The effects of omega-3 fatty acids on neuropsychological functioning and brain morphology in mid-life adults: a randomized clinical trial.

BACKGROUND: The diet of most adults is low in fish and, therefore, provides limited quantities of the long-chain, omega-3 fatty acids (LCn-3FAs), eicosapentaenoic and docosahexaenoic acids (EPA, DHA). Since these compounds serve important roles in the brain, we sought to determine if healthy adults with low-LCn-3FA consumption would exhibit improvements in neuropsychological performance and parallel changes in brain morphology following repletion through fish oil supplementation. METHODS: In a randomized, controlled trial, 271 mid-life adults (30-54 years of age, 118 men, 153 women) consuming ⩽300 mg/day of LCn-3FAs received 18 weeks of supplementation with fish oil capsules (1400 mg/day of EPA and DHA) or matching placebo. All participants completed a neuropsychological test battery examining four cognitive domains: psychomotor speed, executive function, learning/episodic memory, and fluid intelligence. A subset of 122 underwent neuroimaging before and after supplementation to measure whole-brain and subcortical tissue volumes. RESULTS: Capsule adherence was over 95%, participant blinding was verified, and red blood cell EPA and DHA levels increased as expected. Supplementation did not affect performance in any of the four cognitive domains. Exploratory analyses revealed that, compared to placebo, fish oil supplementation improved executive function in participants with low-baseline DHA levels. No changes were observed in any indicator of brain morphology. CONCLUSIONS: In healthy mid-life adults reporting low-dietary intake, supplementation with LCn-3FAs in moderate dose for moderate duration did not affect neuropsychological performance or brain morphology. Whether salutary effects occur in individuals with particularly low-DHA exposure requires further study.

Association between increased serum interleukin-6 levels and sustained attention deficits in patients with major depressive disorder.

BACKGROUND: The pathophysiology of cognitive impairment in patients with the major depressive disorder (MDD) may involve neuroinflammation mediated by cytokines. OBJECTIVE: The aim of this study was to examine the serum interleukin-6 (IL-6) levels, sustained attention, and their association in patients with MDD. METHODS: Thirty patients with MDD and 30 healthy controls were enrolled in this case-control study. Sustained attention was measured using the Rapid Visual Information Processing (RVP) task in the Cambridge Neuropsychological Tests Automated Battery. The serum IL-6 levels of all subjects were assessed by sandwich enzyme-linked immunosorbent assays. RESULTS: There were significant differences in the log10RVP total hits, log10RVP total misses, and log10RVP mean latency between patients with MDD and healthy controls (F = 6.04, p = 0.017; F = 19.77, p < 0.0001; F = 14.42, p < 0.0001, respectively). The serum levels of Log10IL-6 were significantly higher in patients with MDD than in healthy controls (F = 192.27, p < 0.0001). The log10IL-6 levels were also positively correlated with the log10RVP mean latency in patients with MDD (r = 0.45, p = 0.013). A further stepwise multivariate regression analysis indicated that the log10IL-6 levels were significantly associated with the log10RVP mean latency in patients with MDD (ß = 0.31, t = 2.41, p = 0.025). CONCLUSIONS: Our data suggested that increased IL-6 levels were associated with the psychopathology of MDD, and that abnormal IL-6 levels were implicated in the impairment of sustained attention in patients with MDD.

Concurrent physical activity modifies the association between n3 long-chain fatty acids and cardiometabolic risk in midlife adults.

Greater consumption of n3 (ω3) polyunsaturated fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) can reduce risk for cardiovascular disease events, yet their effects on metabolic risk factors and diabetes remain unclear. This cross-sectional study used a community volunteer sample to test whether the associations between n3 fatty acids and cardiometabolic risk vary as a function of physical activity. Participants were 344 generally healthy adults, 30-54 y of age, not taking fish oil supplements or confounding medications. Serum phospholipid EPA and DHA were used together (EPA+DHA) as a biomarker of n3 fatty acid exposure. Cardiometabolic risk was calculated as a continuous measure based on standardized distributions of blood pressure, waist circumference, HDL cholesterol, triglycerides, glucose, and a simple count of risk factors. Insulin resistance was estimated from the homeostatic model assessment. Physical activity was found to predict cardiometabolic risk (P ≤ 0.02) and insulin resistance (P ≤ 0.02) and to moderate the association between EPA+DHA and both cardiometabolic risk (P-interaction ≤ 0.02) and insulin resistance (P-interaction ≤ 0.02). Specifically, higher EPA+DHA was associated with lower cardiometabolic risk and insulin resistance in persons engaged in regular physical activity but not in relatively inactive individuals. These findings were noted in several components of cardiometabolic risk, in men and women separately, and in models adjusted for overall diet quality. In midlife adults, habitual physical activity may be necessary to unmask the salutary effects of n3 fatty acids on cardiometabolic risk and insulin resistance.

Lack of de novo phosphatidylinositol synthesis leads to endoplasmic reticulum stress and hepatic steatosis in cdipt-deficient zebrafish.

UNLABELLED: Hepatic steatosis is the initial stage of nonalcoholic fatty liver disease (NAFLD) and may predispose to more severe hepatic disease, including hepatocellular carcinoma. Endoplasmic reticulum (ER) stress has been recently implicated as a novel mechanism that may lead to NAFLD, although the genetic factors invoking ER stress are largely unknown. During a screen for liver defects from a zebrafish insertional mutant library, we isolated the mutant cdipthi559Tg/+ (hi559). CDIPT is known to play an indispensable role in phosphatidylinositol (PtdIns) synthesis. Here we show that cdipt is expressed in the developing liver, and its disruption in hi559 mutants abrogates de novo PtdIns synthesis, resulting in hepatomegaly at 5 days postfertilization. The hi559 hepatocytes display features of NAFLD, including macrovesicular steatosis, ballooning, and necroapoptosis. Gene set enrichment of microarray profiling revealed significant enrichment of endoplasmic reticulum stress response (ERSR) genes in hi559 mutants. ER stress markers, including atf6, hspa5, calr, and xbp1, are selectively up-regulated in the mutant liver. The hi559 expression profile showed significant overlap with that of mammalian hepatic ER stress and NAFLD. Ultrastructurally, the hi559 hepatocytes display marked disruption of ER architecture with hallmarks of chronic unresolved ER stress. Induction of ER stress by tunicamycin in wild-type larvae results in a fatty liver similar to hi559, suggesting that ER stress could be a fundamental mechanism contributing to hepatic steatosis. CONCLUSION: cdipt-deficient zebrafish exhibit hepatic ER stress and NAFLD pathologies, implicating a novel link between PtdIns, ER stress, and steatosis. The tractability of hi559 mutant provides a valuable tool to dissect ERSR components, their contribution to molecular pathogenesis, and evaluation of novel therapeutics of NAFLD.

3-Hydroxykynurenine and clinical symptoms in first-episode neuroleptic-naive patients with schizophrenia.

One branch of the tryptophan catabolic cascade is the kynurenine pathway, which produces neurotoxic [3-hydroxykynurenine (3-OHKY), quinolinic acid] and neuroinhibitory (kynurenic acid) compounds. Kynurenic acid acts as a competitive antagonist at the glycine site of N-methyl-d-asparate receptors at high concentrations and as a non-competitive antagonist on the α7-nicotinic acetylcholine receptor at low concentrations. Kynurenine compounds also influence cognitive functions known to be disrupted in schizophrenia. Alterations in tryptophan metabolism are therefore of potential significance for the pathophysiology of this disorder. In this paper, tryptophan metabolites were measured from plasma using high-pressure liquid chromatography coupled with electrochemical coulometric array detection, and relationships were tested between these metabolic signatures and clinical symptoms for 25 first-episode neuroleptic-naive schizophrenia patients. Blood samples were collected and clinical and neurological symptoms were rated at baseline and again at 4 wk following initiation of treatment. Level of 3-OHKY and total clinical symptom scores were correlated when patients were unmedicated and neuroleptic-naive, and this relationship differed significantly from the correlation observed for patients 4 wk after beginning treatment. Baseline psychosis symptoms were predicted only by neurological symptoms. Moreover, baseline 3-OHKY predicted clinical change at 4 wk, with the lowest concentrations of 3-OHKY being associated with the greatest improvement in symptoms. Taken together, our findings suggest a neurotoxic product of tryptophan metabolism, 3-OHKY, predicts severity of clinical symptoms during the early phase of illness and before exposure to antipsychotic drugs. Baseline level of 3-OHKY may also predict the degree of clinical improvement following brief treatment with antipsychotics.

Serum phospholipid docosahexaenonic acid is associated with cognitive functioning during middle adulthood.

Existing evidence links greater dietary intake of fish and (n-3) PUFA to better early brain development and lowered risk of cognitive disorders in late life. The mechanisms for these associations remain unclear and may be related to specific (n-3) fatty acids and may concern cognitive function generally rather than only early brain development and age-related cognitive dysfunction. In this investigation, we tested potential associations between (n-3) fatty acids in serum phospholipids and major dimensions of cognitive functioning in mid-life adults. Participants were 280 community volunteers between 35 and 54 y of age, free of major neuropsychiatric disorders, and not taking fish oil supplements. Dietary biomarkers were alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenonic acid (DHA) in serum phospholipids measured using GC. Five major dimensions of cognitive functioning were assessed with a 75-min battery of neuropsychological tests. In covariate adjusted regression models, higher DHA (mol %) was related to better performance on tests of nonverbal reasoning and mental flexibility, working memory, and vocabulary (P

Fine-mapping reveals novel alternative splicing of the dopamine transporter.

The dopamine transporter gene (SLC6A3, DAT) has been implicated in the pathogenesis of numerous psychiatric and neurodevelopmental disorders, including schizophrenia (SZ). We previously detected association between SZ and intronic SLC6A3 variants that replicated in two independent Caucasian samples, but had no obvious function. In follow-up analyses, we sequenced the coding and intronic regions of SLC6A3 to identify complete linkage disequilibrium patterns of common variations. We genotyped 78 polymorphisms, narrowing the potentially causal region to two correlated clusters of associated SNPs localized predominantly to introns 3 and 4. Our computational analysis of these intronic regions predicted a novel cassette exon within intron 3, designated E3b, which is conserved among primates. We confirmed alternative splicing of E3b in post-mortem human substantia nigra (SN). As E3b introduces multiple in-frame stop codons, the SLC6A3 open reading frame is truncated and the spliced product may undergo nonsense mediated decay. Thus, factors that increase E3b splicing could reduce the amount of unspliced product available for translation. Observations consistent with this prediction were made using cellular assays and in post-mortem human SN. In mini-gene constructs, the extent of splicing is also influenced by at least two common haplotypes, so the alternative splicing was evaluated in relation to SZ risk. Meta-analyses across genome-wide association studies did not support the initial associations and further post-mortem studies did not suggest case-control differences in splicing. These studies do not provide a compelling link to schizophrenia. However, the impact of the alternative splicing on other neuropsychiatric disorders should be investigated. © 2010 Wiley-Liss, Inc.

Reduced Levels and Disrupted Biosynthesis Pathways of Plasma Free Fatty Acids in First-Episode Antipsychotic-Naïve Schizophrenia Patients.

Membrane phospholipid deficits have been well-documented in schizophrenia (SZ) patients. Free fatty acids (FFAs) partially come from the hydrolysis of membrane phospholipids and serve as the circulating pool of body fatty acids. These FFAs are involved in many important biochemical reactions such as membrane regeneration, oxidation, and prostaglandin production which may have important implications in SZ pathology. Thus, we compared plasma FFA levels and profiles among healthy controls (HCs), affective psychosis (AP) patients, and first-episode antipsychotic-naïve schizophrenia (FEANS) patients. A significant reduction of total FFAs levels was observed in SZ patients. Specifically, significant reductions of 16:0, 18:2n6c, and 20:4n6 levels were detected in FEANS patients but not in APs when compared with levels in HCs. Also, disrupted metabolism of fatty acids especially in saturated and n-6 fatty acid families were observed by comparing correlations between precursor and product fatty acid levels within each fatty acid family. These findings may suggest an increased demand of membrane regeneration, a homeostatic imbalance of fatty acid biosynthesis pathway and a potential indication of increased beta oxidation. Collectively, these findings could help us better understand the lipid metabolism with regard to SZ pathophysiology.

Impact of estrogen receptor agonists and model of menopause on enzymes involved in brain metabolism, acetyl-CoA production and cholinergic function.

Our goal is to understand how loss of circulating estrogens and estrogen replacement affect brain physiology and function, particularly in brain regions involved in cognitive processes. We recently conducted a large metabolomics study characterizing the effects of rodent models of menopause and treatment with estrogen receptor (ER) agonists on neurochemical targets in hippocampus, frontal cortex, and striatum. Here we characterize effects on levels of several key enzymes involved in glucose utilization and energy production, specifically phosphofructokinase, glyceraldehyde 3-phosphate dehydrogenase, and pyruvate dehydrogenase. We also evaluated effects on levels of ß-actin and α-tubulin, choline acetyltransferase (ChAT) activity, and levels of ATP citrate lyase. All experiments were conducted in young adult rats. Experiment 1 compared the effects of ovariectomy (OVX), a model of surgical menopause, and 4-vinylcyclohexene diepoxide (VCD)-treatments, a model of transitional menopause, with tissues collected at proestrus and at diestrus. Experiment 2 used a separate cohort of rats to evaluate the same targets in OVX and VCD-treated rats treated with estradiol or with selective ER agonists. Differences in the expression of metabolic enzymes between cycling animals and models of surgical and transitional menopause were detected. These differences were model-, region- and time- dependent, and were modulated by selective ER agonists. Collectively, the findings demonstrate that loss of ovarian function and ER agonist treatments have differing effects in OVX vs. VCD-treated rats. Differences may help to explain differences in the effects of estrogen treatments on brain function and cognition in women who have experienced surgical vs. transitional menopause.

Reduced membrane lipids in the cortex of Alzheimer's disease transgenic mice.

Accumulating evidence suggests that the conversion of Abeta peptides to soluble, neurotoxic polymers is the key event in the development of Alzheimer's disease (AD). Moreover, interactions between Abeta peptides and neuronal membrane lipids likely play a vital role in developing the neurotoxicity associated with AD. The aim of this study is to assess whether lipid matrix of neuronal membranes is affected by the accumulation of Abeta peptides in double transgenic mouse model of AD expressing both mutant human beta-amyloid precursor protein (APP) and presenilin 1 (PS1). We apply high pressure liquid chromatography with an evaporative light scattering detector to compare levels of cholesterol, galactocerebrosides, and phospholipid subclasses simultaneously in cortex samples between AD double transgenic mice at 4 months of age when Abeta production and amyloid plaque deposition is just beginning and at 9 months, when there is advanced Abeta levels and plaque deposition compared to age-matched wild-type (B6/SJL) mice. Both cholesterol (CL) and phospholipids (PL) are significantly lower in 9-month-old AD mice than the same age of B6/SJL mice. Among PL subclasses, phosphatidylethanolamine (PE), phosphatidylserine (PS) and phosphatidylcholine (PC) are selectively reduced in 9-month-old AD mice. The molar ratios of CL to PL in 9-month-old AD mice (1.19 +/- 0.27) were significantly higher than those of 9-month-old B6/SJL mice (0.81 +/- 0.08). In keeping with decreased levels of PL, there are also significant reductions of very long-chain n-3 fatty acids (docosahexaenoic acid) and n-6 fatty acid (arachidonic acid) in 9-month-old AD mice. On the other hand, ratios of total n-6 to total n-3 fatty acids were significantly higher in 9-month-old AD mice than in the same age of B6/SJL mice. Taken together, our present data support a role for the interactions of amyloid-beta peptide and neuronal membranes in the subsequent development of AD.

Estradiol and selective estrogen receptor agonists differentially affect brain monoamines and amino acids levels in transitional and surgical menopausal rat models.

Estrogens have many beneficial effects in the brain. Previously, we evaluated the effects of two models of menopause (surgical vs. transitional) on multiple monoaminergic endpoints in different regions of the adult rat brain in comparison with levels in gonadally intact rats. Here we evaluated the effects of estrogen receptor (ER) agonist treatments in these same two models of menopause. Neurochemical endpoints were evaluated in the hippocampus (HPC), frontal cortex (FCX), and striatum (STR) of adult ovariectomized (OVX) rats and in rats that underwent selective and gradual ovarian follicle depletion by daily injection of 4-vinylcyclohexene-diepoxide (VCD), after 1- and 6-weeks treatment with 17ß-estradiol (E2), or with selective ERα (PPT), ERß (DPN), or GPR30 (G-1) agonists. Endpoints included serotonin (5-HT) and 5-Hydroxyindoleacetic acid, dopamine (DA), 3,4-Dihydroxyphenylacetic acid and homovanillic acid, norepinephrine (NE) and epinephrine, as well as the amino acids tryptophan (TRP) and tyrosine (TYR). Significant differences between the models were detected. OVX rats were much more sensitive to ER agonist treatments than VCD-treated rats. Significant differences between brain regions also were detected. Within OVX rats, more agonist effects were detected in the HPC than in any other region. One interesting finding was the substantial decrease in TRP and TYR detected in the HPC and FCX in response to agonist treatments, particularly in OVX rats. This is on top of the substantial decreases in TRP and TYR previously reported one week after OVX or VCD-treatments in comparison with gonadally intact controls. Other interesting findings included increases in the levels of 5-HT, DA, and NE in the HPC of OVX rats treated with DPN, increases in DA detected in the FCX of OVX rats treated with any of the ER agonists, and increases in 5-HT and DA detected in the STR of OVX rats treated with E2. Many effects that were observed after 1-week of treatment were no longer observed after 6-weeks of treatment, demonstrating that effects were temporary despite continued agonist treatment. Collectively, the results demonstrate significant differences in the effects of ER agonists on monoaminergic endpoints in OVX vs. VCD-treated rats that also were brain region-specific and time dependent. The fact that agonist treatments had lesser effects in VCD treated rats than in OVX rats may help to explain reports of lesser effects of estrogen replacement on cognitive performance in women that have undergone transitional vs. surgical menopause.

The orphan transporter Rxt1/NTT4 (SLC6A17) functions as a synaptic vesicle amino acid transporter selective for proline, glycine, leucine, and alanine.

Rxt1/NTT4 (SLC6A17) belongs to a gene family of "orphan transporters" whose substrates and consequently functions remain unidentified. Although Rxt1/NTT4 was previously thought to function as a sodium-dependent plasma membrane transporter, recent studies localized the protein to synaptic vesicles of glutamatergic and GABAergic neurons. Here, we provide evidence indicating that Rxt1/NTT4 functions as a vesicular transporter selective for proline, glycine, leucine, and alanine. Using Western blot, immunoprecipitation, immunocytochemistry, and polymerase chain reaction approaches, we demonstrate that PC12 cells express the Rxt1/NTT4 gene and protein. Small interfering RNA (siRNA)-mediated knockdown of Rxt1/NTT4 in PC12 cells resulted in selective reductions in uptake levels for proline, glycine, leucine, and alanine. Likewise, gas chromatography analysis of amino acid content in an enriched synaptic vesicle fraction from wild-type and siRNA-Rxt1/NTT4 PC12 cells revealed that proline, glycine, leucine, and alanine levels were decreased in siRNA-treated cells compared with wild-type cells. Furthermore, Rxt1/NTT4-transfected Chinese hamster ovary (CHO) cells exhibited significant uptake increases of these amino acids compared with mock-transfected CHO cells. Finally, proline uptake in both PC12 cells and Rxt1/NTT4-transfected CHO cells was dependent on the electrochemical gradient maintained by the vacuolar-type H(+)-ATPase. These data indicate that the orphan Rxt1/NTT4 protein functions as a vesicular transporter for proline, glycine, leucine, and alanine, further suggesting its important role in synaptic transmission.

Semantic memory in schizophrenia: association with cell membrane essential fatty acids.

INTRODUCTION: Semantic memory and language deficits are associated with schizophrenia. Understanding how these systems operate in this disorder will likely require a multi-factorial model that explains their linkages with cognition and modulation by dopamine. A biological factor that may provide causal convergence for these connections is cell membrane composition and dynamics. METHODS: N400 is an electrophysiological measure of semantic memory and language that is sensitive to deficits in schizophrenia. Relationships among N400, cognition, dopamine, and cell membrane polyunsaturated fatty acids (PUFAs) were examined for patients tested under medicated (haloperidol only) and unmedicated (placebo) conditions. Relationships between these factors and clinical symptoms were also evaluated. The sample included 37 male schizophrenia inpatients and 34 male normal controls. The N400 priming effect was measured from visual event-related potentials recorded during a semantic priming-lexical decision task, in which semantic association (related versus unrelated words) and presentation rate (Stimulus Onset Asynchrony/SOAs: 350 and 950 ms) were varied. RESULTS: N400 was associated with cognition (speed, visuoperception, attention) in patients and controls. These relationships were influenced by SOA in both groups, and by pharmacological condition in patients. Levels of total PUFAs and arachidonic acid were associated with N400 in unmedicated patients. Clinical symptoms (paranoia, thought disturbance) were associated with N400, but not with cognition or PUFAs. CONCLUSIONS: Results suggest cell membrane fatty acids are associated with semantic memory and language in schizophrenia. Findings also suggest a series of linkages that are modulated by dopamine: cell membrane fatty acids are associated with N400 semantic priming; N400 semantic priming is associated with clinical symptoms.

Neurosteroids in Schizophrenia: Pathogenic and Therapeutic Implications.

Neurosteroids are a group of important endogenous molecules affecting many neural functions in the brain. Increasing evidence suggests a possible role of these neurosteroids in the pathology and symptomatology of schizophrenia (SZ) and other mental disorders. The aim of this review is to summarize the current knowledge about the neural functions of neurosteroids in the brain, and to evaluate the role of the key neurosteroids as candidate modulators in the etiology and therapeutics of SZ. The present paper provides a brief introduction of neurosteroid metabolism and distribution, followed by a discussion of the mechanisms underlying neurosteroid actions in the brain. The content regarding the modulation of the GABAA receptor is elaborated, given the considerable knowledge of its interactions with other neurotransmitter and neuroprotective systems, as well as its ameliorating effects on stress that may play a role in the SZ pathophysiology. In addition, several preclinical and clinical studies suggested a therapeutic benefit of neurosteroids in SZ patients, even though the presence of altered neurosteroid pathways in the circulating blood and/or brain remains debatable. Following treatment of antipsychotic drugs in SZ, therapeutic benefits have also been linked to the regulation of neurosteroid signaling. Specifically, the neurosteroids such as pregnenolone and dehydroepiandrosterone affect a broad spectrum of behavioral functions through their unique molecular characteristics and may represent innovative therapeutic targets for SZ. Future investigations in larger cohorts with long-term follow-ups will be required to ascertain the neuropsychopharmacological role of this yet unexploited class of neurosteroid agents.

A rapid UPLC-MS/MS assay for eicosanoids in human plasma: Application to evaluate niacin responsivity.

A rapid and sensitive method using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was developed to simultaneously quantify hydroxyeicosatetraenoic (HETE), dihydroxyeicosatrienoic (DiHETrE), epoxyeicosatrienoic acid (EET), and prostaglandin metabolites of arachidonic acid in human plasma. Sample preparation consisted of solid phase extraction with Oasis HLB (30mg) cartridges for all metabolites. Separation of HETEs, EETs, and DiHETrEs was achieved on an Acquity UPLC BEH C18, 1.7µm (100×2.1mm) reversed-phase column (Waters Corp, Millford, MA) with negative electrospray ionization mass spectrometric detection. A second injection of the same extracted sample allowed for separation and assessment of prostaglandin metabolites under optimized UPLC-MS/MS conditions. Additionally, the endogenous levels of these metabolites in five different matrices were determined in order to select the optimal matrix for assay development. Human serum albumin was shown to have the least amount of endogenous metabolites, a recovery efficiency of 79-100% and a matrix effect of 71 - 100%. Linear calibration curves ranging from 0.416 to 66.67ng/ml were validated. Inter-assay and intra-assay variance was less than 15% at most concentrations. This method was successfully applied to quantify metabolite levels in plasma samples of healthy control subjects receiving niacin administration to evaluate the association between niacin administration and eicosanoid plasma level response.

Comparison of transitional vs surgical menopause on monoamine and amino acid levels in the rat brain.

Loss of ovarian function has important effects on neurotransmitter production and release with corresponding effects on cognitive performance. To date, there has been little direct comparison of the effects of surgical and transitional menopause on neurotransmitter pathways in the brain. In this study, effects on monoamines, monoamine metabolites, and the amino acids tryptophan (TRP) and tyrosine (TYR) were evaluated in adult ovariectomized (OVX) rats and in rats that underwent selective and gradual ovarian follicle depletion by daily injection of 4-vinylcyclohexene-diepoxide (VCD). Tissues from the hippocampus (HPC), frontal cortex (FCX), and striatum (STR) were dissected and analyzed at 1- and 6-weeks following OVX or VCD treatments. Tissues from gonadally intact rats were collected at proestrus and diestrus to represent neurochemical levels during natural states of high and low estrogens. In gonadally intact rats, higher levels of serotonin (5-HT) were detected at proestrus than at diestrus in the FCX. In addition, the ratio of 5-hydroxyindoleacetic acid (5-HIAA)/5HT in the FCX and HPC was lower at proestrus than at diestrus, suggesting an effect on 5-HT turnover in these regions. No other significant differences between proestrus and diestrus were observed. In OVX- and VCD-treated rats, changes were observed which were both brain region- and time point-dependent. In the HPC levels of norepinephrine, 5-HIAA, TRP and TYR were significantly reduced at 1 week, but not 6 weeks, in both OVX and VCD-treated rats relative to proestrus and diestrus. In the FCX, dopamine levels were elevated at 6 weeks after OVX relative to diestrus. A similar trend was observed at 1 week (but not 6 weeks) following VCD treatment. In the STR, norepinephrine levels were elevated at 1 week following OVX, and HVA levels were elevated at 1 week, but not 6 weeks, following VCD treatment, relative to proestrus and diestrus. Collectively, these data provide the first comprehensive analysis comparing the effects of two models of menopause on multiple neuroendocrine endpoints in the brain. These effects likely contribute to effects of surgical and transitional menopause on brain function and cognitive performance that have been reported.

Docosahexaenoic acid (DHA): An essential nutrient and a nutraceutical for brain health and diseases.

Docosahexaenoic acid (DHA), a polyunsaturated fatty acid (PUFA) enriched in phospholipids in the brain and retina, is known to play multi-functional roles in brain health and diseases. While arachidonic acid (AA) is released from membrane phospholipids by cytosolic phospholipase A2 (cPLA2), DHA is linked to action of the Ca2+-independent iPLA2. DHA undergoes enzymatic conversion by 15-lipoxygenase (Alox 15) to form oxylipins including resolvins and neuroprotectins, which are powerful lipid mediators. DHA can also undergo non-enzymatic conversion by reacting with oxygen free radicals (ROS), which cause the production of 4-hydoxyhexenal (4-HHE), an aldehyde derivative which can form adducts with DNA, proteins and lipids. In studies with both animal models and humans, there is evidence that inadequate intake of maternal n-3 PUFA may lead to aberrant development and function of the central nervous system (CNS). What is less certain is whether consumption of n-3 PUFA is important in maintaining brain health throughout one's life span. Evidence mostly from non-human studies suggests that DHA intake above normal nutritional requirements might modify the risk/course of a number of diseases of the brain. This concept has fueled much of the present interest in DHA research, in particular, in attempts to delineate mechanisms whereby DHA may serve as a nutraceutical and confer neuroprotective effects. Current studies have revealed ability for the oxylipins to regulation of cell redox homeostasis through the Nuclear factor (erythroid-derived 2)-like 2/Antioxidant response element (Nrf2/ARE) anti-oxidant pathway, and impact signaling pathways associated with neurotransmitters, and modulation of neuronal functions involving brain-derived neurotropic factor (BDNF). This review is aimed at describing recent studies elaborating these mechanisms with special regard to aging and Alzheimer's disease, autism spectrum disorder, schizophrenia, traumatic brain injury, and stroke.

Pregnenolone-progesterone-allopregnanolone pathway as a potential therapeutic target in first-episode antipsychotic-naïve patients with schizophrenia.

Neurosteroids are both endogenous and exogenous steroids that rapidly alter neuronal excitability through interactions with ligand-gated ion channels and other cell surface receptors. They are originated from cholesterol and have important implications for schizophrenia (SZ) pathophysiology and treatment strategies. Specifically, pregnenolone (PREG), progesterone (PROG) and allopregnanolone (ALLO) exhibit similar psychotropic properties. Using enzyme immunoassay, we compared the neurosteroids in PREG downstream pathways in plasma between healthy controls (HC, n = 43) and first-episode antipsychotic-naïve patients with SZ (FEAN-SZ, n = 53) before antipsychotic drug (APD) treatment. Comparisons were also made particularly along PREG-PROG-ALLO pathway in the same FEAN-SZ patients across multiple time points following initiation of treatment for 12 months (m). Firstly, at baseline, levels of PREG were significantly higher and those of ALLO were lower in FEAN-SZ than in HC, whereas PROG, cortisol, dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) were not different. Consequently, the molar ratios of ALLO/PREG and ALLO/PROG in FEAN-SZ were significantly reduced. Secondly, in response to APD at 1 month, ALLO levels in FEAN-SZ were markedly elevated, whereas PREG and PROG levels decreased. Thirdly, among FEAN-SZ, lower levels of PROG (reflecting higher conversion to ALLO) at baseline may predict better therapeutic outcome after 1 month of APD treatment. These findings point to the perturbations of the PREG-PROG-ALLO pathway early in psychosis, and further study of this pathway may inform alternative and innovative therapeutic targets for SZ.

High omega-6 and low omega-3 fatty acids are associated with depressive symptoms and neuroticism.

OBJECTIVE: To examine the concentrations of omega-3 and omega-6 polyunsaturated fatty acids in serum obtained from nonpatient community volunteers not selected for hypercholesterolemia. Previously we reported that the relative concentrations of omega-3 and omega-6 polyunsaturated fatty acids in serum covary with depressive symptomatology and neuroticism in hypercholesterolemic adults. METHODS: A total of 116 adults without current Axis I psychopathology completed the Beck Depression Inventory (BDI) and the NEO Personality Inventory--Revised (NEO-PI-R). Fasting serum phospholipid eicosapentaenoic (EPA), docosahexaenoic (DHA), and arachidonic acid (AA) were determined (% of total pool). RESULTS: Higher AA and AA:EPA ratio, adjusted for age, gender, and race, were associated with greater depressive symptomatology (BDI score of >or=10). Lower EPA, and higher AA, AA:EPA ratio and AA:DHA ratio were associated with greater NEO-PI-R Neuroticism. The six Neuroticism subscales were each associated with two or more fatty acid measurements. CONCLUSIONS: In conjunction with other reports, these findings suggest that the omega-3 and omega-6 fatty acids are related to negative affect at both the symptom and trait levels.

Blunted serotonergic responsivity in neuroleptic-naïve patients at first-episode of schizophrenia.

OBJECTIVE: To determine whether serotonergic responsivity, as assessed in platelets, is blunted in treatment-naïve patients with first episode psychosis, similar to observations in chronic schizophrenia. METHODS: Serotonin (5-HT)-amplified platelet aggregation was determined in 26 first-episode treatment-naive patients with psychosis (14 with schizophrenia, 12 with mood disorders with psychosis) and 16 matched healthy comparison subjects. Platelet aggregation was measured in fresh whole blood after stimulation with 5.0 microM adenosine diphosphate (ADP) alone and with the addition of 0.2 microg and 1.0 microg 5-HT. RESULTS: Healthy subjects showed expected robust increases in platelet aggregation (+106% and +146% at 0.2 microg and 1.0 microg 5-HT, respectively). By contrast, patients with schizophrenia showed almost no changes in aggregation (+6% and +3%), while patients with mood disorders showed intermediate increases (+59% and +66%). CONCLUSIONS: Blunted platelet serotonergic responsivity appears to be independent of treatment effects. To determine whether this is trait-related factor will require prospective studies.