología , Ácido Araquidónico/farmacocinética , Mapeo Encefálico/métodos , Encéfalo/diagnóstico por imagen , Encéfalo/fisiología , Circulación Cerebrovascular , Interpretación de Imagen Asistida por Computador/métodos , Fosfolipasas A/metabolismo , Adulto , Anciano , Algoritmos , Velocidad del Flujo Sanguíneo , Determinación del Volumen Sanguíneo/métodos , Encéfalo/irrigación sanguínea , Radioisótopos de Carbono , Humanos , Masculino , Modelos Biológicos , Fosfolipasas A2 , Cintigrafía , Radiofármacos/farmacocinética , Valores de ReferenciaRESUMEN
Fetal and perinatal exposure to selective serotonin (5-HT) reuptake inhibitors (SSRIs) has been reported to alter childhood behavior, while transient early exposure in rodents is reported to alter their behavior and decrease brain extracellular 5-HT in adulthood. Since 5-HT2A/2C receptor-mediated neurotransmission can involve G-protein coupled activation of cytosolic phospholipase A2 (cPLA2), releasing arachidonic acid (ARA) from synaptic membrane phospholipid, we hypothesized that transient postnatal exposure to fluoxetine would alter brain ARA metabolism in adult mice. Brain ARA incorporation coefficients k* and rates Jin were quantitatively imaged following intravenous [1-(14)C]ARA infusion of unanesthetized adult mice that had been injected daily with fluoxetine (10mg/kg i.p.) or saline during postnatal days P4-P21. Expression of brain ARA metabolic enzymes and other relevant markers also was measured. On neuroimaging, k* and Jin was decreased widely in early fluoxetine- compared to saline-treated adult mice. Of the enzymes measured, cPLA2 activity was unchanged, while Ca(2+)-independent iPLA2 activity was increased. There was a significant 74% reduced protein level of cytochrome P450 (CYP) 4A, which can convert ARA to 20-HETE. Reduced brain ARA metabolism in adult mice transiently exposed to postnatal fluoxetine, and a 74% reduction in CYP4A protein, suggest long-term effects independent of drug presence in brain ARA metabolism, and in CYP4A metabolites. These changes might contribute to reported altered behavior following early SSRI in rodents.
Asunto(s)
Ácido Araquidónico/metabolismo , Citocromo P-450 CYP4A/metabolismo , Fluoxetina/efectos adversos , Proteínas del Tejido Nervioso/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/efectos adversos , Transmisión Sináptica/efectos de los fármacos , Animales , Conducta Animal/efectos de los fármacos , Calcio/metabolismo , Señalización del Calcio/efectos de los fármacos , Citocromo P-450 CYP4A/antagonistas & inhibidores , Fluoxetina/farmacología , Masculino , Ratones , Inhibidores Selectivos de la Recaptación de Serotonina/farmacologíaRESUMEN
Eicosapentaenoic acid (EPA, 20:5n-3), a precursor of docosahexaenoic acid (DHA), may benefit cardiovascular and brain health. Quantifying EPA's in vivo kinetics might elucidate these effects. [1-(14)C]EPA was infused i.v. for 5min in unanesthetized male rats fed a standard EPA-DHA diet. Plasma and microwaved tissue were analyzed. Kinetic parameters were calculated using our compartmental model. At 5min, 31-48% of labeled EPA in brain and heart was oxidized, 7% in liver. EPA incorporation rates from brain and liver precursor EPA-CoA pools into lipids, mainly phospholipids, were 36 and 2529nmol/s/g×10(-4), insignificant for heart. Deacylation-reacylation half-lives were 22h and 38-128min. Conversion rates to DHA equaled 0.65 and 25.1nmol/s/g×10(-4), respectively. The low brain concentration and incorporation rate and high oxidation of EPA suggest that, if EPA has a beneficial effect in brain, it might result from its suppression of peripheral inflammation and hepatic conversion to bioactive DHA.
Asunto(s)
Encéfalo/metabolismo , Ácido Eicosapentaenoico/farmacocinética , Ácidos Grasos Omega-3/administración & dosificación , Hígado/metabolismo , Miocardio/metabolismo , Acilcoenzima A/análisis , Animales , Química Encefálica , Radioisótopos de Carbono , Ácidos Docosahexaenoicos/administración & dosificación , Ácidos Docosahexaenoicos/metabolismo , Ácido Eicosapentaenoico/análisis , Ácido Eicosapentaenoico/sangre , Semivida , Cinética , Hígado/química , Masculino , Miocardio/química , Oxidación-Reducción , Ratas , Ratas Endogámicas F344RESUMEN
Docosahexaenoic acid (DHA, 22:6n-3), an n-3 polyunsaturated fatty acid (PUFA) found at high concentrations in brain and retina and critical to their function, can be obtained from fish products or be synthesized from circulating α-linolenic acid (α-LNA, 18:3n-3) mainly in the liver. With aging, liver synthetic enzymes are reported reduced or unchanged in the rat. To test whether liver synthesis-secretion of DHA from α-LNA changes with age, we measured whole-body DHA conversion coefficients and rates in unanesthetized adult male Fischer-344 rats aged 10, 20, or 30 months, fed an eicosapentaenoic acid (EPA, 20:5n-3)- and DHA-containing diet. Unesterified [U- (13) C]α-LNA bound to albumin was infused intravenously for 2 h, while [(13) C]-esterified n-3 PUFAs were measured in arterial plasma, as were unlabeled unesterified and esterified PUFA concentrations. Plasma unesterified n-3 PUFA concentrations declined with age, but esterified n-3 PUFA concentrations did not change significantly. Calculated conversion coefficients were not changed significantly with age, whereas synthesis-secretion rates (product of conversion coefficient and unesterified plasma α-LNA concentration) of esterified DHA and n-3 DPA were reduced. Turnovers of esterified n-3 PUFAs in plasma decreased with age, whereas half-lives increased. The results suggest that hepatic capacity to synthesize DHA and other n-3 PUFAs from circulating α-LNA is maintained with age in the rat, but that reduced plasma α-LNA availability reduces net synthesis-secretion. As unesterified plasma DHA is the form that is incorporated preferentially into brain phospholipid, its reduced synthesis may be deleterious to brain function in aged rats.
Asunto(s)
Envejecimiento/metabolismo , Ácidos Docosahexaenoicos/biosíntesis , Ácidos Docosahexaenoicos/metabolismo , Hígado/metabolismo , Ácido alfa-Linolénico/sangre , Animales , Estudios de Seguimiento , Masculino , Ratas , Ratas Endogámicas F344RESUMEN
BACKGROUND: Disturbances in prefrontal cortex phospholipid and fatty acid composition have been reported in patients with schizophrenia (SCZ), often as an incomplete lipid profile or a percent of total lipid concentration. In this study, we quantified absolute concentrations (nmol/g wet weight) and fractional concentrations (i.e. percent of total fatty acids) of several lipid classes and their constituent fatty acids in postmortem prefrontal cortex of SCZ patients (n = 10) and age-matched controls (n = 10). METHODS: Lipids were extracted, fractionated with thin layer chromatography and assayed. RESULTS: Mean total lipid, phospholipid, individual phospholipids, plasmalogen, triglyceride and cholesteryl ester concentrations did not differ significantly between the groups. Compared to controls, SCZ brains showed significant increases in several monounsaturated and polyunsaturated fatty acid absolute concentrations in cholesteryl ester. Significant increases or decreases occurred in palmitoleic, linoleic, γ-linolenic and n-3 docosapentaenoic acid absolute concentrations in total lipids, triglycerides or phospholipids. Changes in fractional concentrations did not consistently reflect absolute concentration changes. CONCLUSION: These findings suggest disturbed prefrontal cortex fatty acid absolute concentrations, particularly within cholesteryl esters, as a pathological aspect of schizophrenia.
Asunto(s)
Ácidos Grasos/metabolismo , Corteza Prefrontal/metabolismo , Esquizofrenia/patología , Adulto , Anciano , Ésteres del Colesterol/metabolismo , Cromatografía en Capa Delgada , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fosfolípidos/metabolismo , Plasmalógenos/metabolismo , Cambios Post Mortem , Triglicéridos/metabolismoRESUMEN
OBJECTIVE: Chronic alcohol dependence has been associated with disturbed behavior, cerebral atrophy and a low plasma concentration of docosahexaenoic acid (DHA, 22â¶6n-3), particularly if liver disease is present. In animal models, excessive alcohol consumption is reported to reduce brain DHA concentration, suggesting disturbed brain DHA metabolism. We hypothesized that brain DHA metabolism also is abnormal in chronic alcoholics. METHODS: We compared 15 non-smoking chronic alcoholics, studied within 7 days of their last drink, with 22 non-smoking healthy controls. Using published neuroimaging methods with positron emission tomography (PET), we measured regional coefficients (K*) and rates (J(in)) of DHA incorporation from plasma into the brain of each group using [1-(11)C]DHA, and regional cerebral blood flow (rCBF) using [(15)O]water. Data were partial volume error corrected for brain atrophy. Plasma unesterified DHA concentration also was quantified. RESULTS: Mean K* for DHA was significantly and widely elevated by 10-20%, and rCBF was elevated by 7%-34%, in alcoholics compared with controls. Unesterified plasma DHA did not differ significantly between groups nor did whole brain J(in), the product of K* and unesterified plasma DHA concentration. DISCUSSION: Significantly higher values of K* for DHA in alcoholics indicate increased brain avidity for DHA, thus a brain DHA metabolic deficit vis-à-vis plasma DHA availability. Higher rCBF in alcoholics suggests increased energy consumption. These changes may reflect a hypermetabolic state related to early alcohol withdrawal, or a general brain metabolic change in chronic alcoholics.
Asunto(s)
Alcohólicos , Encéfalo/metabolismo , Encéfalo/patología , Circulación Cerebrovascular , Ácidos Docosahexaenoicos/metabolismo , Procesamiento de Imagen Asistido por Computador , Tomografía de Emisión de Positrones , Adulto , Anciano , Atrofia , Encéfalo/irrigación sanguínea , Encéfalo/diagnóstico por imagen , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de Tiempo , Adulto JovenRESUMEN
HIV-1 transgenic (Tg) rats, a model for human HIV-1 associated neurocognitive disorder (HAND), show upregulated markers of brain arachidonic acid (AA) metabolism with neuroinflammation after 7 months of age. Since lithium decreases AA metabolism in a rat lipopolysaccharide model of neuroinflammation, and may be useful in HAND, we hypothesized that lithium would dampen upregulated brain AA metabolism in HIV-1 Tg rats. Regional brain AA incorporation coefficients k* and rates J ( in ), markers of AA signaling and metabolism, were measured in 81 brain regions using quantitative autoradiography, after intravenous [1-(14) C]AA infusion in unanesthetized 10-month-old HIV-1 Tg and age-matched wildtype rats that had been fed a control or LiCl diet for 6 weeks. k* and J ( in ) for AA were significantly higher in HIV-1 Tg than wildtype rats fed the control diet. Lithium feeding reduced plasma unesterified AA concentration in both groups and J ( in ) in wildtype rats, and blocked increments in k* (19 of 54 regions) and J ( in ) (77 of 81 regions) in HIV-1 Tg rats. These in vivo neuroimaging data indicate that lithium treatment dampened upregulated brain AA metabolism in HIV-1 Tg rats. Lithium may improve cognitive dysfunction and be neuroprotective in HIV-1 patients with HAND through a comparable effect.