Calcium
and Essential Fatty Acids
References:
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. ↑ Back To Top
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. ↑ Back To Top
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. ↑ Back To Top
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. ↑ Back To Top
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.
↑ Back To Top
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. ↑ Back To Top
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. ↑ Back To Top
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. ↑ Back To Top
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. ↑ Back To Top
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. ↑ Back To Top
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. ↑ Back To Top
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. ↑ Back To Top
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 ↑ Back To Top
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 ↑ Back To Top
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. ↑ Back To Top
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. ↑ Back To Top
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. ↑ Back To Top
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. ↑ Back To Top
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. ↑ Back To Top
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. ↑ Back To Top
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. ↑ Back To Top
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. ↑ Back To Top
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. ↑ Back To Top
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. ↑ Back To Top
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. ↑ Back To Top
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