Biomedical subjects
Publications and source records attributed to D I Mostofsky.
The postinfancy period is crucial for normal brain development, providing subsequent optimal conditions for learning and cognition. Both iron deficiency and essential fatty acids deficiency may impair normal neurological development. This review examines the limited number of studies that have been performed in preschool children and offers a broader view of the relationships among nutrition, nutrients and cognition.
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.
This report examines a range of models and procedures applicable to polyunsaturated fatty acid (PUFA) research and considers their relative merits. Considerations pertaining to cost, efficiency, and scientific rigor are of particular interest. Parallel activities in other areas of behavioral neuroscience, such as behavioral pharmacology and toxicology, that have profitably exploited various behavior designs for the study of human and animal cognition are noted. Special attention is given to the utility of operant conditioning models and schedules of reinforcement, which are currently underrepresented in PUFA research. Investigations of analogs of complex human behavior as well as implications for generalizing laboratory results to clinical phenomena are addressed.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Ontogenetic differences in seizure thresholds to pentylenetetrazol (PTZ) were examined in young, developing rats (ages: 10, 18, 28, and 60 days). A subconvulsive dose of PTZ (15 mg/kg IP) was administered every 10 min and the occurrence of partial and full (clonic tonic) seizures was noted. Ten day old pups displayed complete seizures more rapidly than any of the other groups (p < .01) without any behavioral indication of going through the partial stages. Among 18 day old pups the development of early seizure stages was followed rapidly by the full seizure, while in the weaned groups the early seizure stages tended to persist much longer before the appearance of the full generalized convulsion. The preweanling rat's immature brain seems less able to suppress PTZ induced generalized convulsions compared to the brain of the older 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.
Previous claims that forced unilateral nostril breathing (FUNB) has several specific measurable effects on the autonomic nervous system were examined. Using the technique suggested by Backon, 4 subjects were tested, using an ABABA design. The results did not demonstrate any significant changes in heart rate, pulse amplitude, temperature, skin conductance response, or respiration force as a result of FUNB.
Repeated administrations of subconvulsive doses of pentylenetetrazol (PTZ) leads to frank convulsions. The number of injections required to bring about such an effect is taken as an index of seizure vulnerability, and was studied in normal rats. This study examined the effect of pain induced by formaline injection or placement on a hot plate on seizure elicitation. The results could be accounted for by the role of arousal and/or endogenous opiates that are generated by the pain induction procedures, wherein the pain appears to provide some elevation of the threshold for seizure vulnerability.