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Neurobiol Lipids 7, 1 (10 April 2008)
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ABSTRACT
Welcome to The Brain Lipids Conference 2008 in Oslo, Norway, 8th-11th September! Register at www.bl2008.org
now. Registration deadline is 15th May. After this date we cannot
guarantee you participation because of hotel accommodation limits. The
main focus of the conference is lipids and oxidative stress in the
brain. Prevention or treatment of mental disorders with omega-3 fatty
acids or antioxidants is a principal topic. We have invited more than
30 speakers from 12 countries and from basic neuroscience, nutritional
sciences, pharmacology, radiology, clinical psychiatry and neurology.
Abstracts of the oral presentations are displayed below. All
participants are encouraged to present posters. The poster abstract
submission deadline is 15th June.
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Several sources of information suggest that human beings evolved on a diet that had a ratio of omega-6 to omega-3 fatty acids (FA) of about 1/1, whereas Western diets have a ratio of 10/1 to 20-25/1, indicating that Western diets are deficient in omega-3 FA compared with the diet on which humans evolved and their genetic patterns were established. An absolute and relative deficiency of omega-3 FA exists in Western diets as a result of agribusiness and modern agriculture. Omega-6 and omega-3 FA are not interconvertible in the human body and are important components of practically all cell membranes. Studies with non-human primates and human newborns indicate that docosahexaenoic acid (DHA) is essential for the normal functional development of the brain and retina, particularly in premature infants. A higher omega-6/omega-3 ratio is associated with increased risk for coronary heart disease, colorectal cancer, asthma, osteoporosis, arthritis, and neurodegenerative diseases, and various aspects of mental illness, violent behavior, and deficient cognition in both children and the elderly. In clinical studies, higher omega-3 FA, EPA and DHA reduced the risk of decline in verbal fluency, particularly in hypertensive and dyslipidemic elderly subjects, suggesting that a moderate intake of EPA and DHA may postpone decline in elderly men. DHA accounts for 40% of the membrane phospholipid FA in the brain and is implicated to have an effect on membrane receptor function and even neurotransmitter generation and metabolism. Although a number of mechanisms have been considered, a major benefit of EPA and DHA in neurodegenerative diseases may be their anti-inflammatory properties and their ability to influence the expression of genes beneficial to health. The balance of omega-6 and omega-3 FA is important for homeostasis and normal development throughout the life cycle.
The interest in polyunsaturated fatty acids (PUFA) supplementation has not been restricted to disciplines dealing with the basic sciences of biochemistry or biophysics, nor with medical applications relating to cardiology, psychiatry, or inflammatory processes. The study of behavior in both animals and humans has attempted to map functional performance against PUFA composition, often with an emphasis on the ω-3/ω-6 ratio. At the same time, demonstrations of PUFA=s effectiveness in relieving depression have even generated some strong caveats to avoid DHA and at best to employ pure, research grade EPA only. A variety of learning paradigms have included PUFA supplementation in animal studies, and in human studies involving sleep, ADHD, cognitive functioning, and mood. Although salutary outcomes are common, small samples, absence of replications, placebo effects, and a host of other methodological problems confuse meaningful interpretation. Furthermore, the translational research applications, from animal studies to human clinical treatment have often been found wanting. Theoretical attempts to attribute PUFA’s behavioral effects to changes in membrane fluidity, and their derivative influences on signaling pathways, remain inconclusive, and claims for a neurogenesis hypothesis is premature. While the range of efficacious behavioral outcomes is impressive, behavioral scientists confront the unanswered question: What does the future hold for behavioral research with PUFA?
Introduction: We have previously shown that adapted dietary uptake of rapeseed oil, a 9% alphalinolenic acid (18:3n-3, ALA) rich oil, could help to control neuronal disorders (1), using both the MDDAS (Magnesium Deficiency-Dependent Audiogenic Seizure) and MES (Maximum Electroshock Seizure) tests. The antiepileptic drug, Carbamazepine (CBZ) gave a similar neuroprotective pattern in the MDDAS test (2). Hereafter, we studied whether a chronic CBZ treatment was improved using omega-3 vs omega-6 diets. Methods: Two groups of mice were fed, for 30 days, Mg-deficient diets (50 ± 5 mg/kg), containing 5% vegetable oils, either omega6 (sunflower:corn 1:3) or omega3 (rapeseed). CBZ (25 mg/kg b.w. dissolved in DMSO: saline solution 1:1) was injected IP, once daily for 10 days. Mg-deficient diets, MDDAS and MES tests were as previously described (1). Increasing doses of NMDA were IP injected in both groups. Results: On the last day of treatment, no convulsive mice appeared in either the MDDAS and MES test (CBZ pharmacological effect). Four days later, in the MDDAS test: (i) All the mice were still protected in the rapeseed group whereas 50% had seizures in the omega6 group (with 2/3 fatal issues) (ii) The pattern of seizures showed a significant increase in the first two step durations as compared to CBZ untreated mice. CBZ minimal lethal dose in NMDA test was higher in the omega3 group. Conclusion: The synergic effect of omega3 diet and CBZ might involve the direct effect of CBZ on NMDA receptor (and the subsequent arachidonic cascade) (3, 4) and the AA membrane phospholipid levels related to diets.
References:
1. Pagès N, Maurois P, Agnani G, Vamecq J, Bac P, Delplanque B. Is
chronic rapeseed oil more neuroprotective than chronic corn/sunflower
diet? Evaluation by audiogenic seizure test in magnesium-deficient mice
(MDDAS)
2. Bac P, Maurois P, Dupont C, Pagès N, Stables JP, Gressens P,
Evrard P, Vamecq J. Magnesium deficiency-dependent audiogenic seizures
(MMDAS) in adult mice. A nutritional model for discriminatory screening
of anticonvulsant drugs and original assessment of neuroprotection
properties. J. Neuroscience 18, 4363-4373 (1998) [PubMed]
3. Bazinet RP, Rao JS, Chang L, Rapoport SI, Lee HJ. Chronic
carbamazepine decreases the incorporation rate and turnover of
arachidonic acid but not docosahexaenoic acid in brain phospholipids of
the unanesthetized rat: relevance to bipolar disorder. Biol Psychiatry
59, 401-407 (2006) [PubMed]
4. Basselin M, Villacreses NE, Chen M, Bell JM, Rapoport SI.
Chronic carbamazepine administration reduces N-methyl-D-aspartate
receptor-initiated signaling via arachidonic acid in rat brain. Biol
Psychiatry 62, 934-43 (2007) [PubMed]
David Horrobin, whom this lecture honors, recognized the importance of nutritionally essential polyunsaturated fatty acids (PUFAs) in brain function and structure, and how their disturbed metabolism can contribute to brain disease. With new methods to quantify the in vivo kinetics of tissue PUFA metabolism, it has been possible to test and elaborate some of Horrobin’s ideas. With regard to n-3 PUFAs and the brain, there is disagreement regarding human daily dietary requirements of eicosapentaenoic acid (EPA, 22:5n-3) and docosahexaenoic acid (DHA, 22:6n-3). However, while dietary supplementation with these PUFAs appears critical in the non-suckling newborn, studies in unanesthetized adult rats using intravenously infused [1-14C]alpha-linolenic acid (alpha-LNA, 18:3n-3) show that the liver can convert alpha-LNA to DHA to satisfy the brain’s needs, if sufficient alpha-LNA is in the diet. The liver’s conversion capacity might become inadequate with liver disease, or if the brain’s needs are increased by neuroinflammation or excitotoxicity. In any case, it would be useful to be able to directly measure the human liver’s ability to synthesize DHA from its shorter chain precursors. Another interest of David Horrobin was bipolar disorder (BD) and schizophrenia. In this regard, when the mood stabilizers, lithium, carbamazepine, and valproic acid are given chronically to rats at therapeutically relevant doses, they reduce brain AA but not DHA metabolism: AA turnover in brain phospholipids and brain expression of AA-selective cPLA2, AA-selective acyl-CoA synthetase, and cyclooxygenase (COX)-2. These effects may partly explain their therapeutic action, as the postmortem BD brain demonstrates upregulated cPLA2 and COX-2 expression, plus markers of neuroinflammation and excitotoxicity. Positron emission tomography could be used to see if brain AA metabolism actually were upregulated in BD patients, as has been done in patients with Alzheimer disease.
This lecture will systematically review the role of omega-3 fatty acids in the pathophysiology and treatment of the following disorders usually first diagnosed in infancy, childhood or adolescence: developmental coordination disorder, autistic disorder, Asperger’s disorder, attention-deficit hyperactivity disorder, dyslexia and childhood depression.
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The relationships between EFA deficiency and ADHD have been demonstrated before. Richardson and Puri summarized studies in England in which fatty acids supplement were given to EFA deficient ADHD children. The results showed that EFA supplement was effective in some studies and having no effect in the other. In Israel, 3 different studies were conducted; In the first study, group of 24 EFA deficit ADHD children (age 9-11) were identified, and were treated in open label study with a mixture of n-3 and n-6 essential fatty acids (ratio 1:4) for 6 weeks. The results showed improvement in subjective and objective measurements of ADHD. This study confirms earlier studies. The second study involved a double blind design study. The aim of the study was to examine the effect of FA treatment on non- EFA deficit ADHD children. 36 ADHD children (aged 9-12) received the FA supplementation, and 35 matched ADHD children received placebo for 6 weeks. The results showed that while both groups greatly improved, no difference was found between the treatment and control groups. In the third study, a group of 40 ADHD children (aged 10-12) who suffered from sever sleep disturbances was studied. Most of those children were also iron deficient. The EFA treated group (6 weeks) showed improvement in the subjective and objective measurements and in the hemoglobin level, while the placebo group did not improve. Taken together, the results demonstrated the complex relationships between ADHD and EFA.
References:
1. Yehuda S., Carasso R.L. Modulation of learning, pain thresholds,
and thermoregulation in the rat by preparations of free purified alpha-
linolenic and linoleic acids: determination of optimal n-3 to n-6
ratio. Proc. Natl. Acad. Sci USA, 90, 10345-10349 (1993) [PubMed]
2. Yehuda S., Rabinovitz S., Mostofsky, D.I. Essential fatty acid
and the brain: From infancy to aging. Neurobiology of Aging. 26S,
98-102 (2005) [PubMed]
3. Yehuda S., Rabinovitz S., Mostofsky D.I. Nutritional
deficiencies in learning and cognition. Journal of Pediatric
Gastroenterology and nutrition. 43(S3), 22-25 (2006) [PubMed]
Introduction: Cross-sectional studies in populations have observed an association between a higher fish or long-chain n-3 PUFA intake and a lower depression rate, suggesting a possible preventive effect of these fatty acids on depression. However, to-date, no prospective study supported this hypothesis. This study aimed to seek whether habitual fish or n-3 long-chain PUFA intake could influence the occurrence of depressive episodes along the follow-up of a cohort. Methods: In a subsample of from a French cohort of men and women, dietary habits have been assessed at the beginning of the follow-up by six 24-hour records, and antidepressant prescriptions, markers of depressive episodes, have been recorded during the 8-year follow-up. Results: Subjects consuming fatty fish or with an intake of long-chain n-3 PUFA higher than 0.10 % of energy intake had a significantly lesser risk of experiencing any depressive episode during the follow-up (OR=0.70 [0.53-0.92] p=0.01). This association was stronger in men (OR=0.50 [0.30-0.82] p<0.01), and in subjects with recurrent depressive episodes (OR=0.37 [0.21-0.67] p=0.001, for subjects with three or more depressive episodes). The association of fatty fish intake with a lower risk of recurrent depressive episodes was marked in non-smokers (85 % of the subjects). In contrast, smokers eating fatty fish had an increased risk of recurrent depression (p for interaction <0.01). Conclusion: These results from a prospective population study suggest that a usual intake of fatty fish or long-chain n-3 PUFA may decrease the risk of recurrent depression. This apparent protective effect might be limited to non-smoker subjects.
References:
1. Astorg P, Couthouis A, Potier de Courcy G, Bertrais S, et al.
Association of folate intake with the occurrence of depressive episodes
in middle-aged French men and women. Br J Nutr (2007) [PubMed]
2. Astorg P, Couthouis A, Bertrais S., Arnault N, et al.
Association of fish and long-chain omega-3 polyunsaturated fatty acid
intakes with the occurrence of depressive episodes in middle-aged
French men and women. Prostaglandins Leukot Essent Fatty Acids 78(3),
171-82 (2008) [PubMed]
Aims: A growing body of evidence indicates the potential importance of fatty acid nutrition to the healthy functioning of the human brain. Our aim was to examine the association between very-long-chain omega-3 fatty acids and mental health morbidity in the population based Western Australian Pregnancy Cohort Study. Methods: The cohort of pregnant women provided information at birth and in subsequent follow-ups that allowed for potential outcomes and confounders to be quantified on their children. In the 14-year follow-up, 1783 adolescents were evaluated using the Child Behaviour Checklist to assess mental health morbidity and the Youth Beck Depression Inventory to assess depression. As an index of dietary intake, erythrocytes were isolated and analysed for fatty acid composition using gas chromatography from 1379 of the adolescents. Eicosapentaenoic acid (EPA), arachidonic acid (AA), docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA) were amongst those measured. Spearman’s correlations were used to determine associations between mental health scores and the very-long-chain omega-3 fatty acids and linear regression models were applied to allow for adjustment of individual (overall dietary intake, physical activity level, body mass index), maternal (age and education) and family factors (family functioning, father living with family, family income). Results: At 14 years the prevalence of total mental health morbidity was 14.1% (internalising behaviours 12.6%, externalising behaviours 15.7%). The prevalence of mild depression was 7.9% and moderate/severe depression was 4.9%. The mean (±SD) AA, EPA, DPA and DHA levels in erythrocytes were 13.45 (2.16), 0.71 (0.21), 4.33 (2.15) and 4.28 (1.07) microg/ml, respectively. We found that higher DPA levels were correlated with significant increases in total mental health scores (R=0.111; P<0.001) including depression (R=0.105; P<0.001). Lower DHA levels were associated with increases in externalising mental health morbidity that approached significance (R= -0.052; P=0.058). Following adjustment for individual, maternal and family factors, higher DPA levels continued to be significantly associated with an increased depression score (B=0.246; P=.021). Conclusion: The unexpected results of this study show a significant association between increased amounts of DPA in erythrocytes and mental health morbidity including depression. It is therefore important to ascertain dietary sources of specific very-long-chain fatty acids including DPA and further investigate appropriate levels of intake for this fatty acid.
At present, little is known about the basic mechanisms that underlie
the schizophrenia disease process. This lack of knowledge is most
likely due to the fact that until recently large-scale expression
profiling studies were technologically impossible. Thus, most
researchers employed a “candidate gene/protein” approach. With recent
technological advances in genomics, proteomics and metabolomics
techniques, it is now possible to globally investigate the molecular
underpinnings of psychiatric conditions which should result in improved
knowledge and hopefully new (pre-symptomatic) diagnostic, therapeutic
and preventative regimes.
Our laboratory combines advanced computing and bioscience technologies
with multi-omics studies. Using this powerful approach we explore the
molecular “fingerprints” of psychotic disorders from early onset
through their progressive stages, exploring alterations at the gene,
protein, lipid and metabolite level. A further aim is to establish
whether disease related changes can be traced in peripheral tissues.
Amongst other tissues, we have investigated T-cell function in
schizophrenia patients and have identified significant alteration in
signaling mechanisms. The key aim of this study is to establish a
suitable surrogate ‘disease model’, allowing for dynamic functional
investigations of disease-associated pathophysiological mechanisms as
well as the identification of schizophrenia biomarkers, whilst limiting
problems such as drug and post mortem effects.
Acknowledgement: Thank you to the Stanley Medical Research Institute for Centre support.
Schizophrenia is a serious psychotic disorder, in which myelination and lipid disturbances in the brain have been reported. Antipsychotic drugs are frequently used in the treatment, but unfortunately, many atypical antipsychotics (e.g., clozapine and olanzapine) but also some typical drugs (e.g., chlorpromazine) often induce weight gain, dyslipidemia and diabetes. The underlying molecular mechanisms are incompletely known. To search for new pathways involved in antipsychotic drug response, we performed global gene expression analysis on cultured human glioma cells exposed to haloperidol or clozapine. Both drugs significantly enhanced the transcription of several genes involved in cholesterol- and fatty acid biosynthesis, all under transcriptional control of the sterol regulatory element-binding proteins SREBP1 and SREBP2 (Fernø et al. 2005). We also demonstrated increased cellular levels of cholesterol and triglycerides. The antipsychotic drugs caused a direct activation of the SREBP transcription factors, which was evident in several glial- and liver cell lines (Fernø et al 2006; Raeder et al 2006). There were marked differences in the ability of the drugs to activate the SREBP system (Fernø et al 2006). We have also found increased expression of SREBP-controlled lipid biosynthesis genes in peripheral blood cells of olanzapine-treated patients (Vik-Mo et al 2008). Finally, we show strong association between variants of the INSIG2 gene in the SREBP system and antipsychotic-related weight gain in patients with schizophrenia (Le Hellard et al 2008). We suggest that drug-induced activation of SREBP-controlled fatty acid- and cholesterol biosynthesis is a novel action of relevance for both the therapeutic efficacy and metabolic adverse effects of antipsychotic drugs.
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A substantive body of evidence suggests that free radical mediated oxidative stress affecting the central nervous system and peripheral tissues is involved in the pathophysiology of schizophrenia. Evaluation of such effects typically involves an assessment of damage to cellular biomolecules such as DNA, lipids and proteins rather than the direct measurement of the radicals per se. In the case of schizophrenia the focus of most investigations has been towards the determination of indices of lipid peroxidation. A series of case/control ex vivo studies have been conducted to determine a profile of biomarkers of DNA, lipids and proteins in schizophrenia patients. A range of analytical techniques have been applied including chromatographic determination of breath alkanes and aldehydic products of lipid peroxidation, immunoassay of plasma protein carbonyls and electrophoretic determination of peripheral DNA damage. Parallel in vitro studies have examined the efficacy of potential adjunctive agents including monophenolics, polyphenolics and polyunsaturated fatty acids as modulators of an oxidative challenge. Levels of plasma protein carbonyls and lymphocyte DNA damage were elevated in the schizophrenia group but the results did not reach statistical significance (NS)1. When the populations were sorted by gender the male patients exhibited elevated levels of protein carbonyls (NS) and lymphocyte DNA damage (p< 0.05) compared to the population of age matched female patients. In contrast, levels of plasma ascorbate were increased ((p< 0.01) in the female patients suggesting a possible protective effect of this dietary derived antioxidant1. In vitro studies demonstrated epigallocatechin gallate and hydroxytyrosol afforded significant cytoprotection of the DNA2.
Acknowledgements: This research involved a number of collaborative studies between the Robert Gordon University (A) and the Ness Foundation (B), Inverness. The key contributors were Julie Young (A), Raymond Reid (A), Klaus WJ Wahle (A), Siofradh McKinney (B), Iain Glen (B) (Principal Investigator , Ness Foundation) and Susanne Boylea (Principal Investigator, RGU). Julie Young was supported by an RGU RDI PhD Studentship and further funding was obtained from TENOVUS Scotland.
References:
1. Young J, McKinney SB, Ross BM, Wahle KWJ and Boyle SP.
Biomarkers of oxidative stress in schizophrenic and control subjects.
Prostaglandins, Leukotrienes and Essential Fatty Acids 76, 73–85 (2007)
[PubMed]
2. Young J, Wahle KWJ and Boyle SP. Cytoprotective effects of
phenolic antioxidants and essential fatty acids in human blood monocyte
and neuroblastoma cell lines: Surrogates for neurological damage in
vivo. Prostaglandins, Leukotrienes and Essential Fatty Acids 78, 45–59
(2008) [PubMed]
Viruses, starvation, oxidative or endoplasmic reticulum stress, activate stress type-specific kinases (pkr, gcn2, hri and perk) that phosphorylate eif2alpha. Phosphorylated eif2alpha shuts down protein synthesis via inhibition of the translation initiation factor EIF2B, while also activating a key transcription factor, ATF4, which controls processes designed to remedy the effects of the initial stressors. This network plays an important role in the pathology of schizophrenia and bipolar disorder 1,2. Numerous susceptibility genes related to these disorders encode for components of its various inputs and outputs, and the stress-responsive network is activated by the environmental risk factors implicated in these diseases (viruses, parasites and famine). EIF2B mutations are responsible for vanishing white matter disease, which selectively targets oligodendrocytes. Disruption of this network may well contribute to the oligodendrocyte cell death that is a feature of both bipolar disorder and schizophrenia. Central to the effects of ATF4 is an ability to promote activation of the glutathione oxidative defense system. Glutathione levels are decreased in the schizophrenic brain, an effect that may contribute to the generation of toxic catecholamine-derived psychotomimetic quinones, as well as to NMDA receptor dysregulation. Glutathione also plays a major role in protecting oligodendrocytes against various cytotoxins. In addition, glutathione possesses antiviral effects against Influenza, Herpes simplex, and Cytomegalovirus, each implicated as risk factors in schizophrenia. Glutathione occupies a central position in relation to many of the pathological processes underlying these disorders and a clearer understanding of its function may further a radically different approach to the treatment of these disorders 3.
References:
1. Carter C.J. Multiple genes and factors associated with bipolar
disorder converge on growth factor and stress activated kinase pathways
controlling translation initiation: implications for oligodendrocyte
viability. Neurochem Int. 50, 461-490 (2007) [PubMed]
2. Carter C. J. eIF2B and Oligodendrocyte Survival: Where Nature
and Nurture Meet in Bipolar Disorder and Schizophrenia? Schizophr.Bull.
33, 1343-1353 (2007) [PubMed]
3. Lavoie S., Murray M.M., Deppen P., Knyazeva M.G., Berk M.,
Boulat O. et al. Glutathione Precursor, N-Acetyl-Cysteine, Improves
Mismatch Negativity in Schizophrenia Patients. Neuropsychopharmacology
(2007); Epub. doi:10.1038/sj.npp.1301624 [PubMed]
Converging evidence favors an abnormal susceptibility to oxidative stress in schizophrenia. Decreased levels of glutathione (GSH), the principal non-protein antioxidant and redox regulator, was observed in cerebrospinal-fluid and prefrontal cortex of patients. Moreover, they have an abnormal GSH synthesis of genetic origin: Two independent case-control studies showed a significant association between schizophrenia and a GAG trinucleotide repeat (TNR) polymorphism in the GSH key synthesizing enzyme glutamate-cysteine-ligase (GCL) catalytic subunit (GCLC) gene. The most common TNR genotype 7/7 was more frequent in controls, whereas the rarest TNR genotype 8/8 was three times more frequent in patients. The disease-associated genotypes correlated with decreased GCLC protein expression, GCL activity and GSH content. Such redox dysregulation during development could underlie structural and functional connectivity anomalies. In experimental models, GSH deficit induces anomalies similar to those observed in patients.
(a) morphology: spine density and GABA-parvalbumine immunoreactivity are decreased in anterior cingulate cortex
(b) physiology: NMDA-dependant synaptic plasticity and dopamine modulation of NMDA response are impaired.
(c) cognition: deficit in olfactory integration and in object recognition.
In a clinical study, GSH precursor N-acetyl cysteine (NAC,
2g/day for 6 months) given as add on therapy, improves the negative
symptoms and decreases the side effects of antipsychotics (Berk et al.,
in press). In an auditory oddball paradigm, NAC improves the mismatched
negativity, an evoked potential related to pre-attention and to NMDA
receptors function.
In summary, clinical and experimental evidence converge to demonstrate
that a genetically induced dysregulation of GSH synthesis represent a
major risk factor contributing to the development of schizophrenia.
Acknowledgements: Swiss National Foundation for Scientific Research, NARSAD, Loterie Romande, Fonds pour la Recherche en Santé du Québec
Website link
References:
1. Cabungcal JH, Nicolas D, Kraftsik R, Cuenod M, Hornung J-P*, Do
KQ§. Glutathione deficit during development induces anomalies in the
rat anterior cingulate GABAergic processes: relevance to schizophrenia.
Neurobiology of Disease. 22, 624-637 (2006) §authors equally
responsible for this work [PubMed]
2. Gysin R, Kraftsik R, Sandell J, Bovet P, Chappuis C, Conus P,
Deppen P, Preisig M, Ruiz V, Steullet P, Tosic M, Werge T, Cuénod M,
and Do KQ. Impaired glutathione synthesis in schizophrenia: Convergent
genetic and functional evidence. Proc Natl Acad Sci USA. 104,
16621-16626 (2007) [PubMed]
3. Lavoie S§, Murray MM§, , Deppen P, Knyazeva M, Berk M, Boulat O,
Bovet P, Conus P, Copolov D, Fornari E, Meuli RA, Solida A, Vianin P,
Cuenod M, Buclin T, Do KQ. A glutathione precursor, N-acetyl-cysteine,
improves mismatch negativity in schizophrenia patients.
Neuropsychopharmacology doi: 10.1038/sj.npp.1301624 § The two first
authors have contributed equally to this work (2007) [PubMed]
4. Steullet P, Lavoie S, Guidi R, Kraftzig R, Cuénod M, Do KQ.
Intracellular glutathione deficit alters dopamine modulation of L-type
calcium channels via D2 and ryanodyne receptors. Free Radical Biology
and Medicine. 44, 1042-1054 (2008) [PubMed]
5. Do K. Q., Bovet P., Cabungcal J.H., Conus P., Gysin R., Lavoie
S., Steullet P. and Cuenod M., Redox dysregulation in schizophrenia:
Genetic susceptibility and pathophysiological mechanisms. Handbook of
neurochemistry and molecular neurobiology. 3rd edition, edited by A
Lajtha, Vol : Schizophrenia , D. Javitt Editor, Springer, New York, in
press.
Introduction: Schizophrenia is a remarkably complex disorder with a
multitude of behavioral and biological perturbations. Whether these
diverse alterations are independent biological processes or a result of
a more fundamental pathology has yet to be determined. A multiplicity
of theories has been proposed over the years that aim to conceptualize
the pathological processes inherent to schizophrenia. Thus, the issue
at hand, firstly, is to identify candidate biological process(es) that
are associated with schizophrenia. Such an approach can lead to the
identification of specific metabolic pathways that can serve as
potential targets for therapeutic monitoring and intervention.
Methods: We apply high-pressure liquid chromatography with a
Coulometric Multi-Electrode Array System to determine multiple
redox-active low-molecular-weight compounds in postmortem brain
samples.
Results: Under physiological conditions, the potential for free
radical-mediated damage is kept in check by the antioxidant defense
system (AODS), comprising a series of enzymatic and non-enzymatic
components. These enzymes act cooperatively at different sites in the
free radical pathways. In brain, a dynamic state is kept in check
during the redox coupling under normal conditions. By contrast, lack of
such correlations in schizophrenia point to a disturbance of redox
coupling mechanisms in the AODS, possibly resulting from a decreased
level of glutathione (GSH) as well as age-related decreases of oxidized
GSH and glutathione reductase activities. In addition, the homeostatic
response of mitochondria to oxidative stress is also altered in
schizophrenia.
Conclusion: Taken together, our data showing altered membrane
dynamics, AODS enzyme activities and purine catabolism, and findings
from other investigators are consistent with the notion of free
radical-mediated neurotoxicity in schizophrenia.
Acknowledgements: Supported in part by the grants from VA Merit Reviews and VA Senior Research Career Scientist Awards.
References:
1. Yao JK, Cheng P. Determination of multiple redox-active
compounds by high-performance liquid chromatography with coulometric
multi-electrode array system. J. Chromatogr. B 810, 93-100 (2004)
[PubMed]
2. Yao JK, Leonard S, Reddy RD. Increased nitric oxide radicals in
postmortem brains from schizophrenic patients. Schizophr Bull. 30,
923-934 (2004) [PubMed]
3. Yao JK, Reddy RD. Metabolic investigation in psychiatric disorders. Mol Neurobiol. 31, 193-203 (2005) [PubMed]
4. Yao JK, Leonard S, Reddy R. Altered glutathione redox state in schizophrenia. Disease Markers. 22, 83-93 (2006) [PubMed]
5. Elamin AH, Day BW, Yao JK. Unraveling Complexity by Integrative
Biological Investigation. In: Fatty Acids and Oxidative Stress in
Neuropsychiatric Disorders. Nova Science Publishers, Inc., Hauppauge,
NY (2008)
The diagnostics, screening and prognostics of brain related diseases
pose generally fundamental difficulties. Recently the application of
body fluid proton (1H) nuclear magnetic resonance (NMR) metabonomics
has received considerable interest also in this area [1]. A brief
introduction to the methodological aspects and recent key findings will
be given in the first part of the talk. Then the focus will move to our
recent application of 1H NMR metabonomics of serum to study if it would
be possible to identify metabolic phenotypes characteristic for mild
cognitive impairment (MCI) [2]. If this were possible there might be
means to identify individuals having an increased risk for Alzheimer’s
disease (AD). Importantly, recent findings point towards a fundamental
role of cholesterol and lipoproteins in AD pathophysiology.
Consequently, 1H NMR metabonomics offers an appealing new approach to
investigate serum metabolism also in relation to MCI and AD [3,4]. We
applied a combination of three molecular windows that leads to
information on lipoprotein subclasses, various low-molecular-weight
metabolites and also individual lipid molecules together with their
degree of (poly)(un)saturation [2]. The data were analysed by
self-organising maps, a methodology facilitating a solely data-driven
overview on the metabolic phenotypes and their associations with the
clinical characteristics [5]. In fact, MCI-related metabolic phenotypes
were identified. Many of the known associations between vascular risk
factors and MCI were revealed. It was also found that low high-density
lipoprotein (HDL) cholesterol and high triglycerides, typical
characteristics of the metabolic syndrome, as well as obesity and
diabetes were clearly associated with MCI.
Acknowledgements: I am grateful to all my colleagues and
co-authors, particularly in reference [2], who share the scientific
interest and endeavour for NMR metabonomics and the multidisciplinary
field of ‘omics sciences. This work has been financially supported by
the Academy of Finland Centre of Excellence program for 2006–2011
Website link
References:
1. Holmes E, Tsang TM, Tabrizi SJ. The application of NMR-based
metabonomics in neurological disorders. NeuroRx. 3, 358-372 (2006) [PubMed]
2. Tukiainen T, Tynkkynen T, Mäkinen VP, Hokkanen J, Soininen P,
Jylänki P, Vehtari A, Gröhn O, Hallikainen M, Soininen H, Kivipelto M,
Groop PH, Laatikainen R, Kaski K, Pirttilä T, Ala-Korpela M.
Characterisation of metabolic phenotypes associated with cognitive
decline by proton NMR metabonomics of serum. In preparation (2008)
3. Ala-Korpela M. Potential role of body fluid 1H NMR metabonomics
as a prognostic and diagnostic tool. Expert Rev Mol Diagn. 7, 761-773
(2007) [PubMed]
4. Ala-Korpela M. Critical evaluation of 1H NMR metabonomics of
serum as a methodology for disease risk assessment and diagnostics.
Clin Chem Lab Med. 46, 27-42 (2008) [PubMed]
5. Mäkinen VP, Soininen P, Forsblom C, Parkkonen M, Ingman P, Kaski
K, Groop PH, Ala-Korpela M. 1H NMR metabonomics approach to the disease
continuum of diabetic complications and premature death. Mol Syst Biol.
4, 167 (2008) [PubMed]
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At magnetic field strengths of 1.5 T or higher, proton neurospectroscopy allows the ascertainment of values of myo-inositol, choline-containing compounds, creatine, glutamate, glutamine and N-acetyl aspartate while 31-phosphorus neurospectroscopy allows the ascertainment of values of phosphomonoesters, inorganic phosphate, phosphodiesters, phosphocreatine, and the gamma, alpha and beta nucleotide triphosphate resonances. Since choline is a common polar head group at the Sn3 position of membrane phospholipid molecules, a raised level of free choline, as indexed by proton neurospectroscopy, can indicate relatively low anabolism of membrane phospholipid molecules. Furthermore, the choline peak includes phosphorylcholine and glycerophosphorylcholine and even ethanolamine. The phosphomonoesters peak includes major contributions from phosphocholine, phosphoethanolamine and L-phosphoserine, which are important precursors of membrane phospholipids, while the phosphodiesters peak includes contributions from glycerophosphocholine and glycerophosphoethanolamine, which are important products of membrane phospholipid catabolism. Meanwhile, serial high-resolution structural brain scans can be precisely aligned using linear or nonlinear methods. Computational subtraction of the three-dimensional cartesian spatial representation matrices of serially acquired data allows the determination of structural cerebral changes with great precision, since voxel signals from unchanged structures are almost completely cancelled. Furthermore, lateral ventricular changes can be accurately quantified using a semi-automated method involving contour production, threshold computation, binary image creation and ventricular extraction. The application of these techniques to the study of fatty acids in the pathophysiology and treatment of several neuropsychiatric disorders is described.
Introduction: Brain structural abnormalities belong to the most
consistent findings in schizophrenia, but only little is known about
the underlying pathomechanisms. Structural changes at the time of first
acute onset are of special interest, since they seem to be progressive
and associated with functional outcome and response to antipsychotic
medication. In our study we aimed to characterise nature and activity
of structural changes in different stages of disorder, investigating
associations between peripheral biochemical parameters and focal brain
changes.
Methods: T1-weighted high resolution magnetic resonance images of
unmedicated schizophrenia patients (24) and healthy controls (25) were
compared using voxel-based morphometry. Considering stage of disorder,
patients were sub-divided into first-episode and recurrent-episode
groups. Serum activity of calcium-independent phospholipase A2 (PLA2),
as key enzyme of phospholipid remodeling/repair, and serum
concentration of S100B, an astrocyte produced modulator of
proliferation and differentiation of neurons and glia cells, served as
peripheral parameters. Both were treated as co-variates within an age
corrected, general linear model based interaction analysis.
Results: Interaction analysis revealed a distinct pattern of
associations between focal structural changes and biochemical
parameters. Affected structures included temporal pole gray matter
(PLA2) and fronto-temporal white matter (S100B). Those patterns
differed significantly between first and recurrent episode patients.
Conclusion: Multimodal approaches are helpful and necessary to
investigate brain structural abnormalities in schizophrenia. The
pattern of associations with PLA2 indicates a regionally defined
process of active structural remodeling at the time of first onset,
shifting to wide-spread less localized and less active alterations in
recurrent-episode patients.
Introduction: The aim was to bring together all the results
volumetric niacin response and cerebral MRI studies in forensic
schizophrenia patients who have dangerously seriously violently
offended in order to determine the extent to which they shed light on
the degree to which the membrane phospholipid hypothesis and the
actions of free radicals and other reactive species are associated with
cerebral pathophysiological mechanisms in this group of patients.
Methods: The patients who underwent niacin testing and MRI
scanning were inpatients from a medium secure unit with a DSM-IV-TR
diagnosis of schizophrenia. There was no history of alcohol dependency
or any other comorbid psychoactive substance misuse disorder. Expert
psychiatric opinion, accepted in court, was that all these patients had
violently offended directly as a result of schizophrenia. These
offences consisted of homicide, attempted murder or wounding with
intent to cause grievous bodily harm. The cerebral MRI scanning
included 31-phosphorus magnetic resonance spectroscopy (1.5 T using an
ISIS sequence, TR=10s; 64 signal averages localized on a 707070 mm3
voxel).
Results: There was a strong, and negative, correlation between the
volumetric niacin response and the metabolite concentration of
inorganic phosphate expressed as a ratio of the total 31-phosphorus
signal (r = -0.78, p<0.005). Compared with age- and sex-matched
controls, in the patient group the mean cerebral beta-nucleotide
triphosphate was lower (p<0.04) and the mean gamma-nucleotide
triphosphate was higher (p<0.04).
Conclusion: The volumetric niacin response to inorganic phosphate
ratio suggests that there is an alteration in energy state in this
patient group.
Introduction: Attenuated skin flush response to local
methylnicotinate (niacin) stimulation represents a robust parameter in
schizophrenia and is considered as biological marker of deregulated
membrane phospholipid turnover and prostaglandin signalling. An
association between attenuated niacin response and decreased
arachidonic acid levels (main product of phospholipid degradation and
major precursor of prostaglandin synthesis) was shown. Skin response to
niacin challenge is a prostaglandin mediated pathway involving G
protein-coupled nicotinic acid receptors at epidermal Langerhans cells,
Ca2+-dependent expression of prostaglandin synthetases, and formation
of vasodilatory prostaglandins. Skin physiology, epidermal lipid
profiles and GPR109B(HM74)-niacin receptor polymorphisms were assessed
as potential co-factors of niacin sensitivity.
Method: 0.1M, 0.01M, 0.001M niacin were applied on the skin of the
volar forearm in 41 neuroleptic naïve first-episode schizophrenia
patients (SCH) and 45 healthy controls. Skin flush response was
recorded every three min over 15 min using optical reflection
spectroscopy. Skin physiology was assessed using TEWAmetry for
epidermal barrier function, Corneometry for stratum corneum
(SC)-hydration and surface pH in vivo. Skin lipid profiles were
measured by combined HPTL/gas-chromatography, receptor polymorphisms by
a PCR-based assay.
Results: Niacin sensitivity was significantly attenuated and a
decrease for SC-hydration and epidermal barrier function was measured
in SCH patients. Co-variance analysis showed a significant correlation
for SC-hydration and niacin sensitivity. Two rare SNPs in the niacin
receptor gene (T173P and F198L) were detected in SCH.
Conclusion: These results are indicative for an influence of SC
hydration on niacin sensitivity with a possible link in the skin lipid
metabolism in addition to the established arachidonic acid
availability.
Introduction: Schizophrenia is a neurodevelopmental disorder with
variable regional gray matter reductions due to reduced dendritic and
spine densities, likely resulting from increased oxidative stress and
reduced neurotrophins. We have hypothesized that omega-3 fatty acids
and conventional antipsychotics will improve the neuropathology and
psychopathology by regulation of oxidative stress and neurotrophins.
Methods: The time dependent temporal treatment effects of
different antipsychotics were studied on blood and brain omega-3 fatty
acids, oxidative stress and neurotrophins in rats and on blood and CSF
in medication naïve first episode and antipsychotic treated
schizophrenic patients.
Results: In rats, the short-term treatment with typical >
atypical antipsychotic was potent in reducing oxidative stress and
increasing neurotrophins in both blood and brain. However, long-term
chronic treatment with typical > atypical was neurotoxic and
increased the oxidative stress, and reduced the fatty acids and
neurotrophin. In medication naïve first episode patients, the levels of
oxidative stress markers were increased, and neurotrophins and omega-3
fatty acids were reduced in both blood and CSF. Again, short-term
treatment with both typical and atypical antipsychotics was beneficial
but chronic treatment was deleterious by increased oxidative stress,
and reduced neurotrophins and omega-3 fatty acids. Furthermore,
adjunctive use of omega-3 fatty acid was found to reduce the oxidative
stress and increase the levels of neurotrophins.
Conclusion: Appropriate use of combinations of omega-3 fatty
acids, antioxidants, antipsychotics and neuroprotective agents will
balance the levels of oxidative stress and neurotrophins and improve
the clinical outcome, reduce the metabolic morbidities and improved
quality of life in schizophrenia.
References:
1. Buckley PF, Mahadik SP, Pillai A, Terry AV Jr. Neurotrophins and schizophrenia. Schizophr Res. 94, 1-11 (2007) [PubMed]
2. Mahadik SP, Pillai A, Joshi S, Foster A. Prevention of oxidative
stress-mediated neuropathology and improved clinical outcome by
adjunctive use of a combination of antioxidants and omega-3 fatty acids
in schizophrenia. Int Rev Psychiatry, 18, 119-31 (2006) [PubMed]
3. Pillai A, Parikh V, Terry AV Jr, Mahadik SP. Long-term
antipsychotic treatments and crossover studies in rats: Differential
effects of typical and atypical agents on the expression of antioxidant
enzymes and membrane lipid peroxidation in rat brain. J Psychiatric
Res. 41,372-86 (2007) [PubMed]
4. Pillai A, Terry AV Jr, Mahadik SP. Differential effects of
long-term treatment with typical and atypical antipsychotics on NGF and
BDNF levels in rat striatum and hippocampus. Schizophr Res. 82 , 95-106
(2006) [PubMed]
5. Ranjekar PK, Hinge A, Hegde MV, Ghate M, Kale A, Sitasawad S,
Wagh U, Debsikdar V, Mahadik SP. Decreased antioxidant enzymes and
membrane essential fatty acids in schizophrenia and bipolar mood
disorder patients. Psychiatry Res. 121, 109-122 (2003) [PubMed]
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EPA exerts multiple biological activities, supported by both in vivo and in vitro studies and also placebo controlled clinical trials. A few biological effects of EPA are to mention are; Cardiovascular – antiplatelet effects, lowering of triglycerides for which it approved medicine in Japan. In Rheumatology and Inflammation, as anti-inflammatory, in oncology EPA is used as an anticancer agent and with anti cachexia activity. However, most of the studies carried out to date are on mixtures of EPA and docosahexaenoic acid (DHA). With the availability of pure EPA, as an ethyl ester we have concentrated our efforts on investigate the effects of EPA in the field of Psychiatry and other CNS disorders. The two areas where clinical effects have been reported are in treatment resistant Depression and Huntington’s disease (HD). Four randomised placebo-controlled studies, including one in bipolar depression, have now shown that the pure ethyl ester of EPA is effective in treating various types of depression which respond poorly to other drugs. Three randomised placebo-controlled studies have now been completed in HD. HD subjects have CAG repeats from 36 to over 100, but with most subjects within the range of 36 to 60 repeat. The greater the number of CAG repeats the earlier the onset of the disease. Evidence suggests that the rate of disease progression is related to the CAG repeat length; this dependency being greater when the number of CAG repeats is below approximately 45. Summary data from three HD trials will be presented and the overall conclusion is that there is now strong supporting evidence for the initial observation that pure EPA (Miraxion) improves symptomatic improvement in subjects with HD, and that the benefit observed at 6 to 12 months is maintained to at least 24 months.
Introduction: Growing evidence strongly suggests that inflammation
contributes to the etiology of neurodegenerative diseases.
Interleukin-1beta (IL-1), the most potent proimflammatory cytokine, can
cause many changes similar to those observed in patients with
Alzheimer’s disease. Recent evidence shows that omega (n)-3 fatty acids
have anti-inflammatory and neuroprotective effects. In this study, we
evaluated the effects of chronic treatment with n-3 fatty acid
eicosapentaenoic acid (EPA) on memory, inflammatory response and
neurotrophin expressions in a neurodegeneration model induced by
chronic IL-1 administration.
Methods: Rats were implanted with two guide cannulae aimed at the
dentate gyrus of the hippocampus for the microdialysis probes and at
the cerebroventricle for saline or IL-1 beta injection for 8 days.
Microdialysis was conducted on day 7, during which animals were trained
and tested in an eight-arm radial maze. Hippocampal ACh was analyzed by
HPLC. Neurotrophin expressions were measured by quantitative PCR and
western blot.
Results: During rat learning and memory retrieve, acetylcholine
(ACh) efflux was much less in the group treated with IL-1which was
correlated to the memory deficit. EPA or IL-1 receptor antagonist
significantly increased ACh release and improved memory. EPA also
reversed the increased mRNA and protein expressions of beta-amyloid
precursor protein in the hippocampus of rats receiving IL-1 injections.
The expression of nerve growth factor and brain-derived neurotrophic
factor were decreased in the hippocampus and frontal cortex following
IL-1 administrations, which were also attenuated by EPA treatment.
Furthermore, EPA attenuated IL-1-induced elevation of prostaglandin E2
concentration and cox2 expression but increased anti-inflammatory
cytokine IL-4 and IL-10.
Conclusion: These results suggest that EPA may treat neurodegenerative diseases induced by inflammation disorders.
Potentially chronic diseases often have a critical point in their course beyond which treatment becomes less effective. In support of this, early treatment in schizophrenia and other psychoses has been linked to better outcome. Intervention prior to the first episode therefore holds the promise of even better outcomes, with the potential to prevent psychotic disorders. In the 1990s, criteria were developed and tested in a series of prospective naturalistic studies which identify a clinical population with subthreshold symptoms at ultra-high-risk for psychosis. The emergence of simultaneous brain volume changes in those ultra-high-risk individuals who develop psychosis indicate an active biological process, and underline the importance of pre-onset treatment. However, pre-psychotic intervention has also been questioned as, using current criteria, only 20-50% of individuals classified as prodromal develop a psychotic disorder within a 1-2 years period. Treatment agents in the pre-psychotic phase should, therefore, not have major side effects. Bioactive lipids are molecules that have both intra- and intercellular roles, including mediation, modulation and control of neurobiological processes, such as ion channel and receptor activity, neurotransmitter release, synaptic plasticity, second messenger pathways and neuronal gene expression. Abnormal membrane glycerol-phospholipids essential fatty acid (EFA) metabolism has been suggested to contribute to the etiopathophysiology of schizophrenia. EFA have been shown effective treatments for both, mood and psychotic symptoms, and they are neuroprotective. When considered, together, with the controversy concerned with the extent to which an intervention is intrusive or may produce harm which outweighs the benefits, EFA can be considered prime candidates for evaluation in individuals with prodromal symptoms. We report on the first randomized, placebo-controlled trial investigating the preventive use of omega-3 fatty acids in 81 individuals with prodromal symptoms.
Introduction: There has been conflicting evidence of a bimodal
distribution of erythrocyte (RBC) polyunsaturated fatty acids (PUFA) in
schizophrenia. In a clinical trial, we tested the bimodality hypothesis
of schizophrenia and schizoaffective disorder.
Methods: Acutely psychotic patients were recruited. All were
prescribed antipsychotic drugs, and were randomly assigned to active or
placebo Ethyl-EPA 2 g/d and active or placebo Vitamin E 364 mg/d +
Vitamin C 1000 mg/d. Patients were followed up for 16 weeks. The main
clinical variable was the Positive and Negative Syndrome Scale (PANSS).
RBC fatty acids, S-α-tocopherol and other biochemical variables were
measured. We used Linear Mixed Model for longitudinal analyses.
Results: 99 patients aged 18-39 years were included. At baseline,
PUFA levels were bimodally distributed, one of three patients having
very low levels compared to healthy controls. The only robust predictor
of low PUFA was low α-tocopherol. In the low PUFA group, negative
symptoms were stronger, hypertriglyceridemia five times as prevalent,
and antipsychotic medication dosage was lower.
The risk of drop-out during the trial was four times higher in
the low PUFA group. In the whole sample, adding EPA or vitamins to
antipsychotic drugs had no significant effect on symptoms. However,
PUFA group was a strong effect modifier. In the low PUFA group only,
EPA and vitamins given separately had a harmful effect on positive
symptoms. Combining agents prevented these effects. PUFA group was also
an effect modifier regarding blood pressure and sustained and selective
attention.
Conclusion: We have validated a bimodal distribution of PUFA
levels among patients with schizophrenia and schizoaffective disorder,
suggesting two genetically different populations. The two differed with
respect to several clinical and biochemical variables.
S-alpha-tocopherol was a robust predictor of the bimodality. A
deficient endogenous redox regulatory system in a subgroup of patients
may best explain our findings.
Acknowledgements: Stanley Medical Research Institute (Grant#
01T-106), USA; Laxdale Ltd., UK; Aker University Hospital, Norway;
Diakonhjemmet Hospital, Norway
Introduction. 70 patients with chronic psychoses were given pure
ethyl EPA with a small amount of evening primrose oil, and
psychotherapy aimed at right brain affect regulation and encouraging
observing-self function. Some patients also received family work, brain
exercises and energy therapy (a variant of EMDR).
Methods: This was a detailed qualitative study. There was an
intensive 3 hour initial assessment of the patient (and where possible
family), and intensive ongoing assessment of clinical changes by
providing supervision of each weekly psychotherapy session. A final
follow up interview with the patient and family took place using a long
questionnaire. The questionnaire covered family history, infantile and
childhood difficulties, physical illness, and symptoms of illness.
Results: 49 patients turned up for the final interview. In all
the patients there was improvement in one or several of the following
modalities: general functioning, mood, obsessional symptoms excluding
ruminations, psychotic symptoms, energy levels and general enthusiasm
for life. In almost all patients there was a history of one or several
of the following: birth complications, ADHD, Dyspraxia, Dyslexia. Most
patients had a family history of one of these and or chronic psychosis,
Autism, Asperger’s disease.
Conclusion: A combination of EPA and psychotherapy utilises the
use-it-or-lose-it principle, and is part of a multipronged treatment
necessary for an illness with a number of causative factors and multi
system pathology. The frequent association of later psychosis with
earlier difficulties points to the urgent need for prevention, starting
preconception and later involving recognition of childhood difficulties
as above.
The neurochemical basis of sleep mechanisms (onset and maintenance) is still controversial, although the phenomenon itself is known to be mediated by more than a single molecule. The list of suggested endogenous sleep substances is rather long, and there is no single 'sleep center' identified in the brain. The role of fatty acids and essential fatty acids in particular, has been ignored in sleep research. This review proposes an integration of the current knowledge about the effects of fatty acids in sleep neurochemistry, where in fatty acids are seen to exert a direct effect on neuronal membrane structure or indirectly on the dynamics of biochemical compounds (complex lipids, prostaglandins, neurotransmitters, amino acids, interleukins) necessary for the initiation and maintenance of sleep. The ability of a specific mixture of essential fatty acids [alpha-linolenic acid (n-3) and linoleic (n-6) in 1:4 ratio] to restore sleep disturbances among elderly and Alzheimer patient has previously been reported. Sleep disturbances accompanied several brain related disorders such as ADHD and anxiety. Treatment with a specific mixture of essential fatty acids elevated ADHD symptoms and decreased student test anxiety level. Sleep disturbances are very common among iron deficient rats and humans. It seems that the sleep disturbances contribute to the cognitive deficits. Treated with the specific mixture of fatty acids improve the cognitive level and hematological values. Experimental induced REM depravation resulted in an increased anxiety and corticosterone levels. Pretreatment with the mixture of fatty acids Protects rats form anxiogenic effects of REM deprivation. All of the results demonstrated the importance of sleep studies.
References:
1. Yehuda S, Rabinovitz S., Carasso RL. Mostofsky DI. Essential
fatty acids preparation (SR-3) improved Alzheimer’s patients quality of
life. Inter J Neurosci 87, 141-149 (1996) [PubMed]
2. Yehuda S, Rabinovitz S. Mostofsky DI Essential fatty acids and
sleep: Mini review and hypothesis. Medical Hypothesis 50, 139-145
(1998) [PubMed]
3. Yehuda S, Rabinovitz S, Mostofsky DI. Mixture of essential fatty
acids lowers test anxiety. Nutritional Neuroscience 8, 265-267 (2005) [PubMed]
4. Yehuda S, Rabinovitz S, Mostofsky DI. Pretreatment with a
mixture of essential fatty acids Protects rats from anxiogenic effects
of REM deprivation. Nutritional Neuroscience. 10, 269-271 (2007) [PubMed]
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The potential of omega-3 polyunsaturated fatty acids (PUFA) in neurology and psychiatry has attracted much attention. One area with significant unmet needs is neurological trauma. This presentation reviews studies which support the idea that omega-3 fatty acids could be used in neurotrauma, with emphasis on spinal cord injury (SCI). SCI has dramatic consequences for patients, and is associated with significant health care costs. There is no treatment which protects the injured cord. The pathogenesis of SCI includes excessive glutamate release and excitotoxicity, increased oxidative stress and neuroinflammation. Omega -3 PUFA could target these mechanisms. We have shown that an intravenous bolus of docosahexaenoic acid (DHA) administered 30 min after spinal cord hemisection or compression injury in adult rats induces significant neuroprotection. The omega-3 PUFA increased neuronal and glial survival, and led to a significantly improved neurological outcome. A combination of acute intravenous and chronic oral treatment with DHA was also investigated in spinal cord compression. The combined DHA treatment regime conferred a marked advantage compared to the acute DHA bolus, in particular in terms of functional recovery. DHA significantly reduced oxidative stress, decreased the recruitment of inflammatory cells to the injury site and the induction of COX-2. DHA also decreased axonal damage and dysfunction. Parallel studies in a peripheral nerve injury model and in primary sensory neurons in culture showed neurotrophic and pro-regenerative effects of DHA. These observations suggest that treatment with omega-3 PUFA has significant therapeutic potential in the management of SCI. improves outcome after spinal cord injury.
References:
1. King VR, Huang WL, Dyall SC, Curran OE, Priestley JV,
Michael-Titus AT. Omega-3 fatty acids improve recovery, whereas omega-6
fatty acids worsen outcome, after spinal cord injury in the adult rat.
J. Neurosci. 26, 4672-4680 (2006) [PubMed]
2. Huang WL, King VR, Curran OE, Dyall SC, Ward RE, Lal N,
Priestley JV, Michael-Titus AT. A combination of intravenous and
dietary docosahexaenoic acid significantly improves outcome after
spinal cord injury. Brain. 130, 3004-3019 (2007) [PubMed]
The substantia nigra pars compacta is particularly affected in idiopathic Parkinson’s disease. Almost all cases of this progressive movement disorder are sporadic. This would tend to point to an environmental cause rather than a genetic one, although rare inherited variants, such as those caused by parkin mutations, have been described and several distinct genetic loci are associated with this disorder. The following direct observations in this disorder are consistent with oxidative stress: increased lipid peroxidation; increased 8-hydroxydeoxyguanosine in mtDNA and total DNA; increased protein carbonyls in the brain (including the substantia nigra) and complex I protein damage; increased nitrotyrosine in the substantia nigra. Similarly, the following indirect evidence in this disorder is also consistent with oxidative stress: decreased levels of reduced glutathione (without a marked rise in oxidized glutathione) in the substantia nigra but not other brain regions; possible changes in glutathione metabolic enzymes (although the evidence here is conflicting); increased iron levels (without altered ferritin levels) in just the substantia nigra pars compacta of the brain; superoxide dismutase changes; reduced coenzyme Q10 levels in platelet mitochondria; increased haem oxygenase I in neurons and astrocytes; increased glycoxidation; increased COX-2; and NF-kappaB activation. In this context, it is likely that mitochondrial dysfunction may be of particular importance; it is of note that early-onset Parkinson’s disease may result from mutation of the PINK1 gene, which codes for the 581-amino acid PINK1 mitochondrial protein containing a mitochondrial targeting sequence at its N-terminus and having putative kinase activity.
Introduction: Epidemiological and animal data have shown that
dietary fat fish and intake of fishoil rich in 3 fatty acids (FA)
such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) may
prevent Alzheimer´s disease (AD).
Objective: To describe effects of supplementation of 3 FA in
patients with mild to moderate AD on cognition, neuropsychiatric
symptoms, inflammatory and biological markers in plasma and
cerebrospinal fluid (CSF).
Methods: 204 patients with AD were included (age range 74 ± 9
years, 54% females) with a stable condition and who had a Mini Mental
State Examination score (MMSE) between 15-30 points were randomized to
a daily intake of 1.7 gram of DHA and 0.6 gram EPA (-3 FA treated
group) or placebo for 6 months, after which all patients received 3
FA supplementation for an additional 6 months. Cognition was measured
with MMSE and Adas-Cog. Neuropsychiatric symptoms were measured with
Neuropsychiatric Inventory (NPI) and Montgomery Åsbergs Depression
Rating Scale (MADRS). Global function with Clinical Dementia Rating
Scale (CDR).All scales were performed at baseline and after 6 and 12
months. From all patients weight and nutritional assessments were
collected. In a subgroup plasma and CSF was collected at baseline and
after 6 months and IL-6, SIL-rII and TNF- were measured and from CSF
T-tau, P-tau and A1-42 was evaluated.
Results: 174 patients fulfilled the trial, 72 % were
APOEε4-carriers. Safety and tolerability was good. No significant
overall treatment effects on general cognition or neuropsychiatric
symptoms were found. Neither were any -3 FA treatment effects detected
on inflammatory or biological markers.
Positive treatment results in cognition were observed in the -3 FA
treated subgroup of patients with mild AD and MMSE>27 points. -3 FA
also showed positive effects in depressive symptoms in APOEε4-non
carriers and in agitation in APOEε4-carriers and a positive impact on
weight and appetite.
Conclusion: No overall general treatment effects with
supplementation of 2.3 gram -3 FA in this group of mild to moderate AD
was observed. However, the effects on memory in the group with very
mild AD suggests that supplementation with -3 FA is beneficial in the
very early events of AD.
Acknowledgements: OmegAD studygroup
Laboratory website link
References:
1. Freund-Levi Y, Eriksdotter-Jönhagen M, Cederholm T, Basun H,
Faxen-Irving G, Garlind A, Vedin I, Vessby B, Wahlund L-O, Palmblad.
Omega 3 fatty acid treatment of 174 patients with mild to moderate
Alzheimer’s disease (Omeg AD).a randomised double blind trial. Arch
Neurol. 63, 1402-1408 (2006) [PubMed]
2. Freund-Levi Y, Basun H, Faxén-Irving G, Garlind A, Grut M, Vedin
I, Palmblad J, Wahlund Lars-Olof, Eriksdotter-Jönhagen Maria. Omega-3
supplementation in mild to moderate Alzheimer’s disease: effects on
neuropsychiatric symptoms. Internat J Geriatr Psychiatry 23(2), 161-9
DOI: 10.1002/gps.1857 (2007) [PubMed]
A small scale double blind, randomised controlled, multi-disciplinary study investigated the effects of Omega-3 oils in people with Alzheimer’s disease. Participants were given three months of Omega-3 or placebo, and a number of measures were used to assess outcome. All participants were assessed by psychiatrists using the NINCDS-ADRDA diagnostic criteria for Alzheimer’s disease, and had an MMSE score between 14 and 24. Lipid analysis was carried out, and participants completed dietary sheets to monitor intake of Omega-3 through diet. A range of neuropsychological assesments were completed pre and post trial, and the occupational therapist conducted functional assessments using the Assessment of Motor and Processing Skills (AMPS). The ADAS-Cog was also used in order to compare Omega-3 directly with studies on acetylcholinesterase inhibitor medication. Well-being, and other non-cognitive aspects of functioning, were also assessed using the Quality of Life in Alzheimer’s Disease (QoL-AD) and a Clinician’s Interview-Based Impression of Change (CIBIC). Findings suggest that, while there was no systematic evidence for improvement in overall cognitive functioning over this time period, other measures such as functional ability and quality of life showed a positive trend. There were no significant life events during the trial that might have accounted for improvements in well-being. No participant made any significant changes to their diet, suggesting that the improvements could be due to Omega-3 supplementation. Further analysis of the neuropsychology will be reported upon, as participants showed more change in some areas of cognitive functioning than others, and this may have implications for the predictive and sensitivity values of different tests. It is important that this research design is replicated with a larger sample size to permit more complex data analysis. The research establishes the value of using such a range of measures; typically, research into the efficacy of treatments for Alzheimer’s disease concentrates on cognitive functioning only and, thus, may miss important non-cognitive benefits of interventions. This is particularly pertinent for people with Alzheimer’s disease and their families as they frequently report that quality of life is more important to them than memory and other cognitive skills.
Background: A number of studies have shown that increased dietary intake of fruits and vegetable extracts high in antioxidants (e.g., blueberries, strawberries and spinach) can retard and even reverse age-related decline in brain function and in cognitive and motor performance in rats. This is the first placebo-controlled human study to evaluate the effect of fruit polyphenols on neuropsychological test scores in combination with measurements of dietary intake clinical parameters in blood as well as influence on whole blood gene regulation. Methods: Sixty-two non-demented, non-depressed men (age 67-77 years) with subjective memory decline, were randomly assigned to a blueberry/grape juice- and placebo-group in a 9 week double blind intervention study. Pre- and post treatment assessment were measured with a computerised neuropsychological test battery (CANTAB), including tests for motor speed, visual reaction time, and spatial memory. Dietary habits were registered before intervention and several clinical biomarkers were measured in plasma/serum before and after the intervention. Pre- and post intervention-samples for measurement of gene regulation were also collected. Results and Conclusion: Preliminary analysis show no significant differences between the two groups on the neuropsychological test scores and clinical parameters measured, except for creatine kinase (CK), which was significantly decreased in the juice-group when compared to placebo. Since CK is characteristic for muscle damage response this may indicate that blueberry/grape-juice may protect against such damage. Analysis of dietary habits, antioxidant status in red blood cells, dietary antioxidants and biomarkers of DNA damage as well as whole blood gene regulation, have yet to be completed.
Evidence is put forward to suggest that myalgic encephalomyelitis, also known as chronic fatigue syndrome, may be associated with persistent viral infection. In turn, such infections are likely to impair the ability of the body to biosynthesize n-3 and n-6 long-chain polyunsaturated fatty acids by inhibiting the delta-6 desaturation of the precursor essential fatty acids alpha-linolenic acid and linoleic acid. In turn, this would impair the proper functioning of cell membranes, including cell signalling, and have an adverse effect of the biosynthesis of eicosanoids from the long-chain polyunsaturated fatty acids dihomo-gamma-linolenic acid, arachidonic acid and eicosapentaenoic acid. These actions might offer an explanation for some of the symptoms and signs of myalgic encephalomyelitis. A potential therapeutic avenue may be offered by bypassing the inhibition of the enzyme delta-6-desaturase by administering both virgin cold-pressed non-raffinated evening primrose oil and eicosapentaenoic acid. The former would supply gamma-linolenic acid and lipophilic pentacyclic triterpenes. The gamma-linolenic acid can readily be converted into dihomo-gamma-linolenic acid and thence arachidonic acid, while triterpenes have important free radical scavenging, cyclooxygenase and neutrophil elastase inhibitory activities. Furthermore, both arachidonic acid and eicosapentaenoic acid are, at relatively low concentrations, directly virucidal. The results of clinical studies using fatty acid preparations are described.
Anxiety disorders, which include generalized anxiety, phobias, post-traumatic stress disorder and obsessive compulsive disorder, are very common psychiatric conditions. Anxiety is also a common feature of many neurological and other psychiatric disorders. The aetiology of anxiety is unclear but likely involves the interplay of many biological and sociological factors. Anxiety has previously been treated with classical drugs such as the benzodiazepines, however these have several significant unwanted effects. More recently the selective serotonin reuptake inhibitors (SSRI) have been found to be efficacious for the treatment of anxiety. SSRIs were originally developed, however, for the treatment of depressive disorders. Such pharmacological overlap between anxiety and depression is mirrored by their tendency to be comorbid, as well as the neurobiological similarities between the two illnesses. Hence, it is of interest that omega-3 polyunsaturated fatty acids (PUFA) are able to ameliorate depressive symptoms and therefore might also be of benefit for patients with anxiety. A number of reports are supportive of such a hypothesis including findings of abnormal fatty acid dependent signaling and low omega-3 PUFA abundance in social phobia. Results of preliminary clinical trials are mixed, with a lack of efficacy being reported in patients with obsessive compulsive disorder but encouraging benefits being observed in various anxiety-associated symptoms in different situations. More extensive observational studies and clinical interventions currently underway will ultimately confirm or refute this hypothesis. Given the success of omega-3 PUFA treatment for depression and its comorbidity with anxiety there is, however, reason to be hopeful.
Introduction: Long-chain polyunsaturated fatty acid interventions
have been suggested for the treatment of a variety of psychiatric
disorders. The aim of this study was to carry out a systematic review
of peer-reviewed papers on the subject of fatty acid interventions in
clinical psychiatric practice.
Methods: A systematic review of PubMed and PsychLit was carried
out and the relevant papers critically appraised for the evidence base
for fatty acid interventions in clinical psychiatric practice.
Results: There was good evidence for some long-chain
polyunsaturated fatty acid interventions, for example the use of
eicosapentaenoic acid in depression and Huntington’s chorea. There was
conflicting evidence for fatty acid interventions in certain
conditions, for example in schizophrenia. There was little or no
evidence for the use of fatty acids in still other psychiatric
disorders for which they have been suggested.
Conclusion: In spite of the suggested theoretical basis for the
use of long-chain polyunsaturated fatty acid interventions in many
psychiatric disorders, research to date has shown only definite
evidence of such efficacy in a limited range of neuropsychiatric
disorders. Further well designed and appropriately statistically
powered studies are needed.
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Conference Abstracts. The Brain Lipids Conference 2008. Neurobiol. Lipids Vol. 7, 1 (10 April 2008) Freely available at: http://neurobiologyoflipids.org/content/7/1/
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