Shlomo Yehuda

THE USE OF THE MORRIS WATER MAZE IN THE STUDY OF MEMORY AND LEARNING

Although the Morris Water Maze (MWM) was introduced only a few years ago, this technique has gained wide popularity, as the large number of publications in which it is employed, testifies. A review of the literature reveals that a wide variety of technical variables were used by the various research groups employing the MWM. This review describes the major changes in research variables, i.e., environmental variables, various manipulations, and the effects of diet or age on performance. The general principles of learning as demonstrated by the MWM are discussed.

ESSENTIAL FATTY ACIDS ARE MEDIATORS OF BRAIN BIOCHEMISTRY AND COGNITIVE FUNCTIONS

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. J. Neurosci. Res. 56:565–570, 1999. 

Essential fatty acids and the brain: From infancy to aging

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.

Essential fatty acid preparation (SR-3) raises the seizure threshold in rats.

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.

Essential fatty acids preparation (SR-3) improves Alzheimer's patients quality of life

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 Alzheimers 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.

Omega-6/omega-3 ratio and brain-related functions.

While the general public typically perceives lipids and fats as ‘harmful’ components of the diet (as in the popular slogan: ‘fat kills’), the scientific story is in fact very different. Among the major scientific research efforts of the recent period, in the area of neuroscience, we find the recognition of the ‘essential fatty acids’ (EFA). The profound effects of various fatty acids, and equally profound effects of their deficits, are appreciated by a variety of disciplines, including (but not necessarily limited to) lipid biochemistry, physiology, nutrition, psychology, psychiatry, and neurosciences at large. Recently, the issue of lipids, and fatty acids ratio in diets, became an important issue. Simopoulos [1] showed the historical shift from a ‘balanced’ omega–6 and omega–3 ratio diet, towards a marked and significant reduction in the omega–3 intake, and explained that the general ‘Western diet’ of today can in actual fact be considered an omega–3deficient diet. Her concern is that this ‘deficiency’ may lead to coronary heart disease and high cancer mortality. Linoleic acid (LA; omega–6; 6; 18:26) is the parent fatty acid of the omega–6 group. Linoleic acid must be supplied to the body by the diet, because the body is unable to synthesize it. All other members of the omega–6 group are derivatives of LA. Similarly, the parent compound of the omega–3 group is alpha-linolenic acid (ALA, omega–3, 3, 18:33). All other members of the omega–3 group are merely derivatives of ALA, and together they form the polyunsaturated fatty acids (PUFA). In each group, the derivatives can convert to longer chain fatty acids by using two mechanisms: desaturation and elongation.

Iron deficiency-induced circadian rhythm reversal of dopaminergic-mediated behaviours and thermoregulation in rats

An iron-free diet for 28 days caused a reduced level of iron in the blood. Iron deficient rats exhibited a lower level of motor activity and reversed circadian rhythms of thermoregulation and motor activity. The hypothermic effect of d-amphetamine was significantly reduced in iron deficient rats, and the magnitude of this effect was correlated with the decrease in the blood and brain. The hypermotility effect of d-amphetamine was also significantly reduced. Apomorphine-induced stereotyped behaviour was greater during the light period in contrast to that of control rats. The results of this study indicate that iron plays a major role in the normal function of the monoaminergic system in the brain, particularly in the dopaminergic system, via modification of dopaminergic receptors.

Mixture of essential fatty acids lowers test anxiety

Abstract 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.

Fatty Acids and Brain Peptides

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.

Clomipramine and Amitriptyline in the Treatment of Severe Pain

Clomipramine is the most potent 5-HT reuptake blockade agent among the antidepressants. A comparison between the effect of clomipramine and a less powerful 5-HT reuptake blockade agent (amitriptyline) could test the hypothesis that brain 5-HT is a mediator of pain sensation. Groups of patients of either sex, with pain indication of trigeminal neuralgia, tension headache or postherpatic neuralgia, received doses of clomipramine or amitriptyline in a single blind clinical experiment. The results after three months of treatment showed that clomipramine: (1) was better than amitriptyline in treating trigeminal neuralgia; (2) tended to be better in the treatment of tension headache; and (3) amitriptyline is better in treating postherpatic neuralgia. Clomipramine was better tolerated. The results support the hypothesis that in certain pain situations, clomipramine exerts a beneficial effect, not only because of its effect on the depression and anxiety level of the patient, but also via its effects on the 5-HT brain system.