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1.  Exercise facilitates the action of dietary DHA on functional recovery after brain trauma 
Neuroscience  2013;248:655-663.
The abilities of docosahexaenoic acid (DHA) and exercise to counteract cognitive decay after TBI is getting increasing recognition; however, the possibility that these actions can be complementary remains just as an intriguing possibility. Here we have examined the likelihood that the combination of diet and exercise has the added potential to facilitate functional recovery following TBI. Rats received mild fluid percussion injury (mFPI) or sham injury and then were maintained on a diet high in DHA (1.2% DHA) with or without voluntary exercise for 12 days. We found that FPI reduced DHA content in the brain, which was accompanied by increased levels of lipid peroxidation assessed using 4-HHE. FPI reduced the enzymes Acox1 and 17 -HSD4, and the calcium-independent phospholipases A2 (iPLA2), which are involved in metabolism of membrane phospholipids. FPI reduced levels of syntaxin-3 (STX-3), involved in the action of membrane DHA on synaptic membrane expansion, and also reduced BDNF signaling through its TrkB receptor. These effects of FPI were optimally counteracted by the combination of DHA and exercise. Our results support the possibility that the complementary action of exercise is exerted on restoring membrane homeostasis after TBI, which is necessary for supporting synaptic plasticity and cognition. It is our contention that strategies that take advantage of the combined applications of diet and exercise may have additional effects to the injured brain.
doi:10.1016/j.neuroscience.2013.06.041
PMCID: PMC3951948  PMID: 23811071
DHA; exercise; BDNF; omega-3 fatty acids; cognition
2.  Vitamin E Protects Against Oxidative Damage and Learning Disability After Mild Traumatic Brain Injury in Rats 
Background
Reactive oxygen species induce neuronal damage, and their role in reducing synaptic plasticity and function is beginning to be understood. Vitamin E is a potent reactive oxygen species scavenger, which has the potential to reduce oxidative damage encountered after traumatic brain injury (TBI). Brain-derived neurotrophic factor (BDNF) can facilitate synaptic function and support learning by modulating the CaMKII system, synapsin I, and cAMP-response element-binding protein (CREB). The elevation of superoxide dismutase (SOD) and Sir2 (silent information regulator 2) play an important role in resistance to oxidative stress.
Objective
We examined the possibility that vitamin E supplemented in the diet may help counteract the effects of TBI on the molecular substrates underlying synaptic plasticity and cognitive function in the hippocampus.
Methods
Rats were fed a regular diet with or without 500 IU/kg of vitamin E for 4 weeks (n = 6-8 per group) before a mild fluid percussion injury (FPI) was performed.
Results
FPI increased protein oxidation as evidenced by elevated levels of protein carbonyls and reduced levels of SOD and Sir2. In addition, FPI resulted in poor performance in the Morris water maze, which was accompanied by reduced levels of BDNF and its downstream effectors on synaptic plasticity, synapsin I, CREB, and CaMKII. Supplementation of vitamin E in the diet counteracted all the observed effects of FPI.
Conclusions
These results suggest that vitamin E dietary supplementation can protect the brain against the effects of mild TBI on synaptic plasticity and cognition, using molecular systems associated with the maintenance of long-term plasticity, such as BDNF and Sir2.
doi:10.1177/1545968309348318
PMCID: PMC2824788  PMID: 19841436
traumatic brain injury; hippocampus; learning; BDNF; vitamin E
3.  Brain and Spinal Cord Interaction: A Dietary Curcumin Derivative Counteracts Locomotor and Cognitive Deficits After Brain Trauma 
Background
In addition to cognitive dysfunction, locomotor deficits are prevalent in traumatic brain injured (TBI) patients; however, it is unclear how a concussive injury can affect spinal cord centers. Moreover, there are no current efficient treatments that can counteract the broad pathology associated with TBI.
Objective
The authors have investigated potential molecular basis for the disruptive effects of TBI on spinal cord and hippocampus and the neuroprotection of a curcumin derivative to reduce the effects of experimental TBI.
Methods
The authors performed fluid percussion injury (FPI) and then rats were exposed to dietary supplementation of the curcumin derivative (CNB-001; 500 ppm). The curry spice curcumin has protective capacity in animal models of neurodegenerative diseases, and the curcumin derivative has enhanced brain absorption and biological activity.
Results
The results show that FPI in rats, in addition to reducing learning ability, reduced locomotor performance. Behavioral deficits were accompanied by reductions in molecular systems important for synaptic plasticity underlying behavioral plasticity in the brain and spinal cord. The post-TBI dietary supplementation of the curcumin derivative normalized levels of BDNF, and its downstream effectors on synaptic plasticity (CREB, synapsin I) and neuronal signaling (CaMKII), as well as levels of oxidative stress–related molecules (SOD, Sir2).
Conclusions
These studies define a mechanism by which TBI can compromise centers related to cognitive processing and locomotion. The findings also show the influence of the curcumin derivative on synaptic plasticity events in the brain and spinal cord and emphasize the therapeutic potential of this noninvasive dietary intervention for TBI.
doi:10.1177/1545968310397706
PMCID: PMC3258099  PMID: 21343524
traumatic brain injury; hippocampus; learning; BDNF; curcumin derivative
4.  DHA dietary supplementation enhances the effects of exercise on synaptic plasticity and cognition 
Neuroscience  2008;155(3):751-759.
Omega-3 fatty acids (i.e., docosahexaenoic acid; DHA), similar to exercise, improve cognitive function, promote neuroplasticity, and protect against neurological lesion. In this study, we investigated a possible synergistic action between DHA dietary supplementation and voluntary exercise on modulating synaptic plasticity and cognition. Rats received DHA dietary supplementation (1.25% DHA) with or without voluntary exercise for 12 days. We found that the DHA-enriched diet significantly increased spatial learning ability, and these effects were enhanced by exercise. The DHA-enriched diet increased levels of pro-BDNF and mature BDNF, whereas the additional application of exercise boosted the levels of both. Furthermore, the levels of the activated forms of CREB and synapsin I were incremented by the DHA-enriched diet with greater elevation by the concurrent application of exercise. While the DHA diet reduced hippocampal oxidized protein levels, a combination of a DHA diet and exercise resulted in a greater reduction rate. The levels of activated forms of hippocampal Akt and CaMKII were increased by the DHA-enriched diet, and with even greater elevation by a combination of diet and exercise. Akt and CaMKII signaling are crucial step by which BDNF exerts its action on synaptic plasticity and learning and memory. These results indicate that the DHA diet enhance the effects of exercise on cognition and BDNF-related synaptic plasticity, a capacity that may be used to promote mental health and reduce risk of neurological disorders.
doi:10.1016/j.neuroscience.2008.05.061
PMCID: PMC3208643  PMID: 18620024
DHA; exercise; BDNF; omega-3 fatty acids; cognition
5.  A pyrazole curcumin derivative restores membrane homeostasis disrupted after brain trauma 
Experimental neurology  2010;226(1):191-199.
We have assessed potential mechanisms associated with the deleterious effects of TBI on the integrity of plasma membranes in the hippocampus, together with consequences for behavioral function. In addition, we have investigated the efficacy of a dietary intervention based on a pyrazole curcumin derivative with demonstrated bioactivity and brain absorption, to re-establish membrane integrity. We report that moderate fluid percussion injury (FPI) increases levels of 4-Hydroxynonenal (HNE), an intermediary for the harmful effects of lipid peroxidation on neurons. A more direct action of FPI on membrane homeostasis was evidenced by a reduction in calcium-independent phospholipase A2 (iPLA2) important for metabolism of membrane phospholipids such as DHA, and an increase in the fatty acid transport protein (FATP) involved in translocation of long-chain fatty acids across the membrane. A potential association between membrane disruption and neuronal function was suggested by reduced levels of the NR2B subunit of the transmembrane NMDA receptor, in association with changes in iPLA2 and syntaxin-3 (STX-3, involved in the action of membrane DHA on synaptic membrane expansion). In addition, changes in iPLA2, 4-HNE, and STX-3 were proportional to reduced performance in a spatial learning task. In turn, the dietary supplementation with the curcumin derivative counteracted all the effects of FPI, effectively restoring parameters of membrane homeostasis. Results show the potential of the curcumin derivative to promote membrane homeostasis following TBI, which may foster a new line of non-invasive therapeutic treatments for TBI patients by endogenous up-regulation of molecules important for neural repair and plasticity.
doi:10.1016/j.expneurol.2010.08.027
PMCID: PMC3225197  PMID: 20816821
rat; membrane damage; curcumin; 4-hydoxynonenal; cognition
6.  Effects of Diet and/or Exercise in Enhancing Spinal Cord Sensorimotor Learning 
PLoS ONE  2012;7(7):e41288.
Given that the spinal cord is capable of learning sensorimotor tasks and that dietary interventions can influence learning involving supraspinal centers, we asked whether the presence of omega-3 fatty acid docosahexaenoic acid (DHA) and the curry spice curcumin (Cur) by themselves or in combination with voluntary exercise could affect spinal cord learning in adult spinal mice. Using an instrumental learning paradigm to assess spinal learning we observed that mice fed a diet containing DHA/Cur performed better in the spinal learning paradigm than mice fed a diet deficient in DHA/Cur. The enhanced performance was accompanied by increases in the mRNA levels of molecular markers of learning, i.e., BDNF, CREB, CaMKII, and syntaxin 3. Concurrent exposure to exercise was complementary to the dietary treatment effects on spinal learning. The diet containing DHA/Cur resulted in higher levels of DHA and lower levels of omega-6 fatty acid arachidonic acid (AA) in the spinal cord than the diet deficient in DHA/Cur. The level of spinal learning was inversely related to the ratio of AA∶DHA. These results emphasize the capacity of select dietary factors and exercise to foster spinal cord learning. Given the non-invasiveness and safety of the modulation of diet and exercise, these interventions should be considered in light of their potential to enhance relearning of sensorimotor tasks during rehabilitative training paradigms after a spinal cord injury.
doi:10.1371/journal.pone.0041288
PMCID: PMC3401098  PMID: 22911773
7.  Dietary Curcumin Supplementation Counteracts Reduction in Levels of Molecules Involved in Energy Homeostasis after Brain Trauma 
Neuroscience  2009;161(4):1037-1044.
Traumatic brain injury (TBI) is followed by an energy crisis that compromises the capacity of the brain to cope with challenges, and often reduces cognitive ability. New research indicates that events that regulate energy homeostasis crucially impact synaptic function and this can compromise the capacity of the brain to respond to challenges during the acute and chronic phases of TBI. The goal of the present study is to determine the influence of the phenolic yellow curry pigment curcumin on molecular systems involved with the monitoring, balance, and transduction of cellular energy, in the hippocampus of animals exposed to mild fluid percussion injury (FPI). Young adult rats were exposed to a regular diet (RD) without or with 500 ppm curcumin (Cur) for four weeks, before an FPI was performed. The rats were assigned to four groups: RD/Sham, Cur/Sham, RD/FPI, and Cur/FPI. We found that FPI decreased the levels of AMP-activated protein kinase (AMPK), ubiquitous mitochondrial creatine kinase (uMtCK) and cytochrome c oxidase II (COX-II) in RD/FPI rats as compared to the RD/sham rats. The curcumin diet counteracted the effects of FPI and elevated the levels of AMPK, uMtCK, COX-II in Cur/FPI rats as compared to RD/sham rats. In addition, in the Cur/sham rats, AMPK and uMtCK increased compared to the RD/sham. Results show the potential of curcumin to regulate molecules involved in energy homeostasis following TBI. These studies may foster a new line of therapeutic treatments for TBI patients by endogenous upregulation of molecules important for functional recovery.
doi:10.1016/j.neuroscience.2009.04.042
PMCID: PMC2805661  PMID: 19393301
curcumin; energy homeostasis; traumatic brain injury
8.  Exercise-induced improvement in cognitive performance after traumatic brain-injury in rats is dependent on BDNF Activation 
Brain research  2009;1288:105-115.
We have previously shown that voluntary exercise upregulates brain-derived neurotrophic factor (BDNF) within the hippocampus and is associated with an enhancement of cognitive recovery after a lateral fluid-percussion injury (FPI). In order to determine if BDNF is critical to this effect we used an immunoadhesin chimera (TrkB-IgG) that inactivates free BDNF. This BDNF inhibitor was administered to adult male rats two weeks after they had received a mild fluid percussion injury (FPI) or sham surgery. These animals were then housed with or without access to a running wheel (RW) from post-injury-day (PID) 14 to 20. On PID 21, rats were tested for spatial learning in a Morris Water Maze. Results showed that exercise counteracted the cognitive deficits associated with the injury. However this exercise-induced cognitive improvement was attenuated in the FPI-RW rats that were treated with TrkB-IgG. Molecules important for synaptic plasticity and learning were measured in a separate group of rats that were sacrificed immediately after exercise (PID 21). Western blot analyses showed that exercise increased the mature form of BDNF, synapsin I and cyclic-AMP response-element-binding protein (CREB) in the vehicle treated Sham-RW group. However, only the mature form of BDNF and CREB were increased in the vehicle treated FPI-RW group. Blocking BDNF (pre administration of TrkB-IgG) greatly reduced the molecular effects of exercise in that exercise-induced increases of BDNF, synapsin I and CREB were not observed. These studies provide evidence that BDNF has a major role in exercise's cognitive effects in traumatically injured brain.
doi:10.1016/j.brainres.2009.06.045
PMCID: PMC2735616  PMID: 19555673
TBI; hippocampus; fluid-percussion-injury; Synapsin I and CREB
9.  Exercise contributes to the effects of DHA dietary supplementation by acting on membrane-related synaptic systems 
Brain research  2009;1341C:32-40.
Dietary omega-3 fatty acid (i.e. docosohexaenoic acid (DHA)) and exercise are gaining recognition for supporting brain function under normal and challenging conditions. Here we evaluate the possibility that the interaction of DHA and exercise can involve specific elements of the synaptic plasma membrane. We found that voluntary exercise potentiated the effects of a 12-day DHA dietary supplementation regimen on increasing the levels of syntaxin 3 (STX-3) and the growth-associated protein (GAP-43) in the adult rat hippocampus region. STX-3 is a synaptic membrane-bound protein involved in the effects of DHA on membrane expansion. The DHA diet and exercise also elevated levels of the NMDA receptor subunit NR2B, which is important for synaptic function underlying learning and memory. The actions of exercise and DHA dietary supplementation reflected on enhanced learning performance in the Morris water maze as learning ability was associated with higher levels of STX-3 and NR2B. The overall findings reveal a mechanism by which exercise can interact with the function of DHA dietary enrichment to elevate the capacity of the adult brain for axonal growth, synaptic plasticity, and cognitive function.
doi:10.1016/j.brainres.2009.05.018
PMCID: PMC2884051  PMID: 19446534
Omega-3 fatty acid; Voluntary exercise; Syntaxin; Synaptic membrane; Hippocampus
10.  Differential effects of exercise and dietary docosahexaenoic acid (DHA) on molecular systems associated with control of allostasis in the hypothalamus and hippocampus 
Neuroscience  2010;168(1):130-137.
Given the robust influence of diet and exercise on brain plasticity and disease, we conducted studies to determine their effects on molecular systems important for control of brain homeostasis. Studies were centered on a battery of proteins implicated in metabolic homeostasis that have the potential to modulate brain plasticity and cognitive function, in rat hypothalamus and hippocampus. Adult male rats were exposed to a docosahexaenoic acid (DHA) enriched diet (1.25% DHA) with or without voluntary exercise for 14 days. Here we report that the DHA diet and exercise influence protein levels of molecular systems important for the control of energy metabolism (primarily phospho - AMPK, silent information regulator type 1), food intake (primarily leptin and ghrelin receptors), stress (primarily glucocorticoid receptors, and 11beta-hydroxysteroid dehydrogenase 1 (11βHSD1). Exercise or DHA dietary supplementation had differential effects on several of these class proteins, and the concurrent application of both altered the pattern of response elicited by the single applications of diet or exercise. For example, exercise elevated levels of glucocorticoids receptors in the hypothalamus and the DHA diet had opposite effects, while the concurrent application of diet and exercise counteracted the single effects of diet or exercise. In most of the cases, the hypothalamus and the hippocampus had a distinctive pattern of response to the diet or exercise. The results harmonize with the concept that exercise and dietary DHA exert specific actions on the hypothalamus and hippocampus, with implications for the regulations of brain plasticity and cognitive function.
doi:10.1016/j.neuroscience.2010.02.070
PMCID: PMC3225187  PMID: 20303394
Stress; metabolism; synaptic plasticity; homeostasis; mood; depression; anxiety
11.  Effect of fish oils containing different amounts of EPA, DHA, and antioxidants on plasma and brain fatty acids and brain nitric oxide synthase activity in rats 
Upsala Journal of Medical Sciences  2009;114(4):206-213.
Background
The interest in n-3 polyunsaturated fatty acids (PUFAs) has expanded significantly in the last few years, due to their many positive effects described. Consequently, the interest in fish oil supplementation has also increased, and many different types of fish oil supplements can be found on the market. Also, it is well known that these types of fatty acids are very easily oxidized, and that stability among supplements varies greatly.
Aims of the study
In this pilot study we investigated the effects of two different types of natural fish oils containing different amounts of the n-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and antioxidants on plasma and brain fatty acids, blood lipids, vitamin E, and in vivo lipid peroxidation, as well as brain nitric oxide synthase (NOS) activity, an enzyme which has been shown to be important for memory and learning ability.
Methods
Sprague-Dawley rats were divided into four groups and fed regular rat chow pellets enriched with 5% (w/w) of butter (control group), a natural fish oil (17.4% EPA and 11.7% DHA, referred to as EPA-rich), and a natural fish oil rich in DHA (7.7% EPA and 28.0% DHA, referred to as DHA-rich). Both of the fish oils were stabilized by a commercial antioxidant protection system (Pufanox®) at production. The fourth group received the same DHA-rich oil, but without Pufanox® stabilization (referred to as unstable). As an index of stability of the oils, their peroxide values were repeatedly measured during 9 weeks. The dietary treatments continued until sacrifice, after 10 days.
Results
Stability of the oils varied greatly. It took the two stabilized oils 9 weeks to reach the same peroxide value as the unstable oil reached after only a few days. Both the stabilized EPA- and DHA-rich diets lowered the triacylglycerols and total cholesterol compared to control (-45%, P < 0.05 and -54%, P < 0.001; -31%, P < 0.05 and -25%, P < 0.01) and so did the unstable oil, but less efficiently. Only the unstable oil increased in vivo lipid peroxidation significantly compared to control (+40%, P < 0.001). Most of the fatty acids in the plasma phospholipids were significantly affected by both the EPA- and DHA-rich diets compared to control, reflecting their specific fatty acid pattern. The unstable oil diet resulted in smaller changes, especially in n-3 PUFAs. In the brain phospholipids the changes were less pronounced, and only the diet enriched with the stabilized DHA-rich oil resulted in a significantly greater incorporation of DHA (+13%, P < 0.01), as well as total n-3 PUFAs (+13%, P < 0.01) compared to control. Only the stabilized DHA-rich oil increased the brain NOS activity (+33%, P < 0.01).
Conclusions
Both the EPA- and DHA-rich diets affected the blood lipids in a similarly positive manner, and they both had a large impact on plasma phospholipid fatty acids. It was only the unstable oil that increased in vivo lipid peroxidation. However, the intake of DHA was more important than that of EPA for brain phospholipid DHA enrichment and brain NOS activity, and the stability of the fish oil was also important for these effects.
doi:10.3109/03009730903268958
PMCID: PMC2852776  PMID: 19961266
Antioxidants; brain; DHA; EPA; fish oil; lipid peroxidation; nitric oxide synthase
12.  Omega-3 Fatty Acid Deficiency during Brain Maturation Reduces Neuronal and Behavioral Plasticity in Adulthood 
PLoS ONE  2011;6(12):e28451.
Omega-3-fatty acid DHA is a structural component of brain plasma membranes, thereby crucial for neuronal signaling; however, the brain is inefficient at synthesizing DHA. We have asked how levels of dietary n-3 fatty acids during brain growth would affect brain function and plasticity during adult life. Pregnant rats and their male offspring were fed an n-3 adequate diet or n-3 deficient diets for 15 weeks. Results showed that the n-3 deficiency increased parameters of anxiety-like behavior using open field and elevated plus maze tests in the male offspring. Behavioral changes were accompanied by a level reduction in the anxiolytic-related neuropeptide Y-1 receptor, and an increase in the anxiogenic-related glucocorticoid receptor in the cognitive related frontal cortex, hypothalamus and hippocampus. The n-3 deficiency reduced brain levels of docosahexaenoic acid (DHA) and increased the ratio n-6/n-3 assessed by gas chromatography. The n-3 deficiency reduced the levels of BDNF and signaling through the BDNF receptor TrkB, in proportion to brain DHA levels, and reduced the activation of the BDNF-related signaling molecule CREB in selected brain regions. The n-3 deficiency also disrupted the insulin signaling pathways as evidenced by changes in insulin receptor (IR) and insulin receptor substrate (IRS). DHA deficiency during brain maturation reduces plasticity and compromises brain function in adulthood. Adequate levels of dietary DHA seem crucial for building long-term neuronal resilience for optimal brain performance and aiding in the battle against neurological disorders.
doi:10.1371/journal.pone.0028451
PMCID: PMC3233581  PMID: 22163304
13.  Depletion of Brain Docosahexaenoic Acid Impairs Recovery from Traumatic Brain Injury 
PLoS ONE  2014;9(1):e86472.
Omega-3 fatty acids are crucial for proper development and function of the brain where docosahexaenoic acid (DHA), the primary omega-3 fatty acid in the brain, is retained avidly by the neuronal membranes. We investigated the effect of DHA depletion in the brain on the outcome of traumatic brain injury (TBI). Pregnant mice were put on an omega-3 fatty acid adequate or deficient diet from gestation day 14 and the pups were raised on the respective diets. Continuation of this dietary regime for three generations resulted in approximately 70% loss of DHA in the brain. Controlled cortical impact was delivered to both groups of mice to produce severe TBI and the functional recovery was compared. Compared to the omega-3 adequate mice, the DHA depleted mice exhibited significantly slower recovery from motor deficits evaluated by the rotarod and the beam walk tests. Furthermore, the DHA deficient mice showed greater anxiety-like behavior tested in the open field test as well as cognitive deficits evaluated by the novel object recognition test. The level of alpha spectrin II breakdown products, the markers of TBI, was significantly elevated in the deficient mouse cortices, indicating that the injury is greater in the deficient brains. This observation was further supported by the reduction of NeuN positive cells around the site of injury in the deficient mice, indicating exacerbated neuronal death after injury. These results suggest an important influence of the brain DHA status on TBI outcome.
doi:10.1371/journal.pone.0086472
PMCID: PMC3903526  PMID: 24475126
14.  Brain metabolism of nutritionally essential polyunsaturated fatty acids depends on both the diet and the liver 
Plasma α-linolenic acid (α-LNA, 18:3n-3) or linoleic acid (LA, 18:2n-6) does not contribute significantly to the brain content of docosahexaenoic acid (DHA, 22:6n-3) or arachidonic acid (AA, 20:4n-6), respectively, and neither DHA nor AA can be synthesized de novo in vertebrate tissue. Therefore, measured rates of incorporation of circulating DHA or AA into brain exactly represent the rates of consumption by brain. Positron emission tomography (PET) has been used to show, based on this information, that the adult human brain consumes AA and DHA at rates of 17.8 and 4.6 mg/day, respectively, and that AA consumption does not change significantly with age. In unanesthetized adult rats fed an n-3 PUFA “adequate” diet containing 4.6% α-LNA (of total fatty acids) as its only n-3 PUFA, the rate of liver synthesis of DHA is more than sufficient to replace maintain brain DHA, whereas the brain’s rate of synthesis is very low and unable to do so. Reducing dietary α-LNA in an DHA-free diet fed to rats leads to upregulation of liver coefficients of α-LNA conversion to DHA and of liver expression of elongases and desaturases that catalyze this conversion. Concurrently, the brain DHA loss slows due to downregulation of several of its DHA-metabolizing enzymes. Dietary α-LNA deficiency also promotes accumulation of brain docosapentaenoic acid (22:5n-6), and upregulates expression of AA-metabolizing enzymes, including cytosolic and secretory phospholipase A2 and cyclooxygenase-2. These changes, plus reduced levels of brain derived neurotrophic factor (BDNF) and cAMP response element-binding protein (CREB), likely render the brain more vulnerable to neuropathological insults.
doi:10.1016/j.plefa.2007.10.023
PMCID: PMC2725409  PMID: 18060754
docosahexaenoic acid; liver; brain; rat; n-3 PUFAs; imaging; metabolism; phospholipase A2; BDNF; diet; arachidonic acid
15.  Upregulated expression of brain enzymatic markers of arachidonic and docosahexaenoic acid metabolism in a rat model of the metabolic syndrome 
BMC Neuroscience  2012;13:131.
Background
In animal models, the metabolic syndrome elicits a cerebral response characterized by altered phospholipid and unesterified fatty acid concentrations and increases in pro-apoptotic inflammatory mediators that may cause synaptic loss and cognitive impairment. We hypothesized that these changes are associated with phospholipase (PLA2) enzymes that regulate arachidonic (AA, 20:4n-6) and docosahexaenoic (DHA, 22:6n-6) acid metabolism, major polyunsaturated fatty acids in brain. Male Wistar rats were fed a control or high-sucrose diet for 8 weeks. Brains were assayed for markers of AA metabolism (calcium-dependent cytosolic cPLA2 IVA and cyclooxygenases), DHA metabolism (calcium-independent iPLA2 VIA and lipoxygenases), brain-derived neurotrophic factor (BDNF), and synaptic integrity (drebrin and synaptophysin). Lipid concentrations were measured in brains subjected to high-energy microwave fixation.
Results
The high-sucrose compared with control diet induced insulin resistance, and increased phosphorylated-cPLA2 protein, cPLA2 and iPLA2 activity and 12-lipoxygenase mRNA, but decreased BDNF mRNA and protein, and drebrin mRNA. The concentration of several n-6 fatty acids in ethanolamine glycerophospholipids and lysophosphatidylcholine was increased, as was unesterified AA concentration. Eicosanoid concentrations (prostaglandin E2, thromboxane B2 and leukotriene B4) did not change.
Conclusion
These findings show upregulated brain AA and DHA metabolism and reduced BDNF and drebrin, but no changes in eicosanoids, in an animal model of the metabolic syndrome. These changes might contribute to altered synaptic plasticity and cognitive impairment in rats and humans with the metabolic syndrome.
doi:10.1186/1471-2202-13-131
PMCID: PMC3531256  PMID: 23110484
Arachidonic acid; Docosahexaenoic acid; BDNF; Brain; Polyunsaturated fatty acids (PUFA); Metabolic syndrome; Drebrin; Sucrose; Insulin resistance
16.  A cross-sectional study of docosahexaenoic acid status and cognitive outcomes in females of reproductive age with phenylketonuria 
Diet therapy for phenylketonuria (PKU) requires restricted phenylalanine (Phe) intake, with the majority of protein and other nutrients coming from synthetic medical food. The fatty acid docosahexaenoic acid (DHA) is important in brain development and function; however, there are reports of low blood DHA concentrations in people treated for PKU. Although the implications of this low blood DHA are unclear, subtle cognitive deficits have been reported in those treated early and continuously for PKU. For this study, we investigated the relationship between DHA status and cognitive performance in 41 females 12 years and older with PKU. Participants were attending the baseline visit of a research-based camp or a supplementation trial. We assessed the domains of verbal ability, processing speed, and executive function using standardized tests, and the proportions of DHA in plasma and red blood cell (RBC) total lipids using gas chromatography/mass spectrometry. Percent plasma and RBC total lipid DHA were significantly lower in the participants compared with laboratory controls (P < .001), and participants consumed no appreciable DHA according to diet records. Plasma and RBC DHA both negatively correlated with plasma Phe (P < .02), and performance on the verbal ability task positively correlated with RBC DHA controlling for plasma Phe (R=.32, P=.03). The relationship between DHA and domains related to verbal ability, such as learning and memory, should be confirmed in a controlled trial. Domains of processing speed and executive function may require a larger sample size to clarify any association with DHA.
doi:10.1007/s10545-011-9277-9
PMCID: PMC4227302  PMID: 21305356
17.  The influence of long chain polyunsaturate supplementation on docosahexaenoic acid and arachidonic acid in baboon neonate central nervous system 
BMC Medicine  2005;3:11.
Background
Docosahexaenoic acid (DHA) and arachidonic acid (ARA) are major components of the cerebral cortex and visual system, where they play a critical role in neural development. We quantitatively mapped fatty acids in 26 regions of the four-week-old breastfed baboon CNS, and studied the influence of dietary DHA and ARA supplementation and prematurity on CNS DHA and ARA concentrations.
Methods
Baboons were randomized into a breastfed (B) and four formula-fed groups: term, no DHA/ARA (T-); term, DHA/ARA supplemented (T+); preterm, no DHA/ARA (P-); preterm and DHA/ARA supplemented (P+). At four weeks adjusted age, brains were dissected and total fatty acids analyzed by gas chromatography and mass spectrometry.
Results
DHA and ARA are rich in many more structures than previously reported. They are most concentrated in structures local to the brain stem and diencephalon, particularly the basal ganglia, limbic regions, thalamus and midbrain, and comparatively lower in white matter. Dietary supplementation increased DHA in all structures but had little influence on ARA concentrations. Supplementation restored DHA concentrations to levels of breastfed neonates in all regions except the cerebral cortex and cerebellum. Prematurity per se did not exert a strong influence on DHA or ARA concentrations.
Conclusion
1) DHA and ARA are found in high concentration throughout the primate CNS, particularly in gray matter such as basal ganglia; 2) DHA concentrations drop across most CNS structures in neonates consuming formulas with no DHA, but ARA levels are relatively immune to ARA in the diet; 3) supplementation of infant formula is effective at restoring DHA concentration in structures other than the cerebral cortex. These results will be useful as a guide to future investigations of CNS function in the absence of dietary DHA and ARA.
doi:10.1186/1741-7015-3-11
PMCID: PMC1184078  PMID: 15975147
18.  Docosahexaenoic Acid Supplementation and Cognitive Decline in Alzheimer Disease 
Jama  2010;304(17):1903-1911.
Context
Docosahexaenoic acid (DHA) is the most abundant long-chain polyunsaturated fatty acid in the brain. Epidemiological studies suggest that consumption of DHA is associated with a reduced incidence of Alzheimer disease. Animal studies demonstrate that oral intake of DHA reduces Alzheimer-like brain pathology.
Objective
To determine if supplementation with DHA slows cognitive and functional decline in individuals with Alzheimer disease.
Design, Setting, and Patients
A randomized, double-blind, placebo-controlled trial of DHA supplementation in individuals with mild to moderate Alzheimer disease (Mini-Mental State Examination scores, 14–26) was conducted between November 2007 and May 2009 at 51 US clinical research sites of the Alzheimer’s Disease Cooperative Study.
Intervention
Participants were randomly assigned to algal DHA at a dose of 2 g/d or to identical placebo (60% were assigned to DHA and 40% were assigned to placebo). Duration of treatment was 18 months.
Main Outcome Measures
Change in the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog) and change in the Clinical Dementia Rating (CDR) sum of boxes. Rate of brain atrophy was also determined by volumetric magnetic resonance imaging in a subsample of participants (n = 102).
Results
A total of 402 individuals were randomized and a total of 295 participants completed the trial while taking study medication (DHA: 171; placebo: 124). Supplementation with DHA had no beneficial effect on rate of change on ADAS-cog score, which increased by a mean of 7.98 points (95% confidence interval [CI], 6.51–9.45 points) for the DHA group during 18 months vs 8.27 points (95% CI, 6.72–9.82 points) for the placebo group (linear mixed-effects model: P = .41). The CDR sum of boxes score increased by 2.87 points (95% CI, 2.44–3.30 points) for the DHA group during 18 months compared with 2.93 points (95% CI, 2.44–3.42 points) for the placebo group (linear mixed-effects model: P = .68). In the subpopulation of participants (DHA: 53; placebo: 49), the rate of brain atrophy was not affected by treatment with DHA. Individuals in the DHA group had a mean decline in total brain volume of 24.7 cm3 (95% CI, 21.4–28.0 cm3) during 18 months and a 1.32% (95% CI, 1.14%–1.50%) volume decline per year compared with 24.0 cm3 (95% CI, 20–28 cm3) for the placebo group during 18 months and a 1.29% (95% CI, 1.07%–1.51%) volume decline per year (P = .79).
Conclusion
Supplementation with DHA compared with placebo did not slow the rate of cognitive and functional decline in patients with mild to moderate Alzheimer disease.
doi:10.1001/jama.2010.1510
PMCID: PMC3259852  PMID: 21045096
19.  Short term effects of different omega-3 fatty acid formulation on lipid metabolism in mice fed high or low fat diet 
Background
Bioactivities of Docosahexaenoic acid (DHA) and Eicosapentaenoic acid (EPA) depend on their chemical forms. The present study was to investigate short term effects of triglyceride (TG), ethyl ester (EE), free fatty acid (FFA) and phospholipid (PL) forms of omega-3 fatty acid (FA) on lipid metabolism in mice, fed high fat or low fat diet.
Method
Male Balb/c mice were fed with 0.7% different Omega-3 fatty acid formulation: DHA bound free fatty acid (DHA-FFA), DHA bound triglyceride (DHA-TG), DHA bound ethyl ester (DHA-EE) and DHA bound phospholipid (DHA-PL) for 1 week, with dietary fat levels at 5% and 22.5%. Serum and hepatic lipid concentrations were analyzed, as well as the fatty acid composition of liver and brain.
Result
At low fat level, serum total cholesterol (TC) level in mice fed diets with DHA-FFA, DHA-EE and DHA-PL were significantly lower than that in the control group (P < 0.05). Hepatic TG level decreased significantly in mice fed diets with DHA-TG (P < 0.05), DHA-EE (P < 0.05) and DHA-PL (P < 0.05), while TC level in liver was significantly lower in mice fed diets with TG and EE compared with the control group (P < 0.05). At high fat level, mice fed diets with DHA-EE and DHA-PL had significantly lower hepatic TC level compared with the control diet (P < 0.05). Hepatic PL concentration experienced a significant increase in mice fed the diet with PL at high fat level (P < 0.05). Furthermore, both at low and high fat levels, hepatic DHA level significantly increased and AA level significantly decreased in all forms of DHA groups (P < 0.05), compared to control groups at two different fat levels, respectively. Additionally, cerebral DHA level in mice fed diets with DHA-FFA, DHA-EE and DHA-PL significantly increased compared with the control at high fat level (P < 0.05), but no significant differences were observed among dietary treatments for mice fed diets with low fat level.
Conclusion
The present study suggested that not only total dietary fat content but also the molecular forms of omega-3 fatty acids contributed to lipid metabolism in mice. DHA-PL showed effective bioactivity in decreasing hepatic and serum TC, TG levels and increasing omega-3 concentration in liver and brain.
doi:10.1186/1476-511X-11-70
PMCID: PMC3393618  PMID: 22676394
Omega-3 fatty acid; DHA; EPA; Lipid metabolism; Triglycerides; Ethyl ester; Phospholipids
20.  Oral Supplementation with Docosahexaenoic Acid and Uridine-5’-Monophosphate Increases Dendritic Spine Density in Adult Gerbil Hippocampus 
Brain research  2007;1182:50-59.
Docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid, is an essential component of membrane phosphatides and has been implicated in cognitive functions. Low levels of circulating or brain DHA are associated with various neurocognitive disorders including Alzheimer’s disease (AD), while laboratory animals, including animal models of AD, can exhibit improved cognitive ability with a diet enriched in DHA. Various cellular mechanisms have been proposed for DHA’s behavioral effects, including increases in cellular membrane fluidity, promotion of neurite extension, and inhibition of apoptosis. However, there is little direct evidence that DHA affects synaptic structure in living animals. Here we show that oral supplementation with DHA substantially increases the number of dendritic spines in adult gerbil hippocampus, particularly when animals are co-supplemented with a uridine source, uridine-5’-monophosphate (UMP), which increases brain levels of the rate-limiting phosphatide precursor CTP. The increase in dendritic spines (> 30%) is accompanied by parallel increases in membrane phosphatides, and in pre- and post-synaptic proteins within the hippocampus. Hence oral DHA may promote neuronal membrane synthesis to increase the number of synapses, particularly when co-administered with UMP. Our findings provide a possible explanation for the effects of DHA on behavior and also suggest a strategy to treat cognitive disorders resulting from synapse loss.
doi:10.1016/j.brainres.2007.08.089
PMCID: PMC2140951  PMID: 17950710
docosahexaenoic acid; uridine; membrane synthesis; spine formation; synaptogenesis; phosphatides
21.  DIETARY N-6 POLYUNSATURATED FATTY ACID DEPRIVATION INCREASES DOCOSAHEXAENOIC ACID METABOLISM IN RAT BRAIN 
Journal of Neurochemistry  2012;120(6):985-997.
Dietary n-6 polyunsaturated fatty acid (PUFA) deprivation in rodents reduces brain arachidonic acid (20:4n-6) concentration and 20:4n-6-preferring cytosolic phospholipase A2 (cPLA2-IVA) and cyclooxygenase (COX)-2 expression, while increasing brain docosahexaenoic acid (DHA, 22:6n-3) concentration and DHA-selective Ca2+-independent iPLA2-VIA expression. We hypothesized that these changes are accompanied by upregulated brain DHA metabolic rates. Using a fatty acid model, brain DHA concentrations and kinetics were measured in unanesthetized male rats fed, for 15 weeks post-weaning, an n-6 PUFA “adequate” (31.4 wt% linoleic acid) or “deficient” (2.7 wt% linoleic acid) diet, each lacking 20:4n-6 and DHA. [1-14C]DHA was infused intravenously, arterial blood was sampled, and the brain was microwaved at 5 min and analyzed. Rats fed the n-6 PUFA deficient compared with adequate diet had significantly reduced n-6 PUFA concentrations in brain phospholipids but increased eicosapentaenoic acid (EPA, 20:5n-3), docosapentaenoic acidn-3 (DPAn-3, 22:5n-3) and DHA (by 9.4%) concentrations, particularly in ethanolamine glycerophospholipid. Incorporation rates of unesterified DHA from plasma, which represent DHA metabolic loss from brain, were increased 45% in brain phospholipids, as was DHA turnover. Increased DHA metabolism following dietary n-6 PUFA deprivation may increase brain concentrations of antiinflammatory DHA metabolites, which with a reduced brain n-6 PUFA content, likely promote neuroprotection. (199 words)
doi:10.1111/j.1471-4159.2011.07597.x
PMCID: PMC3296886  PMID: 22117540
linoleic acid; arachidonic PUFA; diet; turnover; metabolism; docosahexaenoic; kinetics; brain; alpha-linolenic; rat
22.  Dietary ω-3 Fatty Acids Alter Cardiac Mitochondrial Phospholipid Composition and Delay Ca2+-Induced Permeability Transition 
Consumption of ω-3 fatty acids from fish oil, specifically eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), decreases risk for heart failure and attenuates pathologic cardiac remodeling in response to pressure overload. Dietary supplementation with EPA+DHA may also impact cardiac mitochondrial function and energetics through alteration of membrane phospholipids. We assessed the role of EPA+DHA supplementation on left ventricular (LV) function, cardiac mitochondrial membrane phospholipid composition, respiration, and sensitivity to mitochondrial permeability transition pore (MPTP) opening in normal and infarcted myocardium. Rats were subjected to sham surgery or myocardial infarction by coronary artery ligation (n=10–14), and fed a standard diet, or supplemented with EPA+DHA (2.3% of energy intake) for 12 weeks. EPA+DHA altered fatty acid composition of total mitochondrial phospholipids and cardiolipin by reducing arachidonic acid content and increasing DHA incorporation. EPA+DHA significantly increased calcium uptake capacity in both subsarcolemmal and intrafibrillar mitochondria from sham rats. This treatment effect persisted with the addition of cyclosporin A, and was not accompanied by changes in mitochondrial respiration or coupling, or cyclophilin D protein expression. Myocardial infarction resulted in heart failure as evidenced by LV dilation and contractile dysfunction. Infarcted LV myocardium had decreased mitochondrial protein yield and activity of mitochondrial marker enzymes, however respiratory function of isolated mitochondria was normal. EPA+DHA had no effect on LV function, mitochondrial respiration, or MPTP opening in rats with heart failure. In conclusion, dietary supplementation with EPA+DHA altered mitochondrial membrane phospholipid fatty acid composition in normal and infarcted hearts, but delayed MPTP opening only in normal hearts.
doi:10.1016/j.yjmcc.2009.08.014
PMCID: PMC2783943  PMID: 19703463
eicosapentaenoic acid; docosahexaenoic acid; myocardial infarction; mitochondrial permeability transition pore
23.  Effects of chronic clozapine administration on markers of arachidonic acid cascade and synaptic integrity in rat brain 
Psychopharmacology  2012;222(4):663-674.
The mode of action of clozapine, an atypical antipsychotic approved for treating schizophrenia and bipolar disorder (BD) mania, remains unclear. We tested for overlap with the actions of the mood stabilizers, lithium, carbamazepine and valproate, which downregulate arachidonic acid (AA) cascade markers in rat brain and upregulate BDNF. AA cascade markers are upregulated in the postmortem BD brain in association with neuroinflammation and synaptic loss, while BDNF is decreased. Rats were injected intraperitoneally with a therapeutically relevant dose of clozapine (10 mg/kg/day) or with saline for 30 days, and AA cascade and synaptic markers and BDNF were measured in the brain. Compared with saline-injected rats, chronic clozapine increased brain activity, mRNA and protein levels of docosahexaenoic acid (DHA)-selective calcium-independent phospholipase A2 type VIA (iPLA2), mRNA and protein levels of BDNF and of the postsynaptic marker, drebrin, while decreasing cyclooxygenase (COX) activity and concentration of prostaglandin E2 (PGE2), a proinflammatory AA metabolite. Activity and expression of AA-selective calcium-dependent cytosolic cPLA2 type IVA and of secretory sPLA2 Type II were unchanged. These results show overlap with effects of mood stabilizers with regard to downregulation of COX activity and PGE2 and to increased BDNF, and suggest a common action against the reported neuropathology of BD. Additionally, the increased iPLA2 expression following clozapine suggests increased production of anti-inflammatory DHA metabolites, consistent with reports that dietary n-3 polyunsaturated fatty acid supplementation is beneficial in BD.
doi:10.1007/s00213-012-2671-7
PMCID: PMC3478065  PMID: 22414961
atypical; antipsychotic; arachidonic acid; BDNF; bipolar disorder; drebrin; cyclooxygenase; rat; clozapine; brain; docosahexaenoic; schizophrenia; mood stabilizer; iPLA2; PGE2
24.  Docosahexaenoic acid promotes hippocampal neuronal development and synaptic function 
Journal of neurochemistry  2009;111(2):510-521.
Docosahexaenoic acid (DHA, 22:6n-3), the major polyunsaturated fatty acid accumulated in the brain during development, has been implicated in learning and memory, but underlying cellular mechanisms are not clearly understood. Here, we demonstrate that DHA significantly affects hippocampal neuronal development and synaptic function in developing hippocampi. In embryonic neuronal cultures, DHA supplementation uniquely promoted neurite growth, synapsin puncta formation and synaptic protein expression, particularly synapsins and glutamate receptors. In DHA-supplemented neurons, spontaneous synaptic activity was significantly increased, mostly because of enhanced glutamatergic synaptic activity. Conversely, hippocampal neurons from DHA-depleted fetuses showed inhibited neurite growth and synaptogenesis. Furthermore, n-3 fatty acid deprivation during development resulted in marked decreases of synapsins and glutamate receptor subunits in the hippocampi of 18-day-old pups with concomitant impairment of long-term potentiation, a cellular mechanism underlying learning and memory. While levels of synapsins and NMDA receptor subunit NR2A were decreased in most hippocampal regions, NR2A expression was particularly reduced in CA3, suggesting possible role of DHA in CA3-NMDA receptor-dependent learning and memory processes. The DHA-induced neurite growth, synaptogenesis, synapsin, and glutamate receptor expression, and glutamatergic synaptic function may represent important cellular aspects supporting the hippocampus-related cognitive function improved by DHA.
doi:10.1111/j.1471-4159.2009.06335.x
PMCID: PMC2773444  PMID: 19682204
docosahexaenoic acid; hippocampal development; long-term potentiation; neurite growth; synaptic function; synaptogenesis
25.  Docosahexaenoic Acid (DHA) Incorporation into the Brain from Plasma, as an In Vivo Biomarker of Brain DHA Metabolism and Neurotransmission 
Docosahexaenoic acid (DHA) is critical for maintaining normal brain structure and function, and is considered neuroprotective. Its brain concentration depends on dietary DHA content and hepatic conversion from its dietary derived n-3 precursor, α-linolenic acid (α-LNA). We have developed an in vivo method in rats using quantitative autoradiography and intravenously injected radiolabeled DHA to image net incorporation into the brain of unesterified plasma DHA, and showed with this method that the incorporation rate of DHA equals the rate of brain metabolic DHA consumption. The method has been extended for use in humans with positron emission tomography (PET). Furthermore, imaging in unanesthetized rats using DHA incorporation as a biomarker in response to acute N-methyl-D-aspartate administration confirms that regional DHA signaling is independent of extracellular calcium, and likely mediated by a calcium-independent phospholipase A2 (iPLA2). Studies in mice in which iPLA2-VIA (β) was knocked out confirmed that this enzyme is critical for baseline and muscarinic cholinergic signaling involving DHA. Thus, quantitative imaging of DHA incorporation from plasma into brain can be used as an in vivo biomarker of brain DHA metabolism and neurotransmission.
doi:10.1016/j.prostaglandins.2011.06.003
PMCID: PMC3202024  PMID: 21704722
docosahexaenoic acid; PLA2; biomarker; imaging; calcium; PET

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