Brain Phospholipids Research Articles

Phospholipid class-specific brain enrichment in response to lysophosphatidylcholine docosahexaenoic acid infusion

Recent studies suggest that at least two pools of plasma docosahexaenoic acid (DHA) can supply the brain: non-esterified DHA (NE-DHA) and lysophosphatidylcholine (lysoPtdCho)-DHA. In contrast to NE-DHA, brain uptake of lysoPtdCho-DHA appears to be mediated by a specific transporter, but whether both forms of DHA supply undergo the same metabolic fate, particularly with regards to enrichment of specific phospholipid (PL) subclasses, remains to be determined. This study aimed to evaluate brain uptake of NE-DHA and lysoPtdCho-DHA into brain PL classes. Fifteen-week-old rats were infused intravenously with radiolabelled NE-14C-DHA or lysoPtdCho-14C-DHA (n=4/group) over five mins to achieve a steady-state plasma level. PLs were extracted from the brain and separated by thin layer chromatography and radioactivity was quantified by liquid scintillation counting. The net rate of entry of lysoPtdCho-DHA into the brain was between 59% and 86% lower than the net rate of entry of NE-DHA, depending on the PL class. The proportion of total PL radioactivity in the lysoPtdCho-14C-DHA group compared to the NE-14C-DHA group was significantly higher in choline glycerophospholipids (ChoGpl) (48% vs 28%, respectively) but lower in ethanolamine glycerophospholipids (EtnGpl) (32% vs 46%, respectively). In both groups, radioactivity was disproportionally high in phosphatidylinositol and ChoGpl but low in phosphatidylserine and EtnGpl compared to the corresponding DHA pool size. This suggests that DHA undergoes extensive PL remodeling after entry into the brain.

The medical food Souvenaid affects brain phospholipid metabolism in mild Alzheimer\u2019s disease: results from a randomized controlled trial

BackgroundSynaptic dysfunction contributes to cognitive impairment in Alzheimer’s disease and may be countered by increased intake of nutrients that target brain phospholipid metabolism. In this study, we explored whether the medical food Souvenaid affects brain phospholipid metabolism in patients with Alzheimer’s disease.MethodsThirty-four drug-naive patients with mild Alzheimer’s disease (Mini Mental State Examination score ≥20) were enrolled in this exploratory, double-blind, randomized controlled study. Before and after 4-week intervention with Souvenaid or an isocaloric control product, phosphorus and proton magnetic resonance spectroscopy (MRS) was performed to assess surrogate measures of phospholipid synthesis and breakdown (phosphomonoesters [PME] and phosphodiesters [PDEs]), neural integrity (N-acetyl aspartate), gliosis (myo-inositol), and choline metabolism (choline-containing compounds [tCho]). The main outcome parameters were PME and PDE signal intensities and the PME/PDE ratio.ResultsMRS data from 33 patients (60–86 years old; 42% males; Souvenaid arm n = 16; control arm n = 17) were analyzed. PME/PDE and tCho were higher after 4 weeks of Souvenaid compared with control (PME/PDE least squares [LS] mean difference [95% CI] 0.18 [0.06–0.30], p = 0.005; tCho LS mean difference [95% CI] 0.01 [0.00–0.02], p = 0.019). No significant differences were observed in the other MRS outcome parameters.ConclusionsMRS reveals that Souvenaid affects brain phospholipid metabolism in mild Alzheimer’s disease, in line with findings in preclinical studies.Trial registrationNetherlands Trial Register, NTR3346. Registered on 13 March 2012.

Synaptic Membrane Synthesis in Rats Depends on Dietary Sufficiency of Vitamin C, Vitamin E, and Selenium: Relevance for Alzheimer's Disease.

Chronic consumption of a diet enriched with nutritional precursors of phospholipids, including uridine and the polyunsaturated fatty acids, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), was shown previously to enhance levels of brain phospholipids and synaptic proteins in rodents. Vitamin C, vitamin E, and selenium may directly affect the breakdown or synthesis of membrane phospholipids. The present study investigated the necessity of antioxidants for the effectiveness of supplementation with uridine plus DHA and EPA (as fish oil) in rats. Rats were randomized to four treatment groups and received, for 6 weeks, one of four experimental diets, i.e., a diet low in antioxidants, a diet high in antioxidants, a diet low in antioxidants supplemented with DHA+EPA+uridine, or a diet high in antioxidants supplemented with DHA+EPA+uridine. On completion of dietary treatment, rats were sacrificed, and brain levels of phospholipids, synaptic proteins, and two enzymes involved in phospholipid synthesis (choline-phosphate cytidylyltransferase, PCYT1A, and choline/ethanolamine phosphotransferase, CEPT1) were analyzed. Levels of phospholipids, the pre- and post-synaptic proteins Synapsin-1 and PSD95, and the enzymes PCYT1A and CEPT1 were significantly enhanced by combined supplementation of DHA+EPA+uridine and antioxidants and not enhanced by supplementation of DHA+EPA+uridine with insufficient antioxidant levels. Our data suggest that dietary vitamin C, vitamin E, and selenium are essential for the phospholipid precursors’ effects on increasing levels of membrane phospholipids and synaptic proteins, the indirect indicators of synaptogenesis. Their concomitant supply may be relevant in Alzheimer’s disease patients, because the disease is characterized by synapse loss and lower plasma and brain levels of phospholipid precursors and antioxidants.

Chronic sucrose intake decreases concentrations of n6 fatty acids, but not docosahexaenoic acid in the rat brain phospholipids.

We investigated the influence of high sucrose intake, administered in drinking water, on the lipid profile of the brain and on the expression of SREBP1c and Δ-desaturase genes. Adult male rats received 30% sucrose solution for 20 weeks (Sucrose group), or plain water (Control group). After the 20th week of sucrose treatment, the Sucrose group showed permanent hyperglycemia. Sucrose treatment also increased the amount of total lipids and fatty acids in the brain. The brain fatty acid profile of total lipids as well as phosphatidylethanolamine, phosphatidylcholine and cardiolipin of the Sucrose group was extensively changed. The most interesting change was a significant decrease in n6 fatty acids, including the important arachidonic acid, whereas the content of oleic and docosahexaenoic acid remained unchanged. RT-qPCR revealed an increase in Δ-5-desaturase and SREBP1c gene expression. In conclusion, high sucrose intake via drinking water extensively changes rat brain fatty acid profile by decreasing n6 fatty acids, including arachidonic acid. In contrast, the content of docosahexaenoic acid remains constant in the brain total lipids as well as in phospholipids. Changes in the brain fatty acid profile reflect changes in the lipid metabolism of the rat lipogenic tissues and concentrations in the circulation.

Valnoctamide, which reduces rat brain arachidonic acid turnover, is a potential non-teratogenic valproate substitute to treat bipolar disorder

BackgroundValproic 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. HypothesisVCD like VPA will reduce brain AA turnover in unanaesthetized rats. MethodsA 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. ResultsVCD, 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. ConclusionsVCD'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.

Retraction note to: Chronic fluoxetine increases cytosolic phospholipase A2 activity and arachidonic acid turnover in brain phospholipids of the unanesthetized rat.

Retraction note to: Chronic fluoxetine increases cytosolic phospholipase A2 activity and arachidonic acid turnover in brain phospholipids of the unanesthetized rat.

The influence of sex and gonadectomy on hepatic and brain fatty acid composition, lipogenesis and β-oxidation.

The aim of this study was to investigate the influence of sex and castration of rats on liver and brain fatty acid profile and liver mRNA expression of genes involved in lipogenesis and β-oxidation. Castration significantly increased body weight and liver index and decreased serum triglyceride content in the female rats. The fatty acid composition of the liver tissue was influenced by sex and castration. Male rats had higher content of C16:0, C18:1n7, C18:2n6 and C22:5n3, while female rats had higher content of C18:0, C20:4n6 and C22:6n3. Castration of male rats decreased differences caused by sex for C18:2n6, C20:4n6 and C22:6n3. Values for C16:1n7 were higher in the castrated male rats in comparison with all other groups. Liver phospholipids showed a distribution of fatty acids similar to the total lipids. Brain total lipids and phospholipids were not influenced by sex or castration. Castration increased ∆6D gene expression in both the sexes, while ∆5D and ∆9D increased in females and males respectively. Gonadectomy increased expression of the FASN gene in the females and decreased CPT1 and ACOX1 gene expression in the liver tissue of male rats. The observed results of lipid peroxidation, measured by TBARS, were the lowest in the intact females in comparison with all other groups. In conclusion, sex strongly influences both SFA and PUFA in liver tissue, and castration decreases these differences only for PUFA. Castration also influences the expression of the genes involved in lipid metabolism differently in male and female rats, with an increase in lipogenic genes in female rats and a decrease in key genes for mitochondrial and peroxisomal β-oxidation in male rats.

Fatty acid composition of total lipids and phospholipids of muscular tissue and brain of rats under the impact of vibration

Жирні кислоти є важливими структурними компонентами біологічних мембран, енергетичним субстратом клітини, беруть участь у фіксації білків фосфоліпідного бішару, а також виконують роль регуляторів і модуляторів ферментативної активності. Під дією вібраційних коливань можуть виникати зрушення у співвідношенні різних груп жирних кислот, змінюватися ступені їхньої ненасиченості. Дисбаланс між насиченими, мононенасиченими та поліненасиченими жирними кислотами, який виникає надалі у клітинній стінці, порушує плинність і в’язкість ліпідної фази та спричиняє порушення клітинного метаболізму. Мета роботи – вивчити вплив вібраційних коливань на рівень жирних кислот загальних ліпідів м’язової тканини та жирнокислотного складу фосфоліпідів м’язів і головного мозку експериментальних тварин, які піддавалися впливу вертикальних вібраційних коливань із різною частотою протягом 28 днів. Матеріали та методи. Фрагменти тканин чотириголового м’яза стегна та головного мозку щурів використовували для отримання метилових ефірів жирних кислот, що досліджували методом газорідинної хроматографії. Результати. Встановили, що вміст ліпідів, співвідношення їхніх окремих фракцій та жирнокислотний склад у м’язовій тканині та мозку тварин під час дії вібраційних коливань істотно змінюються. Зі збільшенням віброприскорення спостерігається тенденція до збільшення абсолютної кількості жирних кислот загальних ліпідів шляхом зростання рівня насичених і мононенасичених. Ці процеси зумовлені активацією механізмів самозахисту організму за умов відхилень від стабілізованої фізіологічної норми, оскільки адаптація вимагає від організму певних структурно-енергетичних витрат. Прослідковується збільшення відносної кількості насичених і мононенасичених жирних кислот у фосфоліпідах м’язів, головного мозку й одночасне зниження концентрації поліненасичених жирних кислот. Висновки. Зміни служать свідченням про погіршення структурно-функціональної організації клітинних мембран м’язів і головного мозку щурів унаслідок збільшення в’язкості ліпідів, зміни їхньої внутрішньомембранної динаміки.

A Postnatal Diet Containing Phospholipids, Processed to Yield Large, Phospholipid-Coated Lipid Droplets, Affects Specific Cognitive Behaviors in Healthy Male Mice

Background: Infant cognitive development can be positively influenced by breastfeeding rather than formula feeding. The composition of breast milk, especially lipid quality, and the duration of breastfeeding have been linked to this effect.Objective: We investigated whether the physical properties and composition of lipid droplets in milk may contribute to cognitive development.Methods: From postnatal day (P) 16 to P44, healthy male C57BL/6JOlaHsd mice were fed either a control or a concept rodent diet, in which the dietary lipid droplets were large and coated with milk phospholipids, resembling more closely the physical properties and composition of breast milk lipids. Thereafter, all mice were fed an AIN-93M semisynthetic rodent diet. The mice were subjected to various cognitive tests during adolescence (P35–P44) and adulthood (P70–P101). On P102, mice were killed and brain phospholipids were analyzed.Results: The concept diet improved performance in short-term memory tasks that rely on novelty exploration during adolescence (T-maze; spontaneous alternation 87% in concept-fed mice compared with 74% in mice fed control diet; P < 0.05) and adulthood (novel object recognition; preference index 0.48 in concept-fed mice compared with 0.05 in control-fed mice; P < 0.05). Cognitive performance in long-term memory tasks, however, was unaffected by diet. Brain phospholipid composition at P102 was not different between diet groups.Conclusions: Exposure to a diet with lipids mimicking more closely the structure and composition of lipids in breast milk improved specific cognitive behaviors in mice. These data suggest that lipid structure should be considered as a relevant target to improve dietary lipid quality in infant milk formulas.

Fatty acid desaturase 1 knockout mice are lean with improved glycemic control and decreased development of atheromatous plaque.

Delta-5 desaturase (D5D) and delta-6 desaturase (D6D), encoded by fatty acid desaturase 1 (FADS1) and FADS2 genes, respectively, are enzymes in the synthetic pathways for ω3, ω6, and ω9 polyunsaturated fatty acids (PUFAs). Although PUFAs appear to be involved in mammalian metabolic pathways, the physiologic effect of isolated D5D deficiency on these pathways is unclear. After generating >4,650 knockouts (KOs) of independent mouse genes and analyzing them in our high-throughput phenotypic screen, we found that Fads1 KO mice were among the leanest of 3,651 chow-fed KO lines analyzed for body composition and were among the most glucose tolerant of 2,489 high-fat-diet-fed KO lines analyzed by oral glucose tolerance test. In confirmatory studies, chow- or high-fat-diet-fed Fads1 KO mice were leaner than wild-type (WT) littermates; when data from multiple cohorts of adult mice were combined, body fat was 38% and 31% lower in Fads1 male and female KO mice, respectively. Fads1 KO mice also had lower glucose and insulin excursions during oral glucose tolerance tests along with lower fasting glucose, insulin, triglyceride, and total cholesterol levels. In additional studies using a vascular injury model, Fads1 KO mice had significantly decreased femoral artery intima/media ratios consistent with a decreased inflammatory response in their arterial wall. Based on this result, we bred Fads1 KO and WT mice onto an ApoE KO background and fed them a Western diet for 14 weeks; in this atherogenic environment, aortic trees of Fads1 KO mice had 40% less atheromatous plaque compared to WT littermates. Importantly, PUFA levels measured in brain and liver phospholipid fractions of Fads1 KO mice were consistent with decreased D5D activity and normal D6D activity. The beneficial metabolic phenotype demonstrated in Fads1 KO mice suggests that selective D5D inhibitors may be useful in the treatment of human obesity, diabetes, and atherosclerotic cardiovascular disease.

Enzymology of Pyrimidine Metabolism and Neurodegeneration.

It is well known that disorders of pyrimidine pathways may lead to neurological, hematological, immunological diseases, renal impairments, and association with malignancies. Nucleotide homeostasis depends on the three stages of pyrimidine metabolism: de novo synthesis, catabolism and recycling of these metabolites. Cytidine and uridine, in addition to be used as substrates for pyrimidine nucleotide salvaging, also act as the precursors of cytidine triphosphate used in the biosynthetic pathway of both brain's phosphatidylcholine and phosphatidylethanolamine via the Kennedy cycle. The synthesis in the brain of phosphatidylcholine and other membrane phosphatides can utilize, in addition to glucose, three compounds present in the blood stream: choline, uridine, and a polyunsaturated fatty acids like docosahexaenoic acid. Some authors, using rat models, found that oral administration of two phospholipid precursors such as uridine and omega-3 fatty acids, along with choline from the diet, can increase the amount of synaptic membrane generated by surviving striatal neurons in rats with induced Parkinson's disease. Other authors found that in hypertensive rat fed with uridine and choline, cognitive deficit resulted improved. Uridine has also been recently considered as a neuroactive molecule, because of its involvement in important neurological functions by improving memory, sleep disorders, anti-epileptic effects, as well as neuronal plasticity. Cytidine and uridine are uptaken by the brain via specific receptors and successively salvaged to the corresponding nucleotides. The present review is devoted to the enzymology of pyrimidine pathways whose importance has attracted the attention of several researchers investigating on the mechanisms underlying the physiopathology of brain.

Abstract 400: Determining the Contribution of Endothelial Lipase-mediated Lipolysis to Brain Phospholipid Metabolism

Polyunsaturated fatty acids (PUFA) are essential constituents of the cell membrane. Brain PUFA content is critical for synaptic function and neuroinflammation and PUFA deficiency may underlie several neurological disorders. Prior work in murine models has showed that the predominant source of central nervous system (CNS) PUFAs is 2-acyl-lysophophatidylcholine (2-lysoPC), a class of phospholipids (PLs) circulating on blood lipoproteins that is formed from the enzymatic activity of phospholipases. Endothelial lipase (EL) is a phospholipase that is a critical determinant of HDL metabolism in humans and the predominant generator of 2-lysoPC on HDL particles. While the contribution of EL to circulating HDL metabolism is well-established, its contribution to CNS fatty acid availability and brain function has not been explored. In order to investigate the physiological contribution of EL to brain FA availability in vivo, we studied PL-derived PUFA uptake in mice with EL deficiency. We adopted a method for measuring EL activity using a fluorescent synthetic HDL particle containing sn2-TopFluor-PC, a fluorescent precursor of 2-lysoPC and demonstrated its utility in vitro. Next, we tested the clearance of this synthetic HDL-derived 2-lysoPC in C57BL/6 (WT) vs EL KO mice (n=12/group). Circulating plasma 2-lysoPC clearance was significantly impaired in in EL KO mice (-32%, p=0.024) and was accompanied by a slower remodeling of the HDL particles. Measurement of labeled PL content in tissues showed a significant reduction in hepatic uptake in KO mice (22% decrease, p=0.002). No significant differences were observed in total brain PL uptake, but the distribution of PL uptake differed between WT and KOs. Ongoing studies are evaluating the physiological consequences of reduced circulating 2-lysoPC clearance, reduced hepatic uptake, and altered distribution of brain PL uptake in EL KO mice. Collectively, our data demonstrate that EL is a key physiological regulator of systemic PL catabolism.

Comparative efficacy and safety of antidepressive mono- and multimodal therapy with citicoline in elderly patients with depression in psychogeriatric unit

IntroductionCiticoline is a choline donor involved in the biosynthesis of brain phospholipids and acetylcholine, used for treating neurodegenerative disorders. Several studies have shown its beneficial effects both in degenerative and vascular cognitive decline. Due to its effects on the adrenergic and dopaminergic CNS activity, citicoline can also be used as an adjuvant in depression treatment.Objectives and aimsComparative evaluation of efficacy and safety of a multimodal antidepressive therapy with ceraxone (citicoline) plus one of the antidepressants (venlafaxine, agomelatine, or fluvoxamine) and monotherapy with the same antidepressant for the treatment of depression in the elderly. Two groups of patients were included in the study (21 patients in each group) aged from 60 to 79 years old, comparable to the main clinical characteristics.MethodsFirst group patients were treated with a single antidepressant, patients of the second group – with the same antidepressant and intravenous infusions of ceraxone: 10 infusions (500 mg in 100 mL isotonic sodium chloride solution) during 2 weeks, followed by transfer to the drug in solution at 3 mL per os two times a day for six weeks.ResultsA multimodal therapy with ceraxone leads to more rapid and significant therapeutic response along with the reduction of adverse events compared to antidepressant monotherapy.ConclusionObtained data allows to recommend a multimodal antidepressive therapy with ceraxone (citicoline) for the treatment of elderly depressive patients to reduce the risk of adverse effects of antidepressants and to shorten hospitalization period.Disclosure of interestThe authors have not supplied their declaration of competing interest.

The effect of Souvenaid on brain phospholipid metabolism in patients with mild Alzheimer’s disease: results of a randomised controlled 31P-Magnetic Resonance Spectroscopy study

The effect of Souvenaid on brain phospholipid metabolism in patients with mild Alzheimer’s disease: results of a randomised controlled 31P-Magnetic Resonance Spectroscopy study

Alteration of mitochondrial phospholipid due to the PLA2 activation in rat brains under cadmium toxicity.

Cadmium (Cd) is a heavy metal that has received considerable environmental and occupational concern. Cd causes toxic effects due to its accumulation in a variety of tissues, including the kidney, liver and the nervous system (CNS); however, the exact mechanism is poorly understood. In the present study, we tried to explore the impact of acute cadmium exposure on rat brain phospholipids (PLs). Cd exposure significantly reduced PLs in a time dependent manner and the reduction was due to the activation of the Phospholipase A2 enzymes (sPLA2, cPLA2). The release of arachidonic acid from PLs increased during inflammatory conditions by PLA2s. The mRNA expression of cyclooxygenase2 (COX2) and subsequently the pro-inflammatory cytokines, namely, Interleukin 1 (IL-1) and IL-6, were up regulated; however, the expression of anti-inflammatory cytokine IL-10 was reduced in a time dependent manner. The expression of the Tumor necrosis factor alpha (TNF-α), Inducible nitric oxide synthase (iNOS) and Interferon gamma (INF-γ) also experienced increases in the expression. Likewise the mRNA expression of the pro-apoptotic factor, Bcl-2-associated X protein (Bax), was elevated, whereas anti-apoptosis B-cell lymphoma 2 (Bcl2) was down regulated. This present study might help to decipher the effects of cadmium toxicity on rat brain.

Threshold changes in rat brain docosahexaenoic acid incorporation and concentration following graded reductions in dietary alpha-linolenic acid

BackgroundThis study tested the dietary level of alpha-linolenic acid (α-LNA, 18:3n-3) required to maintain brain 14C-Docosahexaenoic acid (DHA, 22:6n-3) metabolism and concentration following graded α-LNA reduction. MethodsFischer-344 (CDF) male rat pups (18–21 days old) were randomized to the AIN-93G diet containing as a % of total fatty acids, 4.6% (“n-3 adequate”), 3.6%, 2.7%, 0.9% or 0.2% (“n-3 deficient”) α-LNA for 15 weeks. Rats were intravenously infused with 14C-DHA to steady state for 5min, serial blood samples collected to obtain plasma, and brains excised following microwave fixation. Labeled and unlabeled DHA concentrations were measured in plasma and brain to calculate the incorporation coefficient, k*, and incorporation rate, Jin. ResultsCompared to 4.6% α-LNA controls, k* was significantly increased in ethanolamine glycerophospholipids in the 0.2% α-LNA group. Circulating unesterified DHA and brain incorporation rates (Jin) were significantly reduced at 0.2% α-LNA. Brain total lipid and phospholipid DHA concentrations were reduced at or below 0.9% α-LNA. ConclusionThreshold changes for brain DHA metabolism and concentration were maintained at or below 0.9% dietary α-LNA, suggesting the presence of homeostatic mechanisms to maintain brain DHA metabolism when dietary α-LNA intake is low.

Differential Sphingolipid and Phospholipid Profiles in Alcohol and Nicotine-Derived Nitrosamine Ketone-Associated White Matter Degeneration.

Alcohol-mediated neurodegeneration is associated with white matter (WM) atrophy due to targeting of myelin and oligodendrocytes. However, variability in disease severity suggests cofactors contribute to WM degeneration. We examined the potential cofactor role of the tobacco-specific nitrosamine, nicotine-derived nitrosamine ketone (NNK), because smoking causes WM atrophy and most heavy drinkers consume tobacco products. This 8-week study of Long Evans rats had 4 treatment groups: control; NNK-2mg/kg, 3×/wk in weeks 3 to 8; ethanol (EtOH) (chronic-26% caloric+binge-2g/kg, 3×/wk in weeks 7 to 8); and EtOH+NNK. Exposure effects on WM lipid biochemical profiles and insitu distributions were examined using matrix-assisted laser desorption/ionization imaging mass spectrometry and tandem mass spectrometry. NNK mainly caused WM fiber degeneration and fiber loss, EtOH caused demyelination, and dual exposures had additive effects. EtOH and EtOH+NNK decreased WM (including corpus callosum) and/or gray matter (hypothalamus, cortex, medial temporal) levels of several phosphatidylserine, phosphatidylinositol, and sphingolipid (sulfatide [ST]) species, while NNK increased or had minimal effect on these lipids. EtOH+NNK had broader and larger inhibitory effects on phospholipids and ST than EtOH or NNK alone. Principal component analysis clustered control with NNK, and EtOH with EtOH+NNK groups, highlighting the independent EtOH- rather than NNK-driven responses. Chronic EtOH exposures decreased several phospholipid and sphingolipid species in brain, while concomitant NNK exposures exacerbated these effects. These findings support our hypothesis that tobacco smoking is a pathogenic cofactor in alcohol-mediated WM degeneration.

Methylmercury Increases and Eicosapentaenoic Acid Decreases the Relative Amounts of Arachidonic Acid-Containing Phospholipids in Mouse Brain.

The membrane phospholipid composition in mammalian brain can be modified either by nutrients such as dietary fatty acids, or by certain toxic substances such as methylmercury (MeHg), leading to various biological and toxic effects. The present study evaluated the effects of eicosapentaenoic acid (EPA) and MeHg on the composition of the two most abundant membrane phospholipid classes, i.e., phosphatidylcholines (PtdCho) and phosphatidylethanolamines (PtdEtn), in mouse brain by using a two-level factorial design. The intact membrane PtdCho and PtdEtn species were analyzed by liquid chromatography-mass spectrometry. The effects of EPA and MeHg on the PtdCho and PtdEtn composition were evaluated by principal component analysis and ANOVA. The results showed that EPA and MeHg had different effects on the composition of membrane PtdCho and PtdEtn species in brain, where EPA showed strongest impact. EPA led to large reductions in the levels of arachidonic acid (ARA)-containing PtdCho and PtdEtn species in brain, while MeHg tended to elevate the levels of ARA-containing PtdCho and PtdEtn species. EPA also significantly increased the levels of PtdCho and PtdEtn species with n-3 fatty acids. Our results indicate that EPA may to some degree counteract the alterations of the PtdCho and PtdEtn pattern induced by MeHg, and thus alleviate the MeHg neurotoxicity in mouse brain through the inhibition of ARA-derived pro-inflammatory factors. These results may assist in the understanding of the interaction between MeHg, EPA and phospholipids, as well as the risk and benefits of a fish diet.

Lipid Profile and Malondialdehyde Concentrations in Cadmium-Induced Rats: A Study with Relation to Doses

Background: Cadmium is a serious environmental and occupational contaminant that may represent a serious health hazard to humans and other animals. Since cadmium cannot be degraded, the risk of environmental exposure is constantly increasing because of accumulation via the food chain. Exposure to cadmium at the cellular level can produce tissue injury and damage various organs, but the underlying mechanism is enigmatic. Methods: In order to investigate its toxicity on lipid profile and malondialdehyde concentration, thirty-two rats were exposed to 100, 200 and 300 ppm cadmium in their drinking water for six weeks while the control group received distilled water for the same period. Results: At all the concentrations, cadmium produced a significant (p<0.05) dosedependent hypocholesterolemia, hypotriglyceridemia and hypophospholipidemia in the plasma and erythrocyte respectively. Exposure to cadmium resulted in increased hepatic triacylglycerol concentration, whereas brain triacylglycerol concentrations were reduced. While cadmium induced brain phospholipidosis, a reduction in liver phospholipid concentration was observed. There was a significant (p<0.05) dose-dependent increase in the plasma, erythrocyte, brain and liver malondialdehyde concentrations corresponding to 56, 89, and 69 % at high dose of 300 ppm respectively compared to control. While positive associations were observed between plasma, liver, brain, erythrocyte malondialdehyde and organ triacylglycerol and phospholipid, negative associations were observed with liver phospholipid.

Brain Arachidonic Acid Incorporation and Turnover are not Altered in the Flinders Sensitive Line Rat Model of Human Depression.

Brain serotonergic signaling is coupled to arachidonic acid (AA)-releasing calcium-dependent phospholipase A2. Increased brain serotonin concentrations and disturbed serotonergic neurotransmission have been reported in the Flinders Sensitive Line (FSL) rat model of depression, suggesting that brain AA metabolism may be elevated. To test this hypothesis, (14)C-AA was intravenously infused to steady-state levels into control and FSL rats derived from the same Sprague-Dawley background strain, and labeled and unlabeled brain phospholipid and plasma fatty acid concentrations were measured to determine the rate of brain AA incorporation and turnover. Brain AA incorporation and turnover did not differ significantly between controls and FSL rats. Compared to controls, plasma unesterified docosahexaenoic acid was increased, and brain phosphatidylinositol AA and total lipid linoleic acid and n-3 and n-6 docosapentaenoic acid were significantly decreased in FSL rats. Several plasma esterified fatty acids differed significantly from controls. In summary, brain AA metabolism did not change in FSL rats despite reported increased levels of serotonin concentrations, suggesting possible post-synaptic dampening of serotonergic neurotransmission involving AA.