Yehuda S, Carasso RL. 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.
Proc Natl Acad Sci U S A 1993 Nov 1;90(21):10345-9.Proc Natl Acad Sci U S A
1993 Nov 1;90(21):10345-9.
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.
Yehuda S, Carasso RL, Mostofsky DI. Essential fatty acid preparation (SR-3)
raises the seizure threshold in rats. Eur J Pharmacol 1994 Mar
11;254(1-2):193-8.Eur J Pharmacol 1994 Mar 11;254(1-2):193-8.
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.
Yehuda S, Carraso RL, Mostofsky DI. Essential fatty acid preparation (SR-3)
rehabilitates learning deficits induced by AF64A and 5,7-DHT. Neuroreport
1995 Feb 15;6(3):511-5.Neuroreport 1995 Feb 15;6(3):511-5.
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.
Yehuda S, Rabinovitz S, Mostofsky DI. Essential fatty acids are mediators of
brain biochemistry and cognitive functions. J Neurosci Res 1999 Jun
15;56(6):565-70.J Neurosci Res 1999 Jun 15;56(6):565-70.
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.
Yehuda S, Rabinovitz S, Carasso RL, Mostofsky DI. Fatty acids and brain
peptides. Peptides 1998;19(2):407-19.Peptides 1998;19(2):407-19.
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.
Biagi PL, Bordoni A, Lorenzini A, Horrobin DF, et al. Essential fatty acid
metabolism in long term primary cultures of rat cardiomyocytes: a beneficial
effect of n-6:n-3 fatty acids supplementation. Mech Ageing Dev 1999 Mar
1;107(2):181-95.Mech Ageing Dev 1999 Mar 1;107(2):181-95.
In long term (21 days) primary cultures of neonatal rat cardiomyocytes,
utilized as a model of in vitro senescence, we investigated the dual effect
of the time length in culture and of the supplementation with n- 6:n-3 fatty
acid mixtures on linoleic (LA) and alpha-linolenic acid (ALA) metabolism.
Cardiomyocytes were divided into groups receiving: (1) control medium; (2)
control medium plus n-3 fatty acids; (3) and (4) control medium plus n-6 and
n-3 fatty acids in the ratio 1:2 or 2:1, respectively. In control cells.
senescence caused a reduction in the conversion of LA and ALA, and the
decrease in their metabolites was bypassed by the different supplementations.
The fatty acid composition of cardiomyocyte lipids was therefore affected by
both senescence and supplementation, as evidenced by the n-6:n-3 fatty acid
ratio and the unsaturation index (U.I.) in cellular lipids. The final result
of ageing in culture and of fatty acid supplementations was in all the groups
of cells but one (n-6:n-3, 2:1) an unbalance in the n-6:n-3 fatty acid ratio.
All the supplementations were able to counteract the decrease in the U.I.
observed with senescence, but only the n-6:n-3 (2:1) was able to do so by
increasing the cellular content of the fatty acids which are precursors of
anti-aggregation eicosanoids without altering the n-6:n-3 fatty acid ratio.