PubMed Health⌕ Search

Biomedical subjects

Norman Salem

Publications and source records attributed to Norman Salem.

At least 19 recordsLinked to original sources
PubMed2004

Docosahexaenoic acid protects from dendritic pathology in an Alzheimer's disease mouse model.

Learning and memory depend on dendritic spine actin assembly and docosahexaenoic acid (DHA), an essential n-3 (omega-3) polyunsaturated fatty acid (PFA). High DHA consumption is associated with reduced Alzheimer's disease (AD) risk, yet mechanisms and therapeutic potential remain elusive. Here, we report that reduction of dietary n-3 PFA in an AD mouse model resulted in 80%-90% losses of the p85alpha subunit of phosphatidylinositol 3-kinase and the postsynaptic actin-regulating protein drebrin, as in AD brain. The loss of postsynaptic proteins was associated with increased oxidation, without concomitant neuron or presynaptic protein loss. n-3 PFA depletion increased caspase-cleaved actin, which was localized in dendrites ultrastructurally. Treatment of n-3 PFA-restricted mice with DHA protected against these effects and behavioral deficits and increased antiapoptotic BAD phosphorylation. Since n-3 PFAs are essential for p85-mediated CNS insulin signaling and selective protection of postsynaptic proteins, these findings have implications for neurodegenerative diseases where synaptic loss is critical, especially AD.

Actins↗
PubMed2004

Effects of an n-3-deficient diet on brain, retina, and liver fatty acyl composition in artificially reared rats.

Rat pups born to dams fed a diet with 3.1% of total fatty acids as alpha-linolenic acid (LNA) were fed, using an artificial rearing system, either an n-3-deficient (n-3-Def) or an n-3-adequate (n-3-Adq) diet. Both diets contained 17.1% linoleic acid, but the n-3-Adq diet also contained 3.1% LNA. The percentage of brain docosahexaenoic acid (DHA) continuously decreased (71%) with time over the 29 days of the experiment, with concomitant increases in docosapentaenoic acid (DPAn-6). In the retina, the percentage of DHA rose in the n-3-Adq group, with an apparent increased rate around the time of eye opening. However, there was a flat curve for the percentage of DHA in the n-3-Def group and a rising DPAn-6 with time. Liver DHA was highest at the time of birth in the n-3-Adq group but fell off somewhat over the course of 29 days. This decrease was more pronounced in the n-3-Def group, and the DPAn-6 rose considerably during the second half of the experiment. This method presents a first-generation model for n-3 deficiency that is more similar to the case of human nutrition than is the commonly employed two-generation model.

Age Factors↗
PubMed2004

Reduced G protein-coupled signaling efficiency in retinal rod outer segments in response to n-3 fatty acid deficiency.

The fatty acid (FA) docosahexaenoic acid (DHA, 22: 6n-3) is highly enriched in membrane phospholipids of the central nervous system and retina. Loss of DHA because of n-3 FA deficiency leads to suboptimal function in learning, memory, olfactory-based discrimination, spatial learning, and visual acuity. G protein-coupled receptor (GPCR) signal transduction is a common signaling motif in these neuronal pathways. Here we investigated the effect of n-3 FA deficiency on GPCR signaling in retinal rod outer segment (ROS) membranes isolated from rats raised on n-3-adequate or -deficient diets. ROS membranes of second generation n-3 FA-deficient rats had approximately 80% less DHA than n-3-adequate rats. DHA was replaced by docosapentaenoic acid (22:5n-6), an n-6 FA. This replacement correlated with desensitization of visual signaling in n-3 FA-deficient ROS, as evidenced by reduced rhodopsin activation, rhodopsin-transducin (G(t)) coupling, cGMP phosphodiesterase activity, and slower formation of metarhodopsin II (MII) and the MII-G(t) complex relative to n-3 FA-adequate ROS. ROS membranes from n-3 FA-deficient rats exhibited a higher degree of phospholipid acyl chain order relative to n-3 FA-adequate rats. These findings reported here provide an explanation for the reduced amplitude and delayed response of the electroretinogram a-wave observed in n-3 FA deficiency in rodents and nonhuman primates. Because members of the GPCR family are widespread in signaling pathways in the nervous system, the effect of reduced GPCR signaling due to the loss of membrane DHA may serve as an explanation for the suboptimal neural signaling observed in n-3 FA deficiency.

Animals↗
PubMed2004

Gray and white matter brain volume in aged rats raised on n-3 fatty acid deficient diets.

Omega-3 or n-3 fatty acids, especially docosahexaenoic acid, are important structural lipids in the brain. Their deficiency leads to a number of sensory, cognitive and behavioral effects. In previous studies, we showed that n-3 deficiency led to a decrease in the neuronal size of a number of brain regions in young rats. In particular, the neuronal size in the hippocampus CA1-CA3 layers decreased with a slight increase in the volumes of these layers. Therefore, we asked whether fatty acid deficiency could affect rat brain morphology in older animals. To address this question, we carried out gross morphological analysis using Magnetic Resonance Imaging on the gray and white matter volumes of brains in older rats (> 15 months) that were raised on n-3 deficient diets for three generations. We did not detect any differences in the total or regional gray and white matter volumes of brains of old rats maintained on a n-3 deficient or supplemented diet.

Aging↗
PubMed2004

Repletion with (n-3) fatty acids reverses bone structural deficits in (n-3)-deficient rats.

(n-3) PUFA deficiency and repletion effects on bone mechanical properties have not been examined. The primary research aim was to evaluate whether changes in the fatty acid composition of bone tissue compartments previously reported to influence bone formation rates would affect bone modeling and mechanical properties. In this investigation, three groups of rats were studied, second generation (n-3)-deficient, (n-3)-repleted, and a control (n-3)-adequate. The (n-3)-adequate diet contained alpha-linolenic acid [LNA, 18:3(n-3), 2.6% of total fatty acids] and docosahexaenoic acid [DHA, 22:6(n-3), 1.3% of total fatty acids]. Fatty acid composition of the hindlimb tissues (bone and muscle) of chronically (n-3)-deficient rats revealed a marked increase in (n-6) PUFA [20:4(n-6), 22:4(n-6), and 22:5(n-6)] and a corresponding decrease in (n-3) PUFA [18:3(n-3), 20:5(n-3), 22:5(n-3) and 22:6(n-3)]. Measurement of bone mechanical properties (energy to peak load) of tibiae showed that (n-3) deficiency diminished structural integrity. Rats repleted with (n-3) fatty acids demonstrated accelerated bone modeling (cross-sectional geometry) and an improved second moment in tibiae compared with control (n-3)-adequate rats after 28 d of dietary treatment. This study showed that repletion with dietary (n-3) fatty acids restored the ratio of (n-6)/(n-3) PUFA in bone compartments and reversed compromised bone modeling in (n-3)-deficient rats.

Animals↗
PubMed2003

Insulin-like growth factor 1 is essential for normal dendritic growth.

This study evaluated somatic and dendritic growth of neurons in the frontoparietal cortex of Igf1-/- brains. Pyramidal neuron density was increased by approximately 25% (P =.005) and soma size reduced by approximately 10% (P <.001). Golgi staining revealed that cortical layer II-III neurons exhibited a significant reduction in dendritic length and complexity in Igf1 null mice. Dendritic spine density and presumably synaptic contacts were reduced by 16% (P =.002). Similar findings were obtained for cortical layer V and piriform cortex pyramids. Supporting a reduction in synapses, synaptotagmin levels were reduced by 30% (P <.02) in the Igf1 null brain. Investigation of factors critically involved in dendritic growth and synaptogenesis showed an approximately 50% reduction in cortical CDC42 protein expression (P <.001) and an approximately 10% reduction in brain cholesterol levels (P <.01) in Igf1 null mice. Evidence is presented that Igf1 deletion causes disruptions in lipid and microtubule metabolism, leading to impaired neuronal somatic and dendritic growth. Published 2003 Wiley-Liss, Inc.

Animals↗
PubMed2003

Docosapentaenoic acid does not completely replace DHA in n-3 FA-deficient rats during early development.

The reciprocal replacement of DHA by docosapentaenoic acid (DPAn-6) was studied in rats that consumed an n-3 FA-deficient or n-3 FA-adequate diet. Dams were fed the two experimental diets from weaning and throughout pregnancy and lactation. Their pups were then fed the respective diets after weaning. Cortex FA analysis was performed at various times (0, 5, 10, 20, 50, and 91 d) after birth to determine whether DPAn-6 completely replaced DHA in the n-3-deficient group. Cortical DHA levels were significantly lower (average 86%) in the n-3-deficient rats. DPAn-6 increased significantly in the n-3-deficient rats starting with a 6.5-fold increase at day 0 up to a 54-fold increase at day 91 compared with the n-3-adequate group. However, this significant increase did not completely replace the loss of DHA at postnatal days 5, 10, and 20 in which there was still an 11.5, 10.3, and 8.0% deficit in the sum of DHA and DPAn-6, respectively, in the n-3-deficient group. Once docosatetraenoic (DTA) and arachidonic acids (AA) were included in the sum (DHA + DPAn-6 + DTA + AA), the levels between the two groups were similar. These results suggest that not only DPAn-6 but also other n-6 FA, including DTA and AA, replace DHA in n-3-deficient rats. The lack of total 22-carbon (22C) FA in the brain during the rapid membrane biogenesis that occurs during early development could be a factor in the nervous system functional deficits associated with n-3 FA deficiency.

Animal Feed↗
PubMed2003

Impact of dietary n-3 FA deficiency on rat bone tissue FA composition.

The effect of dietary n-3 FA deficiency on bone tissue FA composition was evaluated in growing rats. Two mixtures combining hydrogenated coconut oil with safflower oil served as the n-3-deficient dietary treatments and provided two levels of linoleic acid (LA). The n-3 treatments were formulated with added alpha-linolenic acid (LNA) from flaxseed oil (diet LNA) or LNA plus DHA, and both were balanced for LA. This study showed that bone is sensitive to changes in dietary n-3 FA and that DHA is more effective than LNA in maintaining DHA levels in these tissues.

Animals↗
PubMed2003

Recovery of brain docosahexaenoate leads to recovery of spatial task performance.

Infants fed vegetable oil-based formulas may have poorer visual function, lower cognitive scores and acquire learning tasks more slowly in comparison with those breast fed or those fed formulas supplemented with docosahexaenoate. The aim of the present study was to determine the reversibility of losses in brain function associated with the loss of brain DHA. Rats were fed very low or adequate levels of n-3 fatty acids through three generations. The n-3 fatty acid deficient animals of the F3 generation were then given an n-3 adequate diet containing alpha-linolenic and docosahexaenoic acids (DHA) at birth, weaning (3 weeks) or young adulthood (7 weeks). The spatial task performance of these animals returned to the n-3 adequate diet was then compared using the Morris water at two different ages, at 9 or 13 weeks. Our results indicate that animals repleted since birth or at weaning were able to achieve nearly the same level of brain DHA and spatial task performance as animals maintained for three generations on an n-3 adequate diet. In the case of young adult animals, the degree of DHA and behavioral performance recovery depended upon the duration of dietary repletion with substantial recovery in animals after 6 weeks but little recovery of function after two weeks. The significance of these findings is that they indicate that at least some of the adverse effects of DHA deficiency during neurodevelopment may be reversible with an n-3 fatty acid supplemented diet.

Animals↗
PubMed2003

Effects of beef- and fish-based diets on the kinetics of n-3 fatty acid metabolism in human subjects.

BACKGROUND: The quantity and type of dietary polyunsaturated fatty acids (PUFAs) can alter essential fatty acid metabolism in humans. Diets rich in 20- and 22-carbon PUFAs may inhibit desaturase expression or activity and decrease the synthesis of long-chain unsaturated fatty acids. OBJECTIVE: It was theorized that the fat content of a fish-based diet would inhibit the kinetics of the in vivo metabolism of n-3 fatty acids compared with a beef-based diet. DESIGN: A compartmental model was used to determine the coefficients of the kinetic rate constants from the plasma concentration time curves of pentadeuterated (d(5)) 18:3n-3, 20:5n-3, 22:5n-3, and 22:6n-3 of 10 subjects who subsisted on 3 diets with different long-chain PUFA contents. For 3 wk, subjects reported their food intake from their usual diets and then consumed a beef-based diet for 3 wk and then a fish-based diet for an additional 3 wk. Subjects consumed 1 g d(5)-18:3n-3 ethyl ester at weeks 3, 6, and 9. Blood was drawn over 168 h and the plasma analyzed for fatty acids. The coefficients of the kinetic constants of n-3 fatty acid metabolism and the percentage utilization of the substrates were determined. RESULTS: Across all diets, < 1% of plasma 18:3n-3 was utilized for long-chain PUFA synthesis. There was a 70% reduction in the value of the rate constant coefficient that regulated transfer of the isotope from the 22:5n-3 compartment to 22:6n-3 when the fish-based diet was compared with the beef-based diet. The turnover rate of plasma d(5)-22:6n-3 also decreased. CONCLUSIONS: The primary effect of a fish-based diet on the kinetics of n-3 metabolism involves processes that inhibit the synthesis of 22:6n-3 from 22:5n-3. These processes may involve a system of feedback control mechanisms responsive to the plasma concentration of 22:6n-3.

Adult↗
PubMed2002

Long-term n-3 FA deficiency modifies peroxisome proliferator-activated receptor beta mRNA abundance in rat ocular tissues.

Peroxisomal proliferator-activated receptors (PPAR) are a FA-response system involved in diverse cellular responses. FA regulate PPAR activity and modulate PPAR mRNA abundance. Increasing evidence indicates that PUFA are required for optimal neuronal development and function. To gain insight into the mechanism for nutrition-induced impairment of neuronal development and function we investigated the effect of chronic n-3 FA deficiency on PPAR mRNA levels in rat brain and ocular tissues. Rats were fed for three generations a diet designed to reduce DHA levels in tissues, and the abundance of PPARalpha and PPARbeta transcripts was measured by hybridization with specific probes. Chronic consumption of the a-linolenic acid (LNA)-insufficient diet caused a remarkable modification in DHA content in membrane phospholipids. The results reported here indicate that PPARa mRNA levels did not exhibit significant variation in ocular, hepatic, or nervous tissues from rats fed the experimental diet. In contrast, PPARalpha mRNA normalized to beta-actin mRNA was 21% higher in ocular tissue from F3 generation rats consuming the LNA-deficient diet but was independent of diet in hepatic and nervous tissues. The absolute abundance of PPARbeta transcripts showed a 17% increase in ocular tissue from rats consuming the LNA-deficient diet (F3 generation). The biological significance of the reported changes in PPARbeta mRNA in ocular tissue remains to be determined.

Actins↗
PubMed2002

Retinal sensitivity loss in third-generation n-3 PUFA-deficient rats.

A previous study conducted in guinea pigs suggested that ingestion of diets high in EPA and DHA may result in suboptimal retinal function. The aim of the present study was to evaluate retinal function in pigmented (Long-Evans) rats, raised to a third generation on diets that were either deficient in n-3 PUFA or adequate (with the addition of DHA). Electroretinographic assessment employed full-field white flash stimulation. Photoreceptor responses were evaluated in terms of peak amplitudes and implicit times (a-wave, b-wave), intensity-response functions (Naka-Rushton), and the parameters of a model of transduction (P3). Retinal phospholipid FA composition was measured by capillary GLC. DHA levels were reduced by 55% in n-3-deficient animals compared with the n-3-adequate group, whereas the levels of docosapentaenoic acid n-6 were 44 times higher in n-3-deficient animals. The level of arachidonic acid was marginally higher (12.8%) in n-6-adequate animals. The n-3-deficient animals exhibited significantly reduced retinal sensitivity (sigma and S values were both affected by 0.29 log units) and increased b-wave implicit times compared with those fed the n-3-adequate diet. These data suggest that n-3 PUFA are required for development of retinal sensitivity, more so than other indices of retinal function assessed by current methods, such as maximal response amplitude. However, the benefit for retinal function of adding preformed DHA to diets already replete in n-3 PUFA remains unclear.

Animals↗
PubMed2002

Visual acuity and retinal function in infant monkeys fed long-chain PUFA.

Previous randomized clinical trials suggest that supplementation of the human infant diet with up to 0.35% DHA may benefit visual development. The aim of the current study was to assess the impact of including arachidonic acid (AA) and a higher level of DHA in the postnatal monkey diet on visual development. Infant rhesus monkeys were fed either a control diet (2.0% alpha-linolenic acid as the sole n-3 FA) or a supplemented diet (1.0% DHA and 1.0% AA) from birth. Visual evoked potential acuity was measured at 3 mon of age. Rod and cone function were assessed in terms of parameters describing phototransduction. Electroretinogram (ERG) amplitudes and implicit times were recorded over a wide intensity range (-2.2 to 4.0 log scot td-sec) and assessed in terms of intensity response functions. Plasma DHA and AA were significantly increased (P < 0.001) in the diet-supplemented monkeys compared with the control monkeys. There was an approximately equal effect of diet for the rod phototransduction parameters, sensitivity, and capacitance but in the opposite directions. Diet-supplemented monkeys had significantly shorter b-wave implicit times at low retinal illuminances (<-0.6 log scot td-sec). There were no significant effects of diet for visual acuity or the other 23 ERG parameters measured. The results suggest that supplementation of the infant monkey diet with 1.0% DHA and 1.0% AA neither harms nor provides substantial benefit to the development of visual acuity or retinal function in the first four postnatal months.

Animals↗
PubMed2002

Decrease in neuron size in docosahexaenoic acid-deficient brain.

Docosahexaenoic acid is an important fatty acid for neuronal function because its deficiency leads to many behavioral and functional deficits. In a previous study, we reported that docosahexaenoic acid deficiency caused a reduction in the size of neurons of the CA1 region in the hippocampus. To extend these results to other regions of the brain, the present study entailed a morphologic analysis of neuronal size in hippocampus, hypothalamus, piriform cortex, and parietal cortex in rats that were raised on docosahexaenoic acid-deficient and supplemented diets for three generations. Neuron size in these regions was measured both at weaning (21 days) and maturity (68 days), and docosahexaenoic acid content in the brain was measured on a separate set of sibling rats using fatty acid analysis. Neuron size in hippocampus, hypothalamus, and parietal cortex decreased in weanling and in piriform cortex in mature rats raised on the docosahexaenoic acid-deficient diet. The brains of these rats exhibited a nearly 90% decrease of docosahexaenoic acid. Decrease of neuron size has been linked to a loss of optimal function in neurons. In the United States, human infant-milk formulas use vegetable oils as fat sources that lack docosahexaenoic acid. If docosahexaenoic acid deficiency reduces neuron size, then human infants raised on these formulas may also have smaller neurons relative to breast-fed infants.

Animals↗
PubMed2002

Cognitive deficits in docosahexaenoic acid-deficient rats.

This study investigated the influence of brain docosahexaenoic acid (DHA) deficiency on simple and complex olfactory-based learning and memory in 2nd generation (F2) adult male rats. Rats raised and maintained on either an n-3-adequate or an n-3-deficient diet were tested for acquisition of an olfactory learning set and an olfactory memory task, and for motivation to obtain a water reward. Despite a 76% decrease in brain DHA, n-3-deficient rats were able to acquire most simple 2-odor discrimination tasks but were deficient in the acquisition of a 20-problem olfactory learning set. This deficit could not be attributed to changes in sensory capacity but, instead, appeared to represent a deficit in higher order learning.

Animals↗
PubMed2002

A decrease in cell size accompanies a loss of docosahexaenoate in the rat hippocampus.

Rats raised on n-3 essential fatty acid deficient diets demonstrate spatial memory deficits. To investigate neuroanatomical correlates of these deficits, morphological analysis of the hippocampus were carried out. Adult, female rats were raised for three generations on n-3 deficient or n-3 supplemented diets. Two n-3 deficient diets contained adequate linoleic acid (LA), or high linoleic acid (high LA), and two supplemented diets contained LA supplemented with alpha-linolenic acid (+LNA), or linoleic supplementation with alpha-linolenic and docosahexaenoic acids (+LNA/DHA). The total fatty acid composition of the hippocampus revealed a profound loss (90%) in docosahexaenoic acid (DHA) in the hippocampi of LA and high LA animals compared to those on +LNA and +LNA/DHA diets with a reciprocal increase in docosapentaenoic acid (DPAn-6) in all phospholipid species. The volume, density, total number, and cell body size of neurons in CA1-3, granular and hilar layers of the hippocampus were measured at septal and temporal locations using unbiased stereology. No differences were detected in any of these measures except for in cell body size; CA1 pyramidal neurons in the LA group were significantly (p < 0.04) smaller than neurons in the +LNA/DHA group at the septal location.

Animals↗
PubMed2002

Fatty acid formula supplementation and neuromotor development in rhesus monkey neonates.

Docosahexaenoic acid (DHA) is an omega-3 fatty acid that is highly concentrated in CNS tissues. Although breast milk contains the fatty acids DHA and arachidonic acid, infant formulas marketed in North America do not contain these nutrients. The potential deleterious effects of rearing infants with formulas devoid of these nutrients was assessed by comparing nursery-reared rhesus macaque infants (Macaca mulatta) fed standard formula with infants fed standard formula supplemented with physiologically relevant concentrations of DHA (1.0%) and arachidonic acid (1.0%). Neurobehavioral assessments were conducted on d 7, 14, 21, and 30 of life using blinded raters. The 30-min assessment consisted of 45 test items measuring orienting, temperament, reflex capabilities, and motor skills. Plasma concentrations of DHA in standard formula-fed infants were significantly lower than those fed supplemented formula or mother-raised (breast-fed) infants; however, infants fed the supplemented formula exhibited higher arachidonic acid levels than either mother-reared infants or infants fed standard formula. Infant monkeys fed the supplemented formula exhibited stronger orienting and motor skills than infants fed the standard formula, with the differences most pronounced during d 7 and 14. This pattern suggests an earlier maturation of specific visual and motor abilities in the supplemented infants. Supplementation did not affect measures of activity or state control, indicating no effect on temperament. These data support the assertion that preformed DHA and arachidonic acid in infant formulas are required for optimal development.

Animal Feed↗