The salutary effects of DHA dietary supplementation on cognition, neuroplasticity, and membrane homeostasis after brain trauma

The pathology of traumatic brain injury (TBI) is characterized by the decreased capacity of neurons to metabolize energy and sustain synaptic function, likely resulting in cognitive and emotional disorders. Based on the broad nature of the pathology, we have assessed the potential of the omega-3 fatty acid docosahexaenoic acid (DHA) to counteract the effects of concussive injury on important aspects of neuronal function and cognition. Fluid percussion injury (FPI) or sham injury was performed, and rats were then maintained on a diet high in DHA (1.2% DHA) for 12 days. We found that DHA supplementation, which elevates brain DHA content, normalized levels of brain-derived neurotrophic factor (BDNF), synapsin I (Syn-1), cAMP-responsive element-binding protein (CREB), and calcium/calmodulin-dependent kinase II (CaMKII), and improved learning ability in FPI rats. It is known that BDNF facilitates synaptic transmission and learning ability by modulating Syn-I, CREB, and CaMKII signaling. The DHA diet also counteracted the FPI-reduced manganese superoxide dismutase (SOD) and Sir2 (a NAD+-dependent deacetylase). Given the involvement of SOD and Sir2 in promoting metabolic homeostasis, DHA may help the injured brain by providing resistance to oxidative stress. Furthermore, DHA normalized levels of calcium-independent phospholipase A2 (iPLA2) and syntaxin-3, which may help preserve membrane homeostasis and function after FPI. The overall results emphasize the potential of dietary DHA to counteract broad and fundamental aspects of TBI pathology that may translate into preserved cognitive capacity.     

Time window for voluntary exercise-induced increases in hippocampal neuroplasticity molecules after traumatic brain injury is severity dependent

We recently found that an exercise-induced increase in hippocampal brain-derived neurotrophic factor (BDNF) is dependent when exercise is initiated after traumatic brain injury (TBI). When voluntary exercise was delayed by 2 weeks after a mild fluid-percussion injury (FPI) in rats, an increase in BDNF and an improvement in behavioral outcome were observed. This suggests that following FPI there is a therapeutic window for the implementation of voluntary exercise. To determine if more severely injured animals require more time after TBI before voluntary exercise can increase neuroplasticity, adult male rats with a moderate lateral FPI or sham injury were housed with or without access to a running wheel from post-injury-day (PID) 0-6, 14-20 or 30-36. Rats with a mild injury only had access to the running wheel from PID 0-6 or 14-20. Rats were sacrificed at PID 7, 21, or 37. BDNF, synapsin I, and cyclic AMP response element binding protein (CREB) were analyzed within the ipsilateral hippocampus. Whereas BDNF levels significantly increased with exercise in the mild FPI rats that were exercised from PID 14 to 20, the moderate FPI rats only showed significant increases in BDNF when exercised from PID 30 to 36. In addition, moderate FPI rats that were allowed to exercise from PID 30 to 36 also exhibited significant increases in synapsin I and CREB. These results indicate that the time window for exercise-induced increases in BDNF, synapsin I, and CREB is dependent on injury severity.     

Alterations in BDNF and synapsin I within the occipital cortex and hippocampus after mild traumatic brain injury in the developing rat: reflections of injury-induced neuroplasticity

Brain-derived neurotrophic factor (BDNF), its signal transduction receptor trkB, and its downstream effector, synapsin I, were measured in the hippocampus and occipital cortex of young animals after fluid-percussion brain injury (FPI). Isofluorane anaesthetized postnatal day 19 rats were subjected to a mild lateral FPI or sham injury. Rats were sacrificed at 24 h, 7 days, or 14 days after injury in order to determine mRNA expression. Additional animals were sacrificed at 7 and 14 days after injury for protein analysis. Only FPI animals exhibited hemispheric differences in BDNF levels. These animals exhibited a contralateral increase, ranging from 40% to 75%, in BDNF mRNA within both the hippocampus and occipital cortex at 24 h and 7 days after injury. The increase in message within the occipital cortex was accompanied by an increase in BDNF protein at 7 and 14 days after injury. However, hippocampal BDNF protein increased in both hemispheres at postinjury day 7 and was restricted to the ipsilateral hippocampus at postinjury day 14. At postinjury day 7, both trkB and synapsin I mRNA expression increased ipsilaterally and decreased contralaterally in the occipital cortex. In addition, synapsin I phosphorylation was increased by 20% in the ipsilateral cortex and by 30% in the hippocampus on this day. These results indicate that the developing brain responds to a mild injury by modifying factors related to synaptic plasticity and suggest that regions remote from the site of injury express neurotrophic signals potentially needed for compensatory responses.     

Omega-3 fatty acids supplementation restores mechanisms that maintain brain homeostasis in traumatic brain injury

Traumatic brain injury (TBI) produces a state of vulnerability that reduces the brain capacity to cope with secondary insults. The silent information regulator 2 (Sir2) has been implicated with maintaining genomic stability and cellular homeostasis under challenging situation. Here we explore the possibility that the action of Sir2alpha (mammalian Sir2) in the brain can extend to serve neuronal plasticity. We provide novel evidence showing that mild TBI reduces the expression of Sir2alpha in the hippocampus, in proportion to increased levels of protein oxidation. In addition, we show that dietary supplementation of omega-3 fatty acids that ameliorates protein oxidation was effective to reverse the reduction of Sir2alpha level in injured rats. Given that oxidative stress is a subproduct of dysfunctional energy homeostasis, we measured AMP-activated protein kinase (AMPK) and phosphorylated-AMPK (p-AMPK) to have an indication of the energy status of cells. Hippocampal levels of total and phosphorylated AMPK were reduced after TBI and levels were normalized by omega-3 fatty acts supplements. Further, we found that TBI reduced ubiquitous mitochondrial creatine kinase (uMtCK), an enzyme implicated in the energetic regulation of Ca2+-pumps and in the maintenance of Ca2+-homeostasis. Omega-3 fatty acids supplements normalized the levels of uMtCK after lesion. Furthermore, we found that the correlation between Sir2alpha and AMPK or p-AMPK was disrupted by TBI, but restored by omega-3 fatty acids supplements. Our results suggest that TBI may compromise neuronal protective mechanisms by involving the action of Sir2alpha. In addition, results show the capacity of omega-3 fatty acids to counteract some of the effects of TBI by normalizing levels of molecular systems associated with energy homeostasis.     

Dietary omega-3 fatty acids may be associated with increased neuropathic pain in nerve-injured rats

Certain dietary proteins and oils are capable of decreasing chronic neuropathic pain levels in rats after partial sciatic nerve ligation injury. We tested, for the first time, the role of dietary polyunsaturated fatty acids in suppressing pain in partial sciatic nerve ligation-injured rats. Six groups of male Wistar rats were fed an identical casein-based, fat-free diet for 1 wk preceding partial sciatic nerve ligation injury and for 1 wk thereafter. In addition, rats received, via gavage, 1 mL/day of pure canola, corn, hemp, soy, or sunflower oil, differing significantly in their omega-3 and omega-6 polyunsaturated fatty acid content, or 1 mL of plain water. Responses to tactile and noxious heat stimuli were recorded before and after surgery and a difference score was calculated for each group by subtracting the preoperative from the post-partial sciatic nerve ligation values. Heat hyperalgesia, but not tactile allodynia, was significantly different among the dietary groups (P = 0.005). Heat hyperalgesia of rats fed hemp oil, developing the most robust response, was significantly larger compared with rats fed corn oil, developing the least pain model (difference score: 24.3 +/- 4.1 s versus 6.1 +/- 3.1 s, respectively; P < 0.001). These oils contain similar levels of omega-6 polyunsaturated fatty acids (hemp, 60%; corn, 58%) but their omega-3 levels are 28-fold different (20% versus 0.7%, respectively). A significant correlation was found among dietary levels of omega-3, but not omega-6 or the omega-3/omega-6 ratio, of the six dietary groups and heat hyperalgesia (P = 0.006). We conclude that dietary oil might predict levels of neuropathic pain in rats and that this effect may be associated with dietary omega-3 levels. IMPLICATIONS: We found that certain commonly used oils can have a significant analgesic effect in rats with persistent pain after partial nerve injury. This effect may be associated with the amounts of omega-3 fatty acids consumed by rats.     

Fatty acids and osteoarthritis: different types,different effects

While the association between obesity and osteoarthritis used to be solely regarded as a result of increased mechanical loading, systemic factors also likely play a role in the pathophysiology of osteoarthritis. Nutrient excess leading to obesity may result in lipotoxicity, which might be involved in the development of osteoarthritis. The different fatty acid types have distinct effects on inflammation. This review focusses on the currently available studies, summarizing the effects of the different fatty acid types on osteoarthritis and involved joint tissues. In animal studies omega-3 polyunsaturated fatty acids reduced the expression of inflammatory markers, cartilage degradation and oxidative stress in chondrocytes. In contrast, these markers were increased upon omega-6 polyunsaturated fatty acid and saturated fatty acid stimulation. Additionally, a decrease in pain and dysfunction was observed upon omega-3 supplementation in cats and dogs. In line, most human in vitro studies show pro-apoptotic and pro-inflammatory actions of saturated fatty acids. While all polyunsaturated fatty acids reduced markers of oxidative stress, omega-3 polyunsaturated fatty acids additionally decreased prostaglandin production. Human intervention studies with omega-3 polyunsaturated fatty acid supplementation may indicate a beneficial effect on pain and function and might be associated with less structural damage. In contrast, an adverse effect of saturated fatty acids on osteoarthritis has been observed. Monounsaturated fatty acids have been infrequently studied and findings are inconclusive. Existing studies indicate a promising effect of especially omega-3 polyunsaturated fatty acids on osteoarthritis signs and symptoms. However, more human intervention studies are warranted to draw robust conclusions.     

Influence of dietary fat composition on development of insulin resistance in rats. Relationship to muscle triglyceride and omega-3 fatty acids in muscle phospholipid

High levels of some but not all dietary fats lead to insulin resistance in rats. The aim of this study was to investigate the important determinants underlying this observation. Insulin action was assessed with the euglycemic clamp. Diets high in saturated, monounsaturated (omega-9), or polyunsaturated (omega-6) fatty acids led to severe insulin resistance; glucose infusion rates [GIR] to maintain euglycemia at approximately 1000 pM insulin were 6.2 +/- 0.9, 8.9 +/- 0.9, and 9.7 +/- 0.4 mg.kg-1. min-1, respectively, versus 16.1 +/- 1.0 mg.kg-1.min-1 in chow-fed controls. Substituting 11% of fatty acids in the polyunsaturated fat diet with long-chain omega-3 fatty acids from fish oils normalized insulin action (GIR 15.0 +/- 1.3 mg.kg-1.min-1). Similar replacement with short-chain omega-3 (alpha-linolenic acid, 18:3 omega 3) was ineffective in the polyunsaturated diet (GIR 9.9 +/- 0.5 mg.kg-1.min-1) but completely prevented the insulin resistance induced by a saturated-fat diet (GIR 16.0 +/- 1.5 mg.kg-1.min-1) and did so in both the liver and peripheral tissues. Insulin sensitivity in skeletal muscle was inversely correlated with mean muscle triglyceride accumulation (r = 0.95 and 0.86 for soleus and red quadriceps, respectively; both P less than 0.01). Furthermore, percentage of long-chain omega-3 fatty acid in phospholipid measured in red quadriceps correlated highly with insulin action in that muscle (r = 0.97). We conclude that 1) the particular fatty acids and the lipid environment in which they are presented in high-fat diets determine insulin sensitivity in rats; 2) impaired insulin action in skeletal muscle relates to triglyceride accumulation, suggesting intracellular glucose-fatty acid cycle involvement; and 3) long-chain omega-3 fatty acids in phospholipid of skeletal muscle may be important for efficient insulin action.     

Acute omega-3 fatty acid enrichment selectively reverses high-saturated fat feeding-induced insulin hypersecretion but does not improve peripheral insulin resistance

In rats fed a high-saturated fat diet, replacement of a small percentage of total fatty acids with long-chain omega-3 fatty acids from fish oil for the duration of high-fat feeding prevents the development of insulin resistance. We investigated the effect of acute (24-h) modulation of dietary fat composition on glucose-stimulated insulin secretion (GSIS) in rats made insulin resistant by high-saturated fat feeding for 4 weeks. Insulin secretion after an intravenous glucose challenge was greatly increased by high-saturated fat feeding. Glucose tolerance was minimally perturbed, demonstrating insulin hypersecretion compensated for insulin resistance. The effect of high-saturated fat feeding to enhance GSIS was retained in perifused islets, such that glucose stimulus-secretion coupling was potentiated. Acute replacement of 7% of dietary fatty acids with long-chain omega-3 fatty acids reversed insulin hypersecretion in vivo, and the effect of long-term high-saturated fat feeding to enhance insulin secretion by perifused islets was also completely reversed. Although a hyperbolic relationship existed between insulin secretion and action in the high-saturated fat and control groups, lowered insulin secretion in the acute fish oil-supplemented group was not accompanied by improved insulin action, and glucose tolerance was adversely affected. Our studies are important because they demonstrate that hyperinsulinemia can be rapidly reversed via the dietary provision of small amounts of long-chain omega-3 fatty acids. However, this "insulin sparing" action of acute dietary long-chain omega-3 fatty acids occurs in the absence of an acute improvement in insulin sensitivity and therefore at the expense of maintenance of glucose tolerance.     

Immunonutrition nach Trauma

Immunonutrition may be superior to standard clinical nutrition in specific clinical situations. After severe trauma, an enteral immuno-enhancing diet, enriched with arginine, omega-3 fatty acids, and nucleotides, decreases infectious complications. During acute respiratory distress syndrome, a continuous enteral diet with high-dose omega-3 fatty acids, gamma-linolenic acid, and antioxidants improved clinical outcome. Glutamine should be administered enterally or parenterally whenever total parenteral nutrition is indicated.     

Differential effects of voluntary and forced exercise on stress responses after traumatic brain injury

Voluntary exercise increases levels of brain-derived neurotrophic factor (BDNF) after traumatic brain injury (TBI) when it occurs during a delayed time window. In contrast, acute post-TBI exercise does not increase BDNF. It is well known that increases in glucocorticoids suppress levels of BDNF. Moreover, recent work from our laboratory showed that there is a heightened stress response after fluid percussion injury (FPI). In order to determine if a heightened stress response is also observed with acute exercise, at post-injury days 0-4 and 7-11, corticosterone (CORT) and adrenocorticotropic hormone (ACTH) release were measured in rats running voluntarily or exposed to two daily 20-min periods of forced running wheel exercise. Forced, but not voluntary exercise, continuously elevated CORT. ACTH levels were initially elevated with forced exercise, but decreased by post-injury day 7 in the control, but not the FPI animals. As previously reported, voluntary exercise did not increase BDNF in the FPI group as it did in the control animals. Forced exercise did not increase levels of BDNF in any group. It did, however, decrease hippocampal glucocorticoid receptors in the control group. The results suggest that exercise regimens with strong stress responses may not be beneficial during the early post-injury period.     

Centella asiatica alleviates diabetes-induced changes in fatty acid profile and oxidative damage in rat testis

The in vivo effects of Centella asiatica L. Urban (Family: Apiaceae; CA) on diabetes-induced testicular fatty acid misdistribution and oxidative injury were investigated. Diabetic rats were treated with vehicle, CA or metformin daily for 14 days by oral gavage. Fatty acid (FA) content in testis was analysed using gas chromatography-flame ionisation detection while redox indices were measured as peroxide value (PV), malondialdehyde (MDA), oxygen radical antioxidant capacity (ORAC), reduced glutathione (GSH), glutathione S-transferase (GST) and glutathione peroxidase (GPx) activities. Diabetes increased omega-6 (61%), and decreased omega-3 (23%) and monounsaturated fatty acids (MUFA; 18%) compared to non-diabetic controls. Oxidative injury in diabetic rats was confirmed by increases in PV (112%) and MDA (77%) in addition to decreases in GSH (41%) and activities of GST (19%) & GPx (24%) compared to non-diabetic controls. CA treatment led to 17% reduction in omega-6 and 33% rise in MUFA compared to diabetic controls. Additionally, CA ameliorated the oxidative injury and improved antioxidant capacity by increasing GSH (49%), GST (16%) and GPx (23%) when compared to diabetic controls. Data suggest CA potential in alleviating the alterations caused by diabetes in testes through effects on omega-6 and MUFA; and via increased GSH level and dependent enzyme activities.     

Effect of fatty acids on bone marrow lesions and knee cartilage in healthy, middle-aged subjects without clinical knee osteoarthritis

OBJECTIVE: There is evidence that omega-3 polyunsaturated fatty acids alleviate the progression of osteoarthritis (OA). However, little work has been done to investigate the effect of fatty acids on bone marrow lesions and knee cartilage in healthy subjects. We examined this in a cohort of healthy middle-aged subjects without clinical knee OA. METHODS: Two hundred and ninety-three healthy adults without knee pain or injury were recruited from an existing community-based cohort. Intakes of fatty acids and food sources of these were estimated from a food frequency questionnaire at baseline. Tibial cartilage volume, tibial plateau bone area, tibiofemoral cartilage defects and bone marrow lesions were assessed approximately 10 years later using magnetic resonance imaging. RESULTS: In multivariate analyses, higher intakes of monounsaturated fatty acids (OR=2.14, 95% CI 1.04-4.39, P=0.04), total (OR=1.77, 95% CI 1.13-2.77, P=0.01) and n-6 polyunsaturated fatty acids (OR=1.69, 95% CI 1.10-2.61, P=0.02) were associated with an increased risk of bone marrow lesions. Intake of fatty acids was not significantly associated with cartilage volume or cartilage defects. CONCLUSION: These findings support the dietary recommendation towards a shift to foods rich in n-3 polyunsaturated fatty acids in order to maintain an optimal balance between dietary n-3 and n-6 polyunsaturated fatty acids, which is also important in the prevention of atherosclerosis. Although our findings will need to be confirmed in longitudinal studies, they suggest the potential of fatty acids to adversely effect the knee joint.     

Can dietary changes reduce blood pressure in the long term?

PURPOSE OF REVIEW: Recent dietary guidelines for the prevention and treatment of hypertension emphasized a healthy eating pattern called the Dietary Approaches to Stop Hypertension (DASH) diet, in addition to avoidance of obesity, high salt intake, and excessive alcohol intake. Our new challenge is to examine the long-term efficacy and effectiveness of dietary change, including the DASH diet, on blood pressure in the general population, or in a high-risk population. We reviewed recent short-term and long-term studies, both observational and interventional, which investigated whether dietary change can reduce blood pressure. RECENT FINDINGS: The efficacy of several nutrients has been investigated in short-term trials (e.g. polyunsaturated fatty acids, including omega-3 fatty acids, and trans fatty acids), but no substantial effect of these nutrients on blood pressure has been proved, except for dietary fiber. The PREMIER trial showed the effectiveness of implementing the DASH diet for 6 months in addition to the established recommendations on lifestyle modification, but other long-term trials of dietary modification did not show sufficient blood pressure reduction. However, long-term observational studies have shown that a higher intake of fruit and vegetables and a lower intake of red meat (except fish) can prevent higher blood pressure increase with age. SUMMARY: More effective programs of dietary modification are needed to achieve greater reduction of blood pressure. Long-term studies of population-wide dietary interventions to decrease the blood pressure level of a whole population are also needed.     

Increased Myocardial Uptake of Dietary Fatty Acids Linked to Cardiac Dysfunction in Glucose-Intolerant Humans

Impaired cardiac systolic and diastolic function has been observed in preclinical models and in subjects with type 2 diabetes. Using a recently validated positron emission tomography (PET) imaging method with 14(R,S)-[¹⁸F]-fluoro-6-thia-heptadecanoic acid to quantify organ-specific dietary fatty acid partitioning, we demonstrate in this study that overweight and obese subjects with impaired glucose tolerance (IGT⁺) display significant increase in fractional myocardial dietary fatty acid uptake over the first 6 h postprandial compared with control individuals (IGT⁻). Measured by [¹¹C]acetate with PET, IGT⁺ subjects have a significant increase in myocardial oxidative index. IGT⁺ subjects have significantly reduced left ventricular stroke volume and ejection fraction (LVEF) and tend to display impaired diastolic function, as assessed by PET ventriculography. We demonstrate an inverse relationship between increased myocardial dietary fatty acid partitioning and LVEF. Fractional dietary fatty acid uptake is reduced in subcutaneous abdominal and visceral adipose tissues in IGT⁺ directly associated with central obesity. Fractional dietary fatty acid uptake in skeletal muscles or liver is, however, similar in IGT⁺ versus IGT⁻. The current study demonstrates, for the first time, that excessive myocardial partitioning of dietary fatty acids occurs in prediabetic individuals and is associated with early impairment of left ventricular function and increased myocardial oxidative metabolism.Elevation of circulating fatty acids in humans has been shown to induce insulin resistance and impair β-cell function (1). Prediabetic and diabetic subjects display inefficient adipose tissue storage of dietary fatty acids during the postprandial state (2). This may lead to increased postprandial triglyceride (TG) and/or nonesterified fatty acid (NEFA) circulating levels produced from dietary fatty acids with increased flux of dietary fatty acids to lean tissues (3,4) that is directly related to the presence of abdominal obesity (5). Despite this elevated NEFA flux in type 2 diabetes (T2D), muscle NEFA uptake is not necessarily elevated because of reduced postprandial muscle blood flow (6). Regulation of tissue dietary fatty acid uptake is complex and involves lipoprotein lipase (LpL)-mediated TG lipolysis, and cellular membrane transporter–mediated NEFA uptake that may be differentially activated in the various tissues (7). Thus, the contribution of dietary fatty acids to organ-specific postprandial fatty acid exposure cannot be assessed simply by measurement of circulating NEFA and TG fluxes.Increased cardiac LpL-mediated uptake of fatty acids in mice leads to lipotoxicity and impaired cardiac function (8). We have recently developed a noninvasive method using the oral administration of 14(R,S)-[¹⁸F]-fluoro-6-thia-heptadecanoic acid (¹⁸FTHA), a long-chain fatty acid analog, measured with positron emission tomography (PET) to assess organ-specific partitioning of dietary fatty acids in rodents and humans (9). We showed in diabetic rats an increase in myocardial dietary fatty acid uptake associated with maintained cardiac oxidative metabolism in the face of reduced contractile function (10).We aimed to determine whether organ-specific dietary fatty acid partitioning, cardiac function, and myocardial energy metabolism are abnormal in obese, impaired glucose-tolerant (IGT⁺) individuals. We hypothesized that IGT⁺ subjects would display an increase in myocardial dietary fatty acid partitioning associated with reduced left ventricular function and reduced adipose tissue storage of dietary fatty acids.     

柴胡皂苷A通过cAMP/CREB信号通路对脑损伤大鼠认知功能的影响

目的观察柴胡皂苷A(SSA)对创伤性脑损伤大鼠认知功能及海马组织内cAMP/CREB信号通路及其调控的脑源性神经生长因子(BDNF)表达的影响。方法成年雄性SD大鼠60只,体重360~400g,随机分为假手术组(S组)、创伤组(T组)和创伤加SSA组(A组)。创伤后每天腹腔注射5mg/kg SSA(A组)或等容量生理盐水(S组、T组),连续5d。于创伤后1、3、7、14d,采用Morris水迷宫检测大鼠潜伏期和游泳距离;末次行为学测试后处死大鼠,采用ELISA法测定海马组织中BDNF和cAMP浓度,采用Western blot检测环磷酸腺苷反应元件结合蛋白(CREB)和磷酸化的环磷酸腺苷反应元件结合蛋白(pCREB)浓度。结果创伤后1、3、7、14dT组和创伤后1、3dA组大鼠潜伏期和游泳距离明显长于S组(P0.05);创伤后7、14dA组大鼠潜伏期和游泳距离明显短于T组(P0.05);T组BDNF、cAMP、CREB及pCREB浓度明显低于S组(P0.05);A组BDNF、cAMP、CREB及pCREB浓度明显高于T组(P0.05)。结论 SSA能够明显改善创伤性脑损伤大鼠认知功能,其机制可能与其激活cAMP/CREB信号通路及上调BDNF的表达有关。     

Effects of omega-3 fish oils on plasma lipids, lipoprotein composition, and postheparin lipoprotein lipase in women with IDDM

Because the apparent reduction in cardiovascular risk noted in nondiabetic populations that ingest diets rich in marine lipids containing omega-3 fatty acids is believed to result in part from their capacity to modify the composition and physicochemical behavior of lipoproteins, we sought to determine whether dietary supplementation with marine lipids might favorably affect lipoprotein composition in insulin-dependent diabetes mellitus (IDDM). Eight normolipidemic IDDM women (mean +/- SD age 29.8 +/- 4.7 yr) were studied before and 3 mo after receiving a marine-lipid concentrate (Super-EPA) containing 6 g omega-3 fatty acids and a total of 12 mg of cholesterol daily. Weight, insulin requirements, and glycosylated hemoglobin remained stable. After treatment, mean +/- SD plasma triglyceride (TG) levels fell (before, 81.7 +/- 22 mg/dl; after, 69.19 +/- 17; P less than 0.025). High-density lipoprotein2 (HDL2) cholesterol (before, 10.98 +/- 5.45 mg/dl; after, 18.43 +/- 7.93; P less than 0.01), its major apolipoprotein A-I (apoAI), and the major phospholipids (sphingomyelin and lecithin) all rose significantly. ApoB and plasma and low-density lipoprotein cholesterol levels and HDL3 composition were unchanged. Postheparin hepatic and lipoprotein lipase activities were unaffected by marine lipids. These data indicate that women with IDDM experience apparently beneficial effects on TG and HDL2 from dietary supplementation with omega-3 fatty acids administered in a low-cholesterol-containing oil without adversely affecting overall diabetes management. If these changes in lipoprotein concentration and composition prove to have antiatherogenic consequences and are free of long-term toxicity, these agents may have a role in the therapy of IDDM patients.     

Glucagon protects against impaired NMDA-mediated cerebrovasodilation and cerebral autoregulation during hypotension after brain injury by activating cAMP protein kinase A and inhibiting upregulation of tPA

Outcome of traumatic brain injury (TBI) is impaired by hyperglycemia, hypotension, and glutamate, and improved by insulin. Insulin reduces glutamate concentration, making it uncertain whether its beneficial effect accrues from euglycemia. Glucagon decreases CNS glutamate, lessens neuronal cell injury, and improves neurological scores in mice after TBI. In vitro, glucagon limits NMDA-mediated excitotoxicity by increasing cAMP and protein kinase A (PKA). NMDA receptor activation couples cerebral blood flow (CBF) to metabolism. Dilation induced by NMDA is impaired after fluid percussion brain injury (FPI) due to upregulation of endogenous tPA, which further disturbs cerebral autoregulation during hypotension after fluid percussion injury (FPI). We hypothesized that glucagon prevents impaired NMDA receptor-mediated dilation after FPI by upregulating cAMP, which decreases release of tPA. NMDA-induced pial artery dilation (PAD) was reversed to vasoconstriction after FPI. Glucagon 30?min before or 30?min after FPI blocked NMDA-mediated vasoconstriction and restored the response to vasodilation. PAD during hypotension was blunted after FPI, but protected by glucagon. Glucagon prevented FPI-induced reductions in CSF cAMP, yielding a net increase in cAMP, and blocked FPI-induced elevation of CSF tPA. Co-administration of the PKA antagonist Rp 8Br cAMPs prevented glucagon-mediated preservation of NMDA-mediated dilation after FPI. The pKA agonist Sp 8Br cAMPs prevented impairment of NMDA-induced dilation. These data indicate that glucagon protects against impaired cerebrovasodilation by upregulating cAMP, which decreases release of tPA, suggesting that it may provide neuroprotection when given after TBI, or prior to certain neurosurgical or cardiac interventions in which the incidence of perioperative ischemia is high.     

Enteral nutrition with supplemental arginine, RNA, and omega-3 fatty acids in patients after operation: immunologic, metabolic, and clinical outcome.

The individual nutrients arginine, RNA, and omega-3 fatty acids improve immune function, but prospective trials have not demonstrated their effects on clinical outcome. Patients (n = 85) who underwent operation for upper gastrointestinal malignancies were randomized to receive the supplemental diet or a standard enteral diet after surgery. Clinical patient characteristics were similar between the two groups. Mean caloric intakes (1421 vs 1285 kcal/day) were similar between groups. Mean nitrogen intakes (15.6 vs 9.0 gm/day) and nitrogen balances (-2.2 vs -6.6 gm/day) measured in the first 20 patients were significantly greater in the supplemented group than in the standard group (p = 0.05). In vitro lymphocyte mitogenesis was measured in the first 31 patients and was decreased on postoperative day 1 in both groups, but normal levels were regained only in the supplemented group. In the cohort of 77 eligible patients, infectious and wound complications occurred significantly less often (11% vs 37%) in the supplemented group than in the standard group (p = 0.02). Linear logistic models for infectious/wound complications with control for the amount of nitrogen suggested (p = 0.10) dietary treatment as the major factor. Mean length of stay in the hospital was significantly shorter (p = 0.01) for the supplemented group (15.8 +/- 5.1 days) than for the standard group (20.2 +/- 9.4 days). These results suggest that postoperative enteral nutrition with supplemental arginine, RNA, and omega-3 fatty acids instead of a standard enteral diet significantly improved immunologic, metabolic, and clinical outcomes in patients with upper gastrointestinal malignancies who were undergoing major elective surgery.     

Astrocyte oxidative metabolism and metabolite trafficking after fluid percussion brain injury in adult rats

Despite various lines of evidence pointing to the compartmentation of metabolism within the brain, few studies have reported the effect of a traumatic brain injury (TBI) on neuronal and astrocyte compartments and/or metabolic trafficking between these cells. In this study we used ex vivo 13C NMR spectroscopy following an infusion of [1-13C] glucose and [1,2-13C?] acetate to study oxidative metabolism in neurons and astrocytes of sham-operated and fluid percussion brain injured (FPI) rats at 1, 5, and 14 days post-surgery. FPI resulted in a decrease in the 13C glucose enrichment of glutamate in neurons in the injured hemisphere at day 1. In contrast, enrichment of glutamine in astrocytes from acetate was not significantly decreased at day 1. At day 5 the 13C enrichment of glutamate and glutamine from glucose in the injured hemisphere of FPI rats did not differ from sham levels, but glutamine derived from acetate metabolism in astrocytes was significantly increased. The 13C glucose enrichment of the C3 position of glutamate (C3) in neurons was significantly decreased ipsilateral to FPI at day 14, whereas the enrichment of glutamine in astrocytes had returned to sham levels at this time point. These findings indicate that the oxidative metabolism of glucose is reduced to a greater extent in neurons compared to astrocytes following a FPI. The increased utilization of acetate to synthesize glutamine, and the acetate enrichment of glutamate via the glutamate-glutamine cycle, suggests an integral protective role for astrocytes in maintaining metabolic function following TBI-induced impairments in glucose metabolism.     

Altered bidirectional plasticity and reduced implicit motor learning in concussed athletes

Persistent motor/cognitive alterations and increased prevalence of Alzheimer's disease are known consequences of recurrent sports concussions, the most prevalent cause of mild traumatic brain injury (TBI) among youth. Animal models of TBI demonstrated that impaired learning was related to persistent synaptic plasticity suppression in the form of long-term potentiation (LTP) and depression (LTD). In humans, single and repeated concussive injuries lead to lifelong and cumulative enhancements of gamma-aminobutyric acid (GABA)-mediated inhibition, which is known to suppress LTP/LTD plasticity. To test the hypothesis that increased GABAergic inhibition after repeated concussions suppresses LTP/LTD and contributes to learning impairments, we used a paired associative stimulation (PAS) protocol to induce LTP/LTD-like effects in primary motor cortex (M1) jointly with an implicit motor learning task (serial reaction time task, SRTT). Our results indicate that repeated concussions induced persistent elevations of GABA(B)-mediated intracortical inhibition in M1, which was associated with suppressed PAS-induced LTP/LTD-like synaptic plasticity. This synaptic plasticity suppression was related to reduced implicit motor learning on the SRTT task relative to normal LTP/LTD-like synaptic plasticity in unconcussed teammates. These findings identify GABA neurotransmission alterations after repeated concussions and suggest that impaired learning after multiple concussions could at least partly be related to compromised GABA-dependent LTP/LTD synaptic plasticity.