Calcium and Essential Fatty Acids

Prostaglandins Other Lipid Mediat. 2001 Aug;66(1):53-63
Effect of arachidonic acid on duodenal enterocyte ATPases.
Haag M, Kearns SD, Magada ON, Mphata PR, Claassen N, Kruger MC.
Department of Physiology, University of Pretoria, South Africa.

Duodenal ion transport processes are supported by ATPase enzymes in basolateral membranes of the enterocyte. In vivo studies have shown that long term n-6 poly-unsaturated fatty acid (PUFA) supplementation in rats causes increases in intestinal Ca absorption, coupled with a higher total calcium balance and bone calcium content. The present in vitro study was undertaken to test the effect of arachidonic acid (AA), a highly unsaturated (and thus physiologically potent) member of the n-6 PUFA family, on ATPases in enterocyte basolateral membranes isolated with a sorbitol density gradient procedure. This paper presents results which show that AA inhibits Na+,K+-ATPase in a dose-dependent manner (-67% of basal activity at a concentration of 30 microg/ml, P < 0.005) but that this effect is not mediated by protein kinase C, as shown by the use of the protein kinase C blocker calphostin (0.5 microM). Indomethacin (IDM) at 0.1 mM, a cyclo-oxygenase blocker, could also not reverse the inhibitory effect of AA on Na+,K+-ATPase. Ca2+-ATPase, on the other hand, is not affected significantly (-10%, P > 0.05) by arachidonic acid at 30 microg/ml.

Prostaglandins Leukot Essent Fatty Acids. 1999 Dec;61(6):381-90
Oestrogen and essential fatty acid supplementation corrects bone loss due to ovariectomy in the female Sprague Dawley rat.
Schlemmer CK, Coetzer H, Claassen N, Kruger MC.
Department of Physiology, University of Pretoria, South Africa.

Essential fatty acid deficient animals develop osteoporosis. Eicosapentaenoic acid and gamma-linoleic acid have been reported to have positive effects on bone metabolism in both the growing male rat and the ovariectomized (OVX) female rat. These effects have been further investigated using a novel gamma-linolenic/eicosapentaenoic acid diester together with an oestrogen implant in the ovariectomized, female Sprague Dawley rat. Rats were sham-operated or ovariectomized at age 11 weeks. Two groups of OVX rats received an oestrogen implant at ovariectomy. Animals received fatty acids, linoleic acid (control) or a diester with gamma-linolenic acid and eicosapentaenoic acid as part of a semi-synthetic diet. Bone calcium content and excretion of deoxypyridinolines as marker of bone degradation were measured at 14 weeks. Oestrogen, as well as diester alone, increased calcium/femur to sham levels. Oestrogen plus diester potentiated the effect of oestrogen on bone calcium (P < 0.05 vs OVX). At the same time, oestrogen alone and the combination of oestrogen plus diester significantly reduced (P < 0.05 vs OVX) urinary deoxypyridinoline and hydroxyproline excretion. Again, the diester potentiated the effect of oestrogen. The effects of the diester alone, together with the potentiated effects of oestrogen by the essential fatty acids on osteoporosis, are novel findings.

Prostaglandins Leukot Essent Fatty Acids. 1995 Jul;53(1):13-9.
The effect of different n-6/n-3 essential fatty acid ratios on calcium balance and bone in rats.
Claassen N, Coetzer H, Steinmann CM, Kruger MC.
Department of Physiology, Faculty of Medicine, University of Pretoria, South Africa.

Prostaglandins (PGs) are known to have various effects on bone metabolism. The supplementation of essential fatty acids (EFAs), the precursors of PGs, leads to increased intestinal calcium absorption and calcium balance. It is, however, not known whether increased calcium absorption and calcium balance will enhance the calcium content in bone. Male Sprague-Dawley rats (n = 40) aged 5-12 weeks were supplemented with EFAs. The main dietary EFAs, linoleic acid (LA) and alpha-linolenic acid (ALA) were administered in a ratio of 3:1 as a control group. The conversion of LA to ALA to the PG precursors is slow, with the first step, delta-6-desaturation being rate limiting. Fatty acids beyond this rate-limiting step, gamma-linolenic acid (GLA, n-6) and eicoapentaenioc acid (EPA, n-3), were administered to different groups in the ratios 3:1, 1:1 and 1:3 to explore the impact of different ratios of n-6 and n-3 EFAs. Intestinal calcium absorption (mg/24 h) increased by 41.5% in the 3:1 supplemented group, compared with the control group. The decrease in urinary calcium (mg/24 h) correlated with the increase in n-3 level. The calcium balance (mg/24 h) and bone calcium (mg/g bone ash) increased significantly in the 3:1 (41.5% and 24.7%) group, compared with the control. The increase in bone calcium might be attributed to an EFA-induced increase in circulating PGs. An increased synthesis of PGs acting on target bone cells, as well as changes in membrane fluidity, may underlie these observations.

Bone. 1995 Apr;16(4 Suppl):385S-392S.
Supplemented gamma-linolenic acid and eicosapentaenoic acid influence bone status in young male rats: effects on free urinary collagen crosslinks, total urinary hydroxyproline, and bone calcium content.
Claassen N,Potgieter HC, Seppa M, Vermaak WJ, Coetzer H, Van Papendorp DH, KrugerMC.
Department of Physiology, Faculty of Medicine, University of Pretoria, Republic of South Africa.

The effect of different ratios of the prostaglandin precursors gamma-linolenic (GLA) and eicosapentaenoic (EPA) acids on bone status in growing rats measured as a function of free urinary pyridinium crosslinks and hydroxyproline levels was investigated. Male Sprague-Dawley rats were weaned onto an essential fatty acid deficient diet and from their fifth week, different groups of rats received a balanced, semisynthetic diet, supplemented with different ratios of GLA:EPA supplied as a mixture of evening primrose oil (EPO) and fish oil (FO). Controls were supplemented with linoleic (LA; sunflower oil) and alpha-linolenic (ALA; linseed oil) acids (3:1) or a commercially available rat chow. Animals were terminated at 84 days and femur length, ash weight, calcium content, free urinary pyridinium crosslinks (Pyd and Dpyd), total hydroxyproline (Hyp), and creatinine levels measured. Free urinary Pyd and Dpyd are good indicators of bone status and they correlated well with Hyp. Pyd and Dpyd excretion were significantly decreased in the higher GLA:EPA dietary groups and correlated well (r = 0.7) with Hyp levels. Concomitantly, bone calcium content increased significantly in the same dietary groups. These results suggest that diet supplementation with relatively high GLA:EPA ratios are more effective in inhibiting bone resorption than LA:ALA.

Pediatr Res. 2002 May;51(5):647-52.
Gamma-linoleic acid and ascorbate improves skeletal ossification in offspring of diabetic rats.
Braddock R, Siman CM, Hamilton K, Garland HO, Sibley CP.
School of Biological Sciences, University of Manchester, Manchester M13 9PT, United Kingdom.

Maternal diabetes causes a range of complications in offspring, including reduced skeletal ossification. This study examined whether feeding gamma-linoleic acid (GLA) and ascorbate, alone or in combination, to diabetic pregnant rats improves skeletal development in their offspring. In addition, Ca(2+) concentration was monitored in maternal plasma and fetal tissue, as well as placental mRNA expression of calbindin-D(9k). Female rats rendered diabetic with streptozotocin were fed GLA (500 mg/kg/d), ascorbate (290 mg/kg/d), ascorbyl-GLA (790 mg/kg/d), or GLA and ascorbate (500 and 290 mg/kg/d, respectively) throughout pregnancy. Fetal skeletons were studied after alizarin red staining. Fewer ossification centers were observed in offspring of diabetic rats compared with offspring of control rats (68 +/- 4% of control, p = 0.01). An almost complete restoration of ossification occurred with all the treatments (92-95 +/- 3% of control). The effects of treatment on fetal ossification could not be explained by altered maternal plasma Ca(2+) concentrations or by mRNA expression of the placental Ca(2+)-transporting protein calbindin-D(9K). We conclude that GLA and/or ascorbate treatment was effective against diabetes-induced fetal ossification defects by a mechanism not related to placental Ca(2+) supply.

Essential Fatty Acids (EFA): All of our cells (and of all animals as well) can produce fats, none can produce the EFAs, the polyunsaturated, which have more than one double bond and are called lipids. They are the omega 6 and the omega 3 EFAs, produced only by plant vegetation on land and plankton in the oceans. Essential means — that for all cells to survive it is a required food and must be a part of our diet, similar to vitamins and minerals which must be ingested as well. However, EFAs are unique in that after we absorb the lower order of the 6s and 3s, linoleic and alpha linolenic acids, a portion of these two EFA families must be metabolized into the higher order polyunsaturated lipids such as GLA and AA (n-6s), and EPA and DHA (n-3s) — which we may be able to do if we are young and healthy — for all large mammals, including humans, become inefficient early on in metabolizing the higher order EFAs and must rely on diet for both the lower and the higher orders. In effect, all the essentials are important, not just the higher order, such as EPA and DHA. However, our current effort to unravel the mysterious world of lipid metabolism is burdened with wide gaps of misunderstanding as to the inner workings of lipid biochemistry leaving us with one of the most important challenges we must face — that of the optimal ratio of omega 6 to omega 3 in our daily diet.

Nutr Neurosci. 2005 Aug;8(4):265-7.
Mixture of essential fatty acids lowers test anxiety.
Yehuda S, Rabinovitz S, Mostofsky DI.
Department of Psychology and Gonda Brain Research Center, Psychopharmacology Laboratory, Bar Ilan University, Ramat Gan, Israel.

Test anxiety is an incapacitating academic syndrome. This study shows that administration of a polyunsaturated fatty acid mixture of omega-3 and -6 can improve the behavioral variables associated with this type of anxiety, i.e. appetite, mood, mental concentration, fatigue, academic organization and poor sleep, as well as lowering elevated cortisol level, with a corresponding reduction of anxiety.

Neurobiol Aging. 2005 Dec;26 Suppl 1:98-102. Epub 2005 Oct 13.
Essential fatty acids and the brain: From infancy to aging.
Yehuda S, Rabinovitz S,Mostofsky DI.
Psychopharmacology Laboratory, Department of Psychology and Brain Research, Institute, Bar Ilan University, Ramat Gan 52900, Israel.

The major effects of essential fatty acids (EFA) on brain structure and functions are reviewed. EFA determine the fluidity of neuronal membrane and control the physiological functions of the brain. EFA is also involved in synthesis and functions of brain neurotransmitters, and in the molecules of the immune system. Since they must be supplied from the diet, a decreased bioavailability is bound to induce major disturbances. While the brain needs a continuous supply during the life span, there are two particularly sensitive periods-infancy and aging. EFA deficiency during infancy delays brain development, and in aging will accelerate deterioration of brain functions. In discussing the role of EFA two issues must be considered — the blood-brain barrier, which determines the bioavailability, and the myelination process, which determines the efficiency of brain and retinal functions.

Psychoneuroendocrinology. 2004 Feb;29(2):113-24.
Anticonvulsant efficiency, behavioral performance and cortisol levels: a comparison of carbamazepine (CBZ) and a fatty acid compound (SR-3).
Rabinovitz S, Mostofsky DI, Yehuda S.
Psychopharmacology Lab, Department of Psychology, Bar Ilan University, Ramat Gan, Israel.

The role of fatty acids (FA) and their impact on nervous system activity and immune function has attracted much attention. The interest extends beyond a basic understanding of the potential role exerted by FA on the neuronal membrane and its properties, to the implications and clinical significance for many neurological disorders. This is especially true for epilepsy, where many conventional anticonvulsant preparations carry undesired side effects, and a significant number of patients remain refractory to the drug treatment. We report on a comparative examination in rats of carbamazepine (CBZ) and SR-3 (a fatty acid compound) with respect to seizure control efficiency, as well as protective features against cognitive impairment and cortisol level elevation. With pentylenetetrazol (PTZ) induced seizures pre-treated by CBZ, or SR-3, both CBZ and SR-3 were equally effective in providing seizure control and both were superior to the saline control. However SR-3 provided greater protection in Morris Water Maze performance and control of cortisol level elevation.

Neurobiol Aging. 2002 Sep-Oct;23(5):843-53.
The role of polyunsaturated fatty acids in restoring the aging neuronal membrane.
Yehuda S, Rabinovitz S, Carasso RL, Mostofsky DI.
Psychopharmacology Laboratory, Department of Psychology, Bar Ilan University, Ramat Gan 52900, Israel.

In addition to a gradual loss of neurons in various brain regions, major biochemical changes in the brain affect the neuronal membrane that is the “site of action” for many essential functions including long-term potentiation (LTP), learning and memory, sleep, pain threshold, and thermoregulation. Normal physiological functioning includes the transmission of axonal information, regulation of membrane-bound enzymes, control of ionic channels and various receptors. All are highly dependent on membrane fluidity, where rigidity is increased during aging. The significantly higher level of cholesterol in aging neuronal membrane, the slow rate of cholesterol turnover, and the decreased level of total polyunsaturated fatty acids (PUFA) may result from poor passage rate via the blood-brain barrier, or from a decreased rate of incorporation into the membrane, or a decrease in the activities of delta-6 and delta-9 desaturase enzymes. The added oxidative stress, which leads to an increase of free radicals leading to a decrease in membrane fluidity, may respond to a restricted diet, and thereby overcome the damaging effects of the free radicals. A central focus of this review is that a specific ratio of n-3/n-6 PUFA can restore many of these age-related effects.

Neuropsychobiology. 2000;41(3):154-7.
The control of blepharospasm by essential fatty acids.
Mostofsky DI, Yehuda S, Rabinovitz S, Carasso R.
Psychopharmacology Laboratory, Department of Psychology, Bar Ilan University, Ramat Gan, Israel.

Dopamine depletion induced by administration of Ro4-1284 produces a condition of rapid and repeated eye blinking in rats. This condition mimics the human disorder, blepharospasm, which often accompanies parkinsonism and other dopamine deficiency disorders. When given a 3-week course of a compound (SR-3) developed from a specific ratio of two free polyunsaturated fatty acids – linoleic acid and alpha-linolenic acid – the eye blinking rate following administration of Ro4-1284 is reduced to saline and no drug control levels. These results suggest a favorable prospect for essential fatty acids in general, and SR-3 in particular, to provide an improved therapeutic option for the clinical management of benign essential blepharospasm.

Int J Neurosci – 01-Jan-2000; 101(1-4): 73-87
Fatty acid mixture counters stress changes in cortisol, cholesterol, and impair learning.
Yehuda S; Rabinovitz S; Carasso RL; Mostofsky DI
Department of Psychology, Bar Ilan University, Ramat Gan, Israel.

A mixture of linoleic and alpha-linolenic acids (free non-esterified unsaturated fatty acids ) administered for 3 weeks prior to injection of cortisol (10 mg/kg), or prior to immersion of rats in a 10 degree C saline bath, prevented elevation of blood levels of cortisol and cholesterol and deficits in Morris water maze spatial learning that usually accompany such stressful conditions. Differences from controls on all behavioural and biochemical measures were statistically significant (P < .05). It is proposed that induction of intense stress, and the associated increase in cortisol, cholesterol and other corticosteroids may damage hippocampal structures and help account for the cognitive decline witnessed in Alzheimer’s disease and other age-related conditions. The modulation of these consequences by the fatty acid mixture may provide an alternative strategy for the study of stress markers and for the development of other intervention options in humans.

J Neurosci Res. 1999 Jun 15;56(6):565-70.
Essential fatty acids are mediators of brain biochemistry and cognitive functions.
Yehuda S, Rabinovitz S, Mostofsky DI.
Department of Psychology, Bar Ilan University, Ramat Gan, Israel.

Major advances have been made in understanding the biochemistry of essential fatty acids (FA) and their interactions with metabolic pathways leading to the production of longer and more complex fatty acids and lipids. Less understood are the roles played by FA which are known to affect neurotransmitters, peptides, releasing factors, hormones, and a variety of physiological and cognitive processes. Based on empirical findings we propose that (a) FA exert a controlling function in the modulation of neuronal membrane fluidity, and (b) the critical factor in FA action and efficacy is not absolute level but rather the ratio between various groups of FA. This approach unifies the biochemical and cognitive results obtained from many different and unrelated fields of research.

Eur J Pharmacol. 1999 Jan 15;365(1):27-34.
Treatment with a polyunsaturated fatty acid prevents deleterious effects of Ro4-1284.
Yehuda S, Rabinovitz S, Mostofsky DI.
Department of Psychology, Bar-Ilan University, Ramat Gan, Israel.

Ro4-1284 (2-Ethyl-1,3,4,6,7,11b-hexahydro-3-isobutyl-9,10-dimethoxy-2H-benzo[a] quinolizin-2-ol hydrochloride), a benzoquinolizine, is a potent dopamine depletion agent whose acute and chronic administration results in a (1) deterioration of learning in the Morris Water Maze and passive avoidance tasks, (2) decrease in locomotion and rearing, (3) intense hypothermia, and (4) decrease in the percentage of polyunsaturated fatty acids and an increase in the level of cholesterol in neuronal membranes. Pretreatment with a specific mixture of free polyunsaturated fatty acids prevents most of the behavioral, physiological, and biochemical effects of Ro4-1284 except for rearing. We propose that the dopamine-mediated functions tested in this study are dependent on the interaction of intact dopamine D1 and D2 receptors. Rearing, which is controlled only by dopamine D1 receptors, remained, therefore, unaffected. Our hypothesis is that SR-3 exerts its beneficial effects by normalizing the structure and function of the neuronal membrane and by restoring dopamine D2 receptor functions

Med Hypotheses. 1998 Feb;50(2):139-45
Essential fatty acids and sleep: mini-review and hypothesis.
Yehuda S, Rabinovitz S, Mostofsky DI.
Department of Psychology, Bar-llan University, Ramat Gan, Israel.

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, wherein 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.

Neurochem Res. 1998 May;23(5):627-34.
Modulation of learning and neuronal membrane composition in the rat by essential fatty acid preparation: time-course analysis.
Yehuda S, Rabinovitz S, Mostofsky DI.
Department of Psychology, Bar Ilan University, Ramat Gan, Israel.

Previous studies have shown that chronic administration of SR-3 (a 1:4 mixture of alpha-linolenic and linoleic acid) affects spatial learning, thermoregulation, pain threshold and protection from seizures. The mode of action is unknown. One possible explanation is that the preparation induces changes in the fatty acids profile and in the cholesterol level in the neuronal membrane. This study used 15 independent groups of rats (n = 12) which were given either saline, mineral oil (vehicle) or SR-3 (25 mg/kg) for 0, 1, 2, 3, or 4 weeks. The learning performance was measured in the Morris Water tank and the fatty acids profile and the cholesterol level were examined by the GC method in synaptosomes obtained from the frontal cortex of the rats. SR-3 improved the learning performance and induced major changes in the neuronal membrane composition, such as an increase in the total level of fatty acids, an increase in the level of essential fatty acids and a decrease in the cholesterol level. Those changes occurred after 3 weeks of treatment. The biochemical variables can predict the behavioral variables but not vice versa. The changes in the neuronal membrane may result in a modification of the membrane fluidity, which may, in turn, enhance cognitive and neuropharmacological effects.

Peptides. 1998;19(2):407-19
Fatty acids and brain peptides.
Yehuda S, Rabinovitz S, Carasso RL, Mostofsky DI.
Department of Psychology, Bar-Ilan University, Ramat Gan, Israel.

The role of fatty acids (FA) as a mediator and modulator of central nervous system activity in general, and peptides in particular, is only recently becoming understood. This paper reviews numerous findings concerned with the activity of fatty acids, particularly with their interaction with diverse neurochemical systems and their consequences for better understanding neurotransmitters, hormones and peptides. The effects include FA as precursors in the manufacture of neurochemical elements, including enzymes, neurotransmitters, and hormones. Of particular interest is the important changes in neuronal membrane composition that have been attributed to FA. Such changes may account for the changes in thermoregulation, learning, and other functions that accompany dietary manipulation of FA intake. While the total level of FA has been the object of many investigations, this report addresses the need to focus on the ratio of FA, especially alpha-linolenic/linoleic acid, which has been shown to be a critical factor in a number of research studies.

Eur J Pharmacol. 1997 Jun 5;328(1):23-9.
Essential fatty acid preparation improves biochemical and cognitive functions in experimental allergic encephalomyelitis rats.
Yehuda S, Rabinovitz S, Mostofsky DI, Huberman M, Sredni B.
Department of Psychology, Bar Ilan University, Ramat Gan, Israel.

This study examined the possible effects of a novel mixture of fatty acids, SR-3 (a specific ratio of alpha-linolenic acids), on brain biochemistry and on learning deficits induced by injection of an agent that induces experimental allergic encephalomyelitis. Treatment with SR-3 caused a decrease in myelin and changes in the fatty acid profile of brain synaptosomes, and a learning deficit. Eighteen days of treatment with SR-3 reversed the biochemical and learning deficit significantly, but did not restore them to normal levels. We propose that, most probably, the main action of SR-3 is the modulation of the cholesterol level, which in turn causes the modulation of the fatty acid profile and enhances learning by allowing improved neuronal communication.

Int J Neurosci. 1996 Nov;87(3-4):141-9.
Essential fatty acids preparation (SR-3) improves Alzheimer’s patients quality of life.
Yehuda S, Rabinovtz S, Carasso RL, Mostofsky DI.
Department of Psychology Bar-Ilan University, Ramat Gan, Israel.

In a number of previous reports we showed the salutary effects on rats of SR-3, a compound comprising a 1:4 ratio of n-3 and n-6 fatty acids. Improvements were noted in learning tasks, thermoregulation, recovery from neurotoxins, and seizure protection. Because we were impressed that these effects are related to changes in membrane fluidity and neuronal functioning and because Alzheimer’s Disease is also associated with lipid defects, we undertook a short term (4 week) double blind study with 100 Alzheimer patients (60 received SR-3 and 40 in a placebo control). The results indicated improvements in mood, cooperation, appetite, sleep, ability to navigate in the home, and short term memory. Overall improvement was reported for 49 patients, and in no case did a guardian report adverse effects to the compound. While not uniform or permanent, and while no mode of action for SR-3 can be precisely identified at this time, the promising results in quality of life for the patient and caregiver warrant further clinical trials and continued basic research into the neuropsychological substrate of the disease and its response to SR-3.

Int J Neurosci. 1996 Sep;86(3-4):249-56.
Essential fatty acid preparation reduces cholesterol and fatty acids in rat cortex.
Yehuda S, Brandys Y, Blumenfeld A, Mostofsky DI.
Psychopharmacology Laboratory, bar Ilan University Ramat Gan, Israel.

Previous studies have shown that chronic administration of SR-3 (a 1:4 mixture of alpha-linolenic and linoleic acid) affects spatial learning, thermoregulation, pain threshold, and protection from seizures. The mode of action of SR-3 is unknown. One possible explanation is that SR-3 induces changes in the FA profile and in the cholesterol level in neuronal membranes. This study used 10 independent groups of rats (ni = 12) given 4 weeks of either saline, mineral oil (vehicle), alpha-tocopherol (antioxidant), alpha-linolenic acid, linoleic acid, or one of 5 different ratios of alpha-linolenic acid:linoleic acid (1:3, 1:4, 1:5, 1:6, 1:7) as free fatty acids. FA profile and cholesterol level were examined by GC method in synaptosomes obtained from the frontal cortex of the rats. The mineral oil treated group served as the control group. No difference was found in the FA profile or cholesterol level except for the SR-3 treated group. The ratio of 1:4 was found to have a significant influence on decreasing the cholesterol level and in inducing major changes in the FA profile, such as an increase in EFA. These effects of SR-3 may result in modification of the membrane fluidity, which may, in turn, enhance cognitive and neuropharmacological effects.

Neuroreport. 1995 Feb 15;6(3):511-5.
Essential fatty acid preparation (SR-3) rehabilitates learning deficits induced by AF64A and 5,7-DHT.
Yehuda S, Carraso RL, Mostofsky DI.
Dept of Psychology, Bar Ilan University, Ramat Gan, Israel.

The purpose of this study was to examine the possible effects of a novel mixture of fatty acids, SR-3 (a specific ratio between alpha-linolenic and linoleic acids) on learning deficits induced by cholinergic (AF64A) and serotonergic (5,7-DHT) neurotoxins in rats. I.c.v. AF64A and 4th ventricle administration of 5,7-DHT induce severe learning deficit using the Morris Water Tank. Three weeks of treatment with SR-3 rehabilitated the learning capacity of rats. However, learning deficits induced by a lesion in area postrema was not rehabilitated by SR-3. The mode of action of SR-3 is unknown. We propose that this combination of free fatty acids modulates the composition of neuronal membrane lipids and allows better neuronal communication.

Eur J Pharmacol. 1994 Mar 11;254(1-2):193-8.
Essential fatty acid preparation (SR-3) raises the seizure threshold in rats.
Yehuda S, Carasso RL, Mostofsky DI.
Department of Psychology, Bar-Ilan University, Ramat Gan, Israel.

The anticonvulsant properties of a mixture of non-esterified alpha-linolenic acid and linoleic acid with a ratio of 1:4 (SR-3) were evaluated in four rat models of epileptic seizures: (1) i.p. injection of a single convulsant dose (50 mg/kg or 100 mg/kg) of pentylenetetrazol; (2) repeated subconvulsant doses of pentylenetetrazol; (3) cortical irritation by intraventricular administration of iron chloride (FeCl3); and (4) audiogenic seizure-prone preparation created by repeated pretreatment with p-cresol. Treatment with SR-3 (about 40 mg/kg i.p.) for a period of 3 weeks prior to challenge was found effective in each of these experimental models and caused up to a 22-fold increase in latency to major motor seizures, up to 84% reduction in the number of rats with seizures, and up to a 97% reduction in the duration of seizures. It is postulated that the anticonvulsant effects of SR-3 may be related to its stabilization of neuronal membranes. SR-3 should be evaluated further as a treatment for epilepsy.

Proc Natl Acad Sci U S A. 1993 Nov 1;90(21):10345-9.
Modulation of learning, pain thresholds, and thermoregulation in the rat by preparations of free purified alpha-linolenic and linoleic acids: determination of the optimal omega 3-to-omega 6 ratio.
Yehuda S, Carasso RL.
Department of Psychology, Bar-Ilan University, Ramat-Gan, Israel.

Ingested polyunsaturated fatty acids are postulated to lead to changes in central nervous system activity, presumably by altering the lipid composition of neuronal membranes. In support of this hypothesis, we and other investigators have previously demonstrated cognitive effects in rats fed oils that contain both alpha-linolenic acid (18:3 omega 3) and linoleic acid (18:2 omega 6), with the relative content of alpha-linolenic acid being seen as the critical variable. The present study in rats examined the effects of preparations containing different ratios of highly purified free alpha-linolenic acid to linoleic acid (about 25 mg/kg of body weight daily) on learning performance (Morris water tank), pain thresholds (heated plate), and thermoregulatory control of d-amphetamine-induced hypothermia during 4 weeks of treatment. Preparations with omega 3-to-omega 6 ratios ranging from 1:3.5 to 1:5 (specifically a ratio of 1:4) produced significant favorable effects on all of these variables. Although the specific mode of action remains to be elucidated, these results suggest that such preparations of free fatty acids should be evaluated in the treatment of memory disorders and pain conditions.

Int J Neurosci. 1987 Feb;32(3-4):919-25.
Effects of dietary fats on learning, pain threshold, thermoregulation and motor activity in rats: interaction with the length of feeding period.
Yehuda S, Carasso RL.

The effects of both a semisynthetic diet containing 20% fat from various sources (soybean oil, sunflower oil and lard) and a control diet on learning capacity, motor activity, pain threshold and thermoregulation were studied in rats which were fed on these diets for various lengths of feeding periods (1, 2, 3 and 4 weeks). Two weeks feeding period of soybean oil source induced an improvement in learning capacity, which was further enhanced by increasing the length of the feeding period. A 3-week feeding period was required to obtain an increase in the pain threshold, by which time the rats were also protected from d-amphetamine induced hypothermia. The analgesia induced by the diet is naloxone-dependent. None of the other diets, including the sunflower oil diet, which is richer in polyunsaturated fatty acids, differed from control diet. While the mode of action of this diet is still unknown, the effects of the soybean oil source diet cannot be attributed to nutritional factors such as changes in energy consumption or body weight.

J Vasc Surg. 2004 Jan;39(1):229-37.
Alpha-tocopherol preserves endothelial cell migration in the presence of cell-oxidized low-density lipoprotein by inhibiting changes in cell membrane fluidity.
van Aalst JAA Burmeister W, Fox PL, Graham LM.
Department of Surgery, Case Western Reserve University, Cleveland, OH, USA.

OBJECTIVE: Endothelial cell (EC) migration is essential for healing areas of arterial injury and angioplasty sites. Iron or copper-oxidized low-density lipoprotein (oxLDL(Cu)) inhibits EC migration in vitro, but the effect of physiologically relevant monocyte/macrophage-oxidized LDL (oxLDL(cell)) is unknown. We postulated that oxLDL(cell) would inhibit EC migration and that this inhibition would be reversed by antioxidants.
METHODS: The effect of oxLDL(Cu) and oxLDL(cell) on EC migration was studied by using a razor scrape assay, and migration was assessed after 24 hours. In addition, ECs were incubated with various antioxidants, including butylated hydroxytoluene (BHT), probucol, or alpha-tocopherol, for 1 hour prior to initiation of the scrape assay and application of oxLDL.
RESULTS: Both oxLDL(Cu) and oxLDL(cell) inhibited migration. The antioxidants did not alter the antimigratory activity of oxLDL(Cu), but alpha-tocopherol preserved EC migration in the presence of oxLDL(cell). The lack of effect of BHT or probucol suggested that the effect of alpha-tocopherol resided not in its antioxidant activity but in its membrane-stabilizing properties. To test this theory, the effect of oxLDL and alpha-tocopherol on relative cell membrane fluidity was assessed by fluorescence recovery after photobleaching. Both oxLDL(Cu) and oxLDL(cell) increased relative membrane fluidity. Preincubation with alpha-tocopherol inhibited the increase in membrane fluidity of ECs incubated in oxLDL(cell) but not in oxLDL(Cu).
CONCLUSIONS: These studies show that alpha-tocopherol preserves EC migration in oxLDL(cell) and hastens restoration of the endothelial monolayer after injury by inhibiting changes in membrane integrity caused by oxLDL.Clinical relevance: Recent studies find that vitamin E is not efficacious in the secondary prevention of cardiovascular events, perhaps because vitamin E does not efficiently block oxidation pathways known to be operative in atherosclerotic arteries. “Non-antioxidant” properties of vitamin E, however, could be important in the primary prevention of atherosclerosis and its complications. Our in vitro studies show that alpha-tocopherol can preserve endothelial migration in the presence of cell-oxidized LDL. This effect might improve the healing of endothelial injuries at sites of arterial repair or angioplasties, especially in lipid-laden arterial walls.

Am J Physiol Gastrointest Liver Physiol. 2004 May;286(5):G822-32
Treatment of EFA deficiency with dietary triglycerides or phospholipids in a murine model of extrahepatic cholestasis.
Werner A Havinga R, Kuipers F, Verkade HJ.
Pediatric Gastroenterology, Pediatric Research Laboratory, CMC IV Rm. Y2115, P. O. Box 30 001, 9700 RB Groningen, The Netherlands.

Essential fatty acid (EFA) deficiency during cholestasis is mainly due to malabsorption of dietary EFA (23). Theoretically, dietary phospholipids (PL) may have a higher bioavailability than dietary triglycerides (TG) during cholestasis. We developed murine models for EFA deficiency (EFAD) with and without extrahepatic cholestasis and compared the efficacy of oral supplementation of EFA as PL or as TG. EFAD was induced in mice by feeding a high-fat EFAD diet. After 3 wk on this diet, bile duct ligation was performed in a subgroup of mice to establish extrahepatic cholestasis. Cholestatic and noncholestatic EFAD mice continued on the EFAD diet (controls) or were supplemented for 3 wk with EFA-rich TG or EFA-rich PL. Fatty acid composition was determined in plasma, erythrocytes, liver, and brain. After 4 wk of EFAD diet, induction of EFAD was confirmed by a sixfold increased triene-to-tetraene ratio (T/T ratio) in erythrocytes of noncholestatic and cholestatic mice (P < 0.001). EFA-rich TG and EFA-rich PL were equally effective in preventing further increase of the erythrocyte T/T ratio, which was observed in cholestatic and noncholestatic nonsupplemented mice (12- and 16-fold the initial value, respectively). In cholestatic mice, EFA-rich PL was superior to EFA-rich TG in decreasing T/T ratios of liver TG and PL (each P < 0.05) and in increasing brain PL concentrations of the long-chain polyunsaturated fatty acids (LCPUFA) docosahexaenoic acid and arachidonic acid (each P < 0.05). We conclude that oral EFA supplementation in the form of PL is more effective than in the form of TG in increasing LCPUFA concentrations in liver and brain of cholestatic EFAD mice.

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