Life Extension Magazine®

Issue: Aug 2010

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Dopamine D2 receptors in addiction-like reward dysfunction and compulsive eating in obese rats.

We found that development of obesity was coupled with emergence of a progressively worsening deficit in neural reward responses. Similar changes in reward homeostasis induced by cocaine or heroin are considered to be crucial in triggering the transition from casual to compulsive drug-taking. Accordingly, we detected compulsive-like feeding behavior in obese but not lean rats, measured as palatable food consumption that was resistant to disruption by an aversive conditioned stimulus. Striatal dopamine D2 receptors (D2Rs) were downregulated in obese rats, as has been reported in humans addicted to drugs. Moreover, lentivirus-mediated knockdown of striatal D2Rs rapidly accelerated the development of addiction-like reward deficits and the onset of compulsive-like food seeking in rats with extended access to palatable high-fat food. These data demonstrate that overconsumption of palatable food triggers addiction-like neuroadaptive responses in brain reward circuits and drives the development of compulsive eating. Common hedonic mechanisms may therefore underlie obesity and drug addiction.

Nat Neurosci. 2010 May;13(5):635-41

Behavioural satiety sequence (BSS): Separating wheat from chaff in the behavioural pharmacology of appetite.

The history of anti-obesity drug development is far from glorious, with transient magic bullets and only a handful of agents currently licensed for clinical use. In view of recent progress in our understanding of the multiplicity of signalling pathways involved in appetite regulation, and the resultant deluge of reports on the anorectic efficacy of novel therapies, it seems timely to stress the need to differentiate treatments that suppress intake by primary means from those that only indirectly achieve this endpoint. The current article reviews the conceptual history of the behavioural satiety sequence (BSS), also known as the behavioural sequence of satiety, post-ingestive satiety, and the postprandial satiety sequence. Early research confirmed that natural satiation, produced by a caloric load on the gut, is associated with a predictable transition from feeding through grooming to resting. Although many less naturalistic manipulations are also capable of reducing food intake, very few do so without disrupting the normal structure of this feeding cycle. Thus, while CCK and d-fenfluramine reduce intake by accelerating but otherwise maintaining the integrity of the BSS, other anorectic interventions disrupt the BSS through response competition (e.g. d-amphetamine), nausea/discomfort (e.g. lithium chloride) and/or interference with taste-mediated positive feedback (e.g. quinine adulteration of the diet). A substantial literature now strongly supports the specific involvement of serotonin 5-HT(1B) and 5-HT(2C) receptor subtypes in satiety and in the anorectic effect of agents such as fenfluramine and fluoxetine. Recent BSS analyses have also identified rather selective anorectic profiles for the dual noradrenaline and 5-HT reuptake inhibitor sibutramine, the orexin-1 receptor antagonist SB-334867, and the broad spectrum opioid receptor antagonist naloxone. However, similar analyses have offered little/no support for the anorectic potential of the gut peptide PYY(3-36) while the acute anorectic efficacy of cannabinoid CB1 receptor antagonist/inverse agonists appears largely to be secondary to response competition. In contrast, studies with low-dose combinations of naloxone and CB1 receptor antagonist/inverse agonists have very recently confirmed the potential of drug polytherapies not only in appetite suppression but also in attenuating/eliminating unwanted side-effects. In sum, as BSS analysis offers a reliable means of differentiating the wheat (primary anorectics) from the chaff (secondary anorectics), it should form an integral part of early phase testing in any anti-obesity drug screening programme.

Pharmacol Biochem Behav. 2010 Mar 7

Valvular heart disease associated with fenfluramine-phentermine.

BACKGROUND: Fenfluramine and phentermine have been individually approved as anorectic agents by the Food and Drug Administration (FDA). When used in combination the drugs may be just as effective as either drug alone, with the added advantages of the need for lower doses of each agent and perhaps fewer side effects. Although the combination has not been approved by the FDA, in 1996 the total number of prescriptions in the United States for fenfluramine and phentermine exceeded 18 million. METHODS: We identified valvular heart disease in 24 women treated with fenfluramine-phentermine who had no history of cardiac disease. The women presented with cardiovascular symptoms or a heart murmur. As increasing numbers of these patients with similar clinical features were identified, there appeared to be an association between these features and fenfluramine-phentermine therapy. RESULTS: Twenty-four women (mean [+/-SD] age, 44+/-8 years) were evaluated 12.3+/-7.1 months after the initiation of fenfluramine-phentermine therapy. Echocardiography demonstrated unusual valvular morphology and regurgitation in all patients. Both right-sided and left-sided heart valves were involved. Eight women also had newly documented pulmonary hypertension. To date, cardiac surgical intervention has been required in five patients. The heart valves had a glistening white appearance. Histopathological findings included plaque-like encasement of the leaflets and chordal structures with intact valve architecture. The histopathological features were identical to those seen in carcinoid or ergotamine-induced valve disease. CONCLUSIONS: These cases arouse concern that fenfluramine-phentermine therapy may be associated with valvular heart disease. Candidates for fenfluramine-phentermine therapy should be informed about serious potential adverse effects, including pulmonary hypertension and valvular heart disease.

N Engl J Med. 1997 Aug 28;337(9):581-8

Serotonin delivery into the ventromedial nucleus of the hypothalamus affects differently feeding pattern and body weight in obese and lean Zucker rats.

AIM: To determine if central serotonin (5-HT)-induced satiety is altered in obesity. METHODS: Obese and lean Zucker rats received infusion of 5-HT (5 microg/0.5 microl/h) or saline into the ventromedial nucleus of the hypothalamus (VMN) for 2 weeks. RESULTS: In lean rats, 5-HT decreased body weight (7%) and total food intake (15%) which was due to a decreased meal size during the dark phase. In obese rats, a decrease of food intake was also observed in the dark phase, but it was compensated by an increased food intake during the light phase, resulting in no significant changes of total food intake and body weight. In obese rats, meal number but not meal size was affected by 5-HT delivery. Body fat content was not affected by 5-HT in obese rats, while cessation of 5-HT delivery in lean rats resulted in 13% increase. CONCLUSION: Intra-VMN 5-HT in obese rats did not increase meal-associated satiety as it did in lean rats, but modulated hunger. These results show that the Zucker obese phenotype is characterized by VMN resistance to 5-HT, which may contribute to neurobiological mechanisms of increased meal size and food intake and may diminish anti-obesity effects of serotonergic anorexiants.

Appetite. 2010 Apr;54(2):346-53

Effects of serotonin (5-HT)(1B) receptor ligands on cocaine-seeking behavior in rats.

Numerous data indicated a significance for the brain dopaminergic pathways in the behavioral effects of cocaine, however recent research also demonstrated involvement of serotonin (5-HT) neurotransmission and particularly 5-HT(1B) receptors in the reinforcing, discriminative stimulus and sensitizing effects of cocaine. In order to substantiate a role of these receptors in incentive motivation for cocaine, we used the extinction/reinstatement model to examine the effects of the 5-HT(1B) receptor ligands on reinstatement of extinguished cocaine-seeking behavior and food-taking behavior. Rats trained to self-administer cocaine (0.5 mg/kg/infusion) subsequently underwent extinction procedures. They were then tested for the cocaine-primed or cocaine-associated cue-induced reinstatement of extinguished cocaine-seeking behavior. Other groups of rats were trained to self-administer food (sweet milk), and after extinction they were tested for the reinstatement of food-taking behavior induced by contingent food presentation. The 5-HT(1B) receptor antagonists SB 216641 (2.5-7.5 mg/kg) and GR 127935 (2.5-10 mg/kg) dose-dependently attenuated the cocaine (10 mg/kg)- and cocaine-associated cue-induced reinstatement of cocaine-seeking behavior whereas they failed to alter reinstatement of food-taking behavior. The 5-HT(1B) receptor agonist CP 94253 (2.5 or 5 mg/kg) combined with a subthreshold priming dose of cocaine (2.5 mg/kg) potentiated reinstatement of the drug seeking-behavior, but inhibited cocaine seeking induced by a submaximal dose (10 mg/kg) of cocaine or the cocaine-associated cue. Moreover, the 5-HT(1B) receptor agonist attenuated reinstatement of food-taking behavior. Facilitatory effect of CP 94253 on cocaine-seeking behavior and its inhibitory effect on food-taking behavior were blocked by SB 216641, but its inhibitory effect on cocaine-seeking behavior remained unaffected by this 5-HT(1B) receptor antagonist. Our results indicate that tonic activation of 5-HT(1B) receptors is involved in cocaine- and cue-induced reinstatement of cocaine-seeking behavior and that the inhibitory effects of 5-HT(1B) receptor antagonists on these phenomena are directly related to motivational aspects of cocaine abuse. The facilitatory 5-HT(1B) receptor-mediated effect of the 5-HT(1B) receptor agonist on cocaine seeking may be related to the earlier reported enhancement of the rewarding properties of cocaine, while its inhibitory effect on cocaine-seeking behavior, unrelated to the 5-HT(1B) receptor activation, may result from a general reduction of motivation.

Pharmacol Rep. 2008 Nov-Dec;60(6):798-810

Twenty-four-hour plasma tryptophan concentrations and ratios are below normal in obese subjects and are not normalized by substantial weight reduction.

BACKGROUND: Plasma tryptophan concentrations and the ratio of tryptophan to other large neutral amino acids (plasma tryptophan ratio) are reportedly low in obese subjects. The plasma tryptophan ratio predicts brain tryptophan uptake and serotonin production. If this ratio is low in obese subjects, serotonin function may also be low. Plasma tryptophan concentrations and ratios have been measured only at single time points in obese subjects; it is not known whether low values for these 2 variables persist throughout a 24-h period. OBJECTIVE: Our objective was to determine whether plasma tryptophan concentrations and ratios in obese subjects are lower than those in normal-weight subjects throughout a 24-h period and whether they increase when body weight is reduced. DESIGN: Plasma tryptophan concentrations and ratios were examined in obese subjects before and after weight loss and in nonobese control subjects. Blood samples were drawn frequently throughout the 24-h period. An insulin tolerance test was also used to determine whether weight loss altered the ability of insulin to modify plasma concentrations of tryptophan and of the other large neutral amino acids. RESULTS: Plasma tryptophan concentrations and ratios in obese subjects were low at all times; these effects persisted after weight reduction. Plasma concentrations of all the large neutral amino acids decreased during insulin infusion in all the groups. CONCLUSIONS: The low 24-h plasma tryptophan ratios in obese and formerly obese subjects suggest that brain tryptophan uptake may be continuously diminished and may remain below normal despite weight reduction.

Am J Clin Nutr. 2003 May;77(5):1112-8

Meal-induced changes in tryptophan:LNAA ratio: effects on craving and binge eating.

This study investigated the effects of meals varying in macronutrient composition on plasma tryptophan/large neutral amino acid (tryp:LNAA) ratios and subsequent appetite and mood in women defined as “food cravers.” Nine women consumed one of each of a high protein, high carbohydrate and mixed meal on three separate days. Blood samples and appetite and mood ratings were taken before and at intervals up to 150 min after meal consumption. The first subsequent ad libitum food intake was recorded in diaries. The tryp:LNAA ratio increased significantly after the carbohydrate meal compared to protein and mixed meals. No significant correlations between change in tryp:LNAA ratio and mood or macronutrient intake at the ad libitum eating episode were observed. There was a negative correlation between tryp:LNAA ratio and desire to binge eat (p=0.03) and a trend towards a negative correlation between tryp:LNAA ratio and craving for carbohydrate-rich foods (p=0.07). Participants whose ad libitum eating episode was categorized as a binge had a trend (p=0.06) toward lower plasma tryp:LNAA ratio than those who did not binge. Regression analysis showed that the effects of change in tryp:LNAA ratio on desire to binge eat was independent of meal type and changes in insulin and glucose concentrations. These findings suggest that reducing plasma tryp:LNAA ratio, via consumption of a protein-rich meal, may mediate the desire to binge eat in susceptible women.

Eat Behav. 2000 Sep;1(1):53-62

Eating behavior and adherence to dietary prescriptions in obese adult subjects treated with 5-hydroxytryptophan.

Previous observations have shown that oral administration of 5-hydroxytryptophan (5-HTP) without dietary prescriptions causes anorexia, decreased food intake, and weight loss in obese subjects. To confirm these data over a longer period of observation and to verify whether adherence to dietary restriction could be improved by 5-HTP, 20 obese patients were randomly assigned to receive either 5-HTP (900 mg/d) or a placebo. The study was double-blinded and was for two consecutive 6-wk periods. No diet was prescribed during the first period, a 5040-kJ/d diet was recommended for the second. Significant weight loss was observed in 5-HTP-treated patients during both periods. A reduction in carbohydrate intake and a consistent presence of early satiety were also found. These findings together with the good tolerance observed suggest that 5-HTP may be safely used to treat obesity.

Am J Clin Nutr. 1992 Nov;56(5):863-7

Effects of oral 5-hydroxy-tryptophan on energy intake and macronutrient selection in non-insulin dependent diabetic patients.

OBJECTIVE: In obese patients, brain serotonergic stimulation via orally administered 5-hydroxy-tryptophan (5-HTP), the precursor of serotonin, causes decreased carbohydrate intake and weight loss. Since diabetes mellitus is associated with depressed brain serotonin, hyperphagia and carbohydrate craving, we hypothesized that in diabetic patients, orally administered 5-HTP stimulates brain serotonergic activity and thus normalizes eating behaviour. To test this hypothesis, we investigated whether in diabetic patients: 1) predicted brain serotonin concentrations are depressed as a result of decreased availability of the precursor, tryptophan; and 2) oral 5-HTP is effective in reducing energy and carbohydrate intake. SUBJECTS AND METHODS: 25 overweight non-insulin dependent diabetic outpatients were enrolled in a double-blind, placebo-controlled study, and randomized to receive either 5-HTP (750 mg/d) or placebo for two consecutive weeks, during which no dietary restriction was prescribed. Energy intake and eating behaviour, as expressed by macronutrient selection, were evaluated using a daily diet diary. Plasma amino acid concentrations and body weight, as well as serum glucose, insulin and glycosylated haemoglobin were assessed. RESULTS: 20 patients (nine from the 5-HTP group and 11 from the Placebo group) completed the study. Brain tryptophan availability in diabetic patients was significantly reduced when compared to a group of healthy controls. Patients receiving 5-HTP significantly decreased their daily energy intake, by reducing carbohydrate and fat intake, and reduced their body weight. CONCLUSIONS: These data confirm the role of the serotonergic system in reducing energy intake, by predominantly inhibiting carbohydrate intake, and suggest that 5-HTP may be safely utilized to improve the compliance to dietary prescriptions in non-insulin dependent diabetes mellitus.

Int J Obes Relat Metab Disord. 1998 Jul;22(7):648-54

Food intake and energy expenditure in obese female bingers and non-bingers.

Since compulsive eating occurs in approximately 30% of obese females and is associated with earlier relapse following weight loss, we compared daily energy intake, dietary composition and energy expenditure among obese binge eaters and obese non-bingers. Nine obese bingers (33 +/- 4 yrs, 95 +/- 6 kg, 39 +/- 1% fat) and nine obese non-bingers (47 +/- 3 yrs, 93 +/- 5 kg, 40 +/- 1% fat) were admitted for 12 days to a metabolic unit. Binge eaters were defined as scoring > 25 on the binge eating scale (BES). During the initial 8 days, subjects ate ad libitum from two computerized vending machines offering a variety of foods and beverages. A weight maintenance diet was then provided for the next 4 days. Twenty-four hour energy expenditure (24EE) and respiratory quotient (24Q) were measured on the last day of both feeding periods in a respiratory chamber. Obese bingers showed a wider range of energy intake compared to non-bingers, but the mean daily energy intake was similar between the two groups (2,587 +/- 454 vs 2,386 +/- 201 kcal/d) during 8 days of ad libitum intake. 24EE was not different between bingers and non-bingers after 8 days of ad libitum intake (2,298 +/- 147 vs 2109 +/- 97 kcal/d, P = 0.3) or 4 days of weight maintenance diet, even more so after adjustment for differences in fat-free mass, fat mass and age. Resting metabolic rate, sleeping metabolic rate, and macronutrient intake and oxidation were also similar between groups.

Int J Obes Relat Metab Disord. 1995 Jan;19(1):11-6

Personality traits and eating behavior in the obese: poor self-control in emotional and external eating but personality assets in restrained eating.

Personality traits can give a fuller understanding for eating behaviors in obesity. The objective was to describe eating behavior (Dutch Eating Behaviour Questionnaire) in terms of the Big Five personality traits (NEO Personality Inventory-Revised) in obesity patients (n=442). Emotional eating was strongly positively associated to Neuroticism, in particular impulsiveness and depression, and further linked to lower Conscientiousness mainly seen in lower self-discipline, and lower Extraversion. External eating was likewise mainly associated to the facets impulsiveness and lower self-discipline. Restrained eating was on the other hand related to higher Conscientiousness, Extraversion and Openness, and lower Neuroticism. These results imply that poor self-control seen in impulsiveness and lower self-discipline was most important for eating due to negative emotions as well as in response to external food stimuli, suggesting that the inhibition of eating and difficulties to govern ones behavior are major aspects of these eating behaviors. Attempts to control food intake and body weight seen in restrained eating were associated with more character strengths and ambitions, and also a more outgoing personality style with more stable emotions.

Eat Behav. 2008 Aug;9(3):285-93

Emotional eating, depressive symptoms and self-reported food consumption. A population-based study.

We examined the associations of emotional eating and depressive symptoms with the consumption of sweet and non-sweet energy-dense foods and vegetables/fruit, also focusing on the possible interplay between emotional eating and depressive symptoms. The participants were 25-64-year-old Finnish men (n=1,679) and women (n=2,035) from the FINRISK 2007 Study (DILGOM substudy). The Three-Factor Eating Questionnaire-R18, Center for Epidemiological Studies Depression Scale, and a 132-item Food Frequency Questionnaire were used. Emotional eating and depressive symptoms correlated positively (r=0.31 among men and women), and both were related to a higher body mass. Emotional eating was related to a higher consumption of sweet foods in both genders and non-sweet foods in men independently of depressive symptoms and restrained eating. The positive associations of depressive symptoms with sweet foods became non-significant after adjustment for emotional eating, but this was not the case for non-sweet foods. Depressive symptoms, but not emotional eating, were related to a lower consumption of vegetables/fruit. These findings suggest that emotional eating and depressive symptoms both affect unhealthy food choices. Emotional eating could be one factor explaining the association between depressive symptoms and consumption of sweet foods, while other factors may be more important with respect to non-sweet foods and vegetables/fruit.

Appetite. 2010 Feb 4

Global prevalence of diabetes: estimates for the year 2000 and projections for 2030.

OBJECTIVE: The goal of this study was to estimate the prevalence of diabetes and the number of people of all ages with diabetes for years 2000 and 2030. RESEARCH DESIGN AND METHODS: Data on diabetes prevalence by age and sex from a limited number of countries were extrapolated to all 191 World Health Organization member states and applied to United Nations’ population estimates for 2000 and 2030. Urban and rural populations were considered separately for developing countries. RESULTS: The prevalence of diabetes for all age-groups worldwide was estimated to be 2.8% in 2000 and 4.4% in 2030. The total number of people with diabetes is projected to rise from 171 million in 2000 to 366 million in 2030. The prevalence of diabetes is higher in men than women, but there are more women with diabetes than men. The urban population in developing countries is projected to double between 2000 and 2030. The most important demographic change to diabetes prevalence across the world appears to be the increase in the proportion of people >65 years of age. CONCLUSIONS: These findings indicate that the “diabetes epidemic” will continue even if levels of obesity remain constant. Given the increasing prevalence of obesity, it is likely that these figures provide an underestimate of future diabetes prevalence.

Diabetes Care. 2004 May;27(5):1047-53

Diabesity: an inflammatory metabolic condition.

Diabesity, that is to say, obesity-dependent diabetes, has emerged as a major public health problem. Though diabesity is basically explained by insulin resistance and pancreatic beta cell dysfunction, new paradigms have evolved to explain these alterations in the context of the modern epidemics of obesity and diabetes. Among these, the association of inflammation with obesity is an important component of the common soil from which diabetes and cardiovascular diseases (CVD) derive. This Review presents our epidemiological findings, based primarily on the ARIC Study, in the context of the other epidemiological studies supporting the inflammatory nature of diabetes, CVD and the metabolic syndrome. We also review the characteristics of the innate immune system, including the molecular interface of innate immunity with metabolism, components of which are responsible for the presence of a state of mild, chronic and systemic inflammation related to diabesity. Finally, we present obesity as an inflammatory condition, obesitis, and propose a conceptual framework that integrates the epidemiological findings with new provocative basic science results.

Clin Chem Lab Med. 2003 Sep;41(9):1120-30

Dietary curcumin significantly improves obesity-associated inflammation and diabetes in mouse models of diabesity.

Obesity is a major risk factor for the development of type 2 diabetes, and both conditions are now recognized to possess significant inflammatory components underlying their pathophysiologies. We tested the hypothesis that the plant polyphenolic compound curcumin, which is known to exert potent antiinflammatory and antioxidant effects, would ameliorate diabetes

and inflammation in murine models of insulin-resistant obesity. We found that dietary curcumin admixture ameliorated diabetes in high-fat diet-induced obese and leptin-deficient ob/ob male C57BL/6J mice as determined by glucose and insulin tolerance testing and hemoglobin A1c percentages. Curcumin treatment also significantly reduced macrophage infiltration of white adipose tissue, increased adipose tissue adiponectin production, and decreased hepatic nuclear factor-kappaB activity, hepatomegaly, and markers of hepatic inflammation. We therefore conclude that orally ingested curcumin reverses many of the inflammatory and metabolic derangements associated with obesity and improves glycemic control in mouse models of type 2 diabetes. This or related compounds warrant further investigation as novel adjunctive therapies for type 2 diabetes in man.

Endocrinology. 2008 Jul;149(7):3549-58

Adipokine and insulin profiles distinguish diabetogenic and non-diabetogenic obesities in mice.

OBJECTIVE: To use longitudinal profiling of plasma adipokines to distinguish diabetogenic vs. non-diabetogenic obesity syndrome in two new mouse models of polygenic obesity. RESEARCH METHODS AND PROCEDURES: Male mice of the NONcNZO5 strain develop a polygenic obesity syndrome uncomplicated by diabetes, whereas NONcNZO10 males develop a comparable polygenic obesity that precipitates type 2 diabetes. A multiplex immunoassay for simultaneous measurement of insulin and a panel of mouse adipokines (leptin, resistin, adiponectin, interleukin-6, tumor necrosis factor alpha, macrophage chemoattractant protein-1, plasminogen activator inhibitor-1)

were used to profile longitudinal changes in these strains between 4 and 16 weeks of age that might distinguish the non-diabetogenic vs. diabetogenic obesity (diabesity). RESULTS: Both strains became adipose, with NONcNZO5 males attaining a higher mean body weight with a higher percentage fat content. Weight gain in NONcNZO5 was accompanied by a transient peak in plasma insulin (PI) at 8 weeks followed by a decline into normal range, with normoglycemia maintained throughout. In contrast, NONcNZO10 showed no early PI secretory response because both body weight and plasma glucose increased between 4 and 8 weeks. Only after 12 weeks, with hyperglycemia established, was a delayed PI secretory response observed. Neither plasma leptin nor adiponectin concentrations significantly differentiated the two syndromes over time. However, repeated measures ANOVA showed that NONcNZO10 males maintained significantly higher plasma concentrations of two adipokines, resistin and plasminogen activator inhibitor-1, and the pro-inflammatory cytokine/adipokine macrophage chemoattractant protein-1. DISCUSSION: Longitudinal profiling of PI and adipokines in two new mouse models developing moderate obesity demonstrated that specific marker signatures differentiated a non-diabetogenic obesity from a diabetogenic obesity.

Obesity (Silver Spring). 2007 Aug;15(8):1961-8

Metabolic dysfunction and chronic stress: a new sight at “diabesity” pandemic.

Chronic stress in Western society can activate the autonomus, neuroendocrine and inflammatory/immunlogic systems. Chronic exposure to stressors can indeed stimulate the hypothalamic-pituitary-adrenal axis and induce a disbalance between anabolic and catabolic hormones, responsible of an increased in visceral fat and of insulin resistance. These metabolic consequences can lead to pre-diabetes. Exposure to chronic stress results in allostatic load and its pathophysiologic consequences. The knowledge of this mecanisms and the cardiovascular and metabolic risk related, should influence our way of thinking about patient care. To decrease allostatic load, practitioners can rely on therapeutic relation. Therapeutic education is one of the skill that can be use to create therapeutic relation.

Rev Med Suisse. 2009 Jun 3;5(206):1273-7

Hypoglycemic effects of turmeric (Curcuma longa L. rhizomes) on genetically diabetic KK-Ay mice.

The turmeric (Curcuma longa L. rhizomes) EtOH extract significantly suppressed an increase in blood glucose level in type 2 diabetic KK-A(y) mice. In an in vitro evaluation, the extract stimulated human adipocyte differentiation in a dose-dependent manner and showed human peroxisome proliferator-activated receptor (PPAR)-gamma ligand-binding activity in a GAL4-PPAR-gamma chimera assay. The main constituents of the extract were identified as curcumin, demethoxycurcumin, bisdemethoxycurcumin, and ar-turmerone, which had also PPAR-gamma ligand-binding activity. These results indicate that turmeric is a promising ingredient of functional food for the prevention and/or amelioration of type 2 diabetes and that curcumin, demethoxycurcumin, bisdemethoxycurcumin, and ar-turmerone mainly contribute to the effects via PPAR-gamma activation.

Biol Pharm Bull. 2005 May;28(5):937-9

Effect of tetrahydrocurcumin on insulin receptor status in type 2 diabetic rats: studies on insulin binding to erythrocytes.

Curcumin is the most active component of turmeric. It is believed that curcumin is a potent antioxidant and anti-inflammatory agent. Tetrahydrocurcumin (THC) is one of the major metabolites of curcumin, and exhibits many of the same physiological and pharmacological activities as curcumin and, in some systems, may exert greater antioxidant activity than curcumin. Using circulating erythrocytes as the cellular mode, the insulin-binding effect of THC and curcumin was investigated. Streptozotocin (STZ)-nicotinamide-induced male Wistar rats were used as the experimental models. THC (80 mg/kg body weight) was administered orally for 45 days. The effect of THC on blood glucose, plasma insulin and insulin binding to its receptor on the cell membrane of erythrocytes were studied. Mean specific binding of insulin was significantly lowered in diabetic rats with a decrease in plasma insulin. This was due to a significant decrease in mean insulin receptors. Erythrocytes from diabetic rats showed a decreased ability for insulin-receptor binding when compared with THC-treated diabetic rats. Scatchard analysis demonstrated that the decrease in insulin binding was accounted for by a decrease in insulin receptor sites per cell, with erythrocytes of diabetic rats having less insulin receptor sites per cell than THC-treated rats. High affinity (K d1), low affinity (K d2) and kinetic analyses revealed an increase in the average receptor affinity of erythrocytes from THC-treated rats compared with those of diabetic rats. These results suggest that acute alteration of the

insulin receptor on the membranes of erythrocytes occurred in diabetic rats. Treatment with THC significantly improved specific insulin binding to the receptors, with receptor numbers and affinity binding reaching near-normal levels. Our study suggests the mechanism by which THC increases the number of total cellular insulin binding sites resulting in a significant increase in plasma insulin. The effect of THC is more prominent than that of curcumin.

J Biosci. 2008 Mar;33(1):63-72

Curcumin supplementation lowers TNF-alpha, IL-6, IL-8, and MCP-1 secretion in high glucose-treated cultured monocytes and blood levels of TNF-alpha, IL-6, MCP-1, glucose, and glycosylated hemoglobin in diabetic rats.

This study examined the hypothesis that curcumin supplementation decreases blood levels of IL-6, MCP-1, TNF-alpha, hyperglycemia, and oxidative stress by using a cell-culture model and a diabetic rat model. U937 monocytes were cultured with control (7 mM) and high glucose (35 mM) in the absence or presence of curcumin (0.01-1 microM) at 37 degrees C for 24 h. Diabetes was induced in Sprague-Dawley rats by injection of streptozotocin (STZ) (i.p., 65 mg/kg BW). Control buffer, olive oil, or curcumin (100 mg/kg BW) supplementation was administered by gavage daily for 7 weeks. Blood was collected by heart puncture with light anesthesia. Results show that the effect of high glucose on lipid peroxidation, IL-6, IL-8, MCP-1, and TNF-alpha secretion was inhibited by curcumin in cultured monocytes. In the rat model, diabetes caused a significant increase in blood levels of IL-6, MCP-1, TNF-alpha,

glucose, HbA(1), and oxidative stress, which was significantly decreased in curcumin-supplemented rats. Thus, curcumin can decrease markers of vascular inflammation and oxidative stress levels in both a cell-culture model and in the blood of diabetic rats. This suggests that curcumin supplementation can reduce glycemia and the risk of vascular inflammation in diabetes.

Antioxid Redox Signal. 2009 Feb;11(2):241-9

Photo-irradiated curcumin supplementation in streptozotocin-induced diabetic rats: effect on lipid peroxidation.

BACKGROUND: Diabetes mellitus is one of the most common endocrine disorders. A large number of studies are in progress to identify natural substances that are effective in reducing the severity of diabetes. Although a number of drugs are currently marketed, their long-term use can cause a number of adverse effects. MATERIALS AND METHODS: In the present study, we examined the effect of photo-irradiated curcumin on experimental diabetes in order to evaluate the antihyperglycaemic effects of this compound on streptozotocin (40 mg/kg bodyweight)-induced diabetes. Photo-irradiated curcumin was given at a dose of 10, 30 and 80 mg/kg bodyweight. The level of blood glucose was elevated in the diabetic animals. The liver, kidney and brain were assayed for the degree of lipid peroxidation, reduced glutathione content and the activity of enzymic and levels of non-enzymic antioxidants. RESULTS: Antioxidant status decreased in the diabetic animals. Oral administration of photo-irradiated curcumin for 45 days resulted in a significant decrease in the levels of blood glucose, together with near normalisation of enzymic activity and the markers of lipid peroxidation. The best results were obtained in rats treated with 30 mg/kg bodyweight of photo-irradiated curcumin.

Therapie. 2004 Nov-Dec;59(6):639-44

Effect of curcumin on the advanced glycation and cross-linking of collagen in diabetic rats.

A close association between increased oxidative stress and hyperglycemia has been postulated to contribute significantly to the accelerated accumulation of advanced glycation end products (AGEs) and the cross-linking of collagen in diabetes mellitus. In the present work, we report the influence of curcumin, an efficient antioxidant, on the level of AGEs and the cross-linking of collagen in diabetic rats. Diabetic rats were given curcumin (200 mg/kg body wt) orally for a duration of 8 weeks. The antioxidant status in serum and the level of AGEs, cross-linking and browning of collagen in tail tendons and skin were investigated. The oxidative stress observed in diabetic rats was reduced significantly by curcumin administration. Nonenzymic antioxidants such as vitamin C, vitamin E, and glutathione were maintained at near normal values in curcumin-treated diabetic animals. Similarly, the accumulation of lipid peroxidation products in diabetic serum was reduced significantly by curcumin. Accelerated accumulation of AGE-collagen in diabetic animals, as detected by ELISA, was prevented by curcumin. Extensive cross-linking of collagen in the tail tendon and skin of diabetic animals was also prevented to a greater extent by curcumin treatment. A correlation between the level of AGEs and collagen cross-linking was noted, suggesting the involvement of advanced glycation in cross-linking. It was also noted that the preventive effect of curcumin on the advanced glycation and cross-linking of collagen was more pronounced than its therapeutic effect. However, the Maillard reaction fluorescence in both tail and skin collagen remained unaltered by curcumin. This study confirms the significance of free radicals in the accumulation of AGEs and cross-linking of collagen in diabetes. It supports curcumin administration for the prevention of AGE-induced complications of diabetes mellitus.

Biochem Pharmacol. 1998 Dec 15;56(12):1607-14

Omega-3 fatty acids for major depressive disorder during pregnancy: results from a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Perinatal depression is common, and treatment remains challenging. Depression has been reported to be associated with the abnormality of omega-3 polyunsaturated fatty acids (PUFAs). A profound decrease of omega-3 PUFAs in the mother during pregnancy is associated with the higher demand of fetal development and might precipitate the occurrence of depression. In this study, we examined the efficacy of omega-3 PUFA monotherapy for the treatment of depression during pregnancy. METHOD: From June 2004 to June 2006, we conducted an 8-week, double-blind, placebo-controlled trial comparing omega-3 PUFAs (3.4 g/d) with placebo in pregnant women with major depressive disorder (DSM-IV criteria). No psychotropic agent was given 1 month prior to or during the study period. The Hamilton Rating Scale for Depression (HAM-D) was scored every other week as the primary measurement of efficacy, while the Edinburgh Postnatal Depression Scale (EPDS) and Beck Depression Inventory (BDI) were secondary measures. RESULTS: Thirty-six subjects were randomly assigned to either omega-3 PUFAs or placebo, and 33 among them were evaluated in more than 2 visits. A total of 24 subjects completed the study. As compared to the placebo group, subjects in the omega-3 group had significantly lower HAM-D scores at weeks 6 (p = .001) and 8 (p = .019), a significantly higher response rate (62% vs. 27%, p = .03), and a higher remission rate, although the latter did not reach statistical significance (38% vs. 18%, p = .28). At the study end point, subjects in the omega-3 group also had significantly lower depressive symptom ratings on the EPDS and BDI. The omega-3 PUFAs were well tolerated and there were no adverse effects on the subjects and newborns. CONCLUSIONS: Omega-3 PUFAs may have therapeutic benefits in depression during pregnancy. In regard to the safety issue and psychotherapeutic effect, as well as health promotion to mothers and their newborns, it is worthy to conduct replication studies in a larger sample with a broad regimen of omega-3 PUFAs in pregnant women with depression. TRIAL REGISTRATION: Identifier:

J Clin Psychiatry. 2008 Apr;69(4):644-51

Ethyl-eicosapentaenoic acid for the treatment of psychological distress and depressive symptoms in middle-aged women: a double-blind, placebo-controlled, randomized clinical trial.

BACKGROUND: Psychological distress (PD) and depressive

symptoms are commonly observed during menopausal transition. Studies suggest that omega-3 (n-3) fatty acids may help alleviate depression. OBJECTIVE: The objective was to compare enriched ethyl-eicosapentaenoic acid (E-EPA) supplementation with placebo for the treatment of PD and depressive symptoms in middle-aged women. DESIGN: Women with moderate-to-severe PD (n = 120) were randomly assigned to receive 1.05 g E-EPA/d plus 0.15 g ethyl-docosahexaenoic acid/d (n = 59) or placebo (n = 61) for 8 wk. The main outcomes were 8-wk changes in PD scores [Psychological General Well-Being Schedule (PGWB)] and depressive scales [20-item Hopkins Symptom Checklist Depression Scale (HSCL-D-20) and the 21-item Hamilton Depression Rating Scale (HAM-D-21)]. RESULTS: At baseline, women with PD were mildly to moderately depressed, and 24% met the major depressive episode (MDE) criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition. After 8 wk, outcomes improved in both groups, but no significant differences were noted between them. Stratification analyses for MDE diagnosis at baseline indicated that differences in adjusted 8-wk changes between the E-EPA group without MDE (n = 46) and the placebo group (n = 45) were 8.0 (95% CI: 0.6, 15.3; P = 0.034) for the PGWB, -0.2 (95% CI: -0.01, -0.4; P = 0.040) for the HSCL-D-20, and -2.7 (95% CI: -0.3, -5.1; P = 0.030) for the HAM-D-21. Differences in adjusted 8-wk changes between the E-EPA group with MDE (n = 13) and the placebo group (n = 16) were not significant. CONCLUSIONS: To our knowledge, this is the first trial of n-3 supplementation in the treatment of PD and depressive symptoms in middle-aged women. In women with PD without MDE at baseline, the 8-wk changes in PD and depressive scales improved significantly more with E-EPA than with placebo.

Am J Clin Nutr. 2009 Feb;89(2):641-51

Omega-3 treatment of childhood depression: a controlled, double-blind pilot study.

OBJECTIVE: Major depressive disorder in children may be more common than previously thought, and its therapeutics are unclear. Because of success in a previous study on omega-3 fatty acids in adult major depressive disorder, the authors planned a pilot study of omega-3 fatty acids in childhood major depression. METHOD: Children who entered the study were between the ages of 6 and 12. Ratings were performed at baseline and at 2, 4, 8, 12, and 16 weeks using Children’s Depression Rating Scale (CDRS), Children’s Depression Inventory (CDI), and Clinical Global Impression (CGI). Children were randomized to omega-3 fatty acids or placebo as pharmacologic monotherapy. Twenty-eight patients were randomized, and 20 completed at least 1 month’s ratings. RESULTS: Analysis of variance showed highly significant effects of omega-3 on symptoms using the CDRS, CDI, and CGI. CONCLUSIONS: Omega-3 fatty acids may have therapeutic benefits in childhood depression.

Am J Psychiatry. 2006 Jun;163(6):1098-100

Long-chain omega-3 polyunsaturated fatty acids in the blood of children and adolescents with juvenile bipolar disorder.

Reduced long-chain omega-3 polyunsaturated fatty acids (LCn-3PUFA), including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have been reported in adult patients suffering from depression and bipolar disorder (BD). LCn-3PUFA status has not previously been examined in children and adolescents with BD compared with healthy controls. Fifteen children and adolescents (9-18 years, M +/- SD = 14.4 +/- 3.48) diagnosed with juvenile bipolar disorder (JBD) and fifteen healthy age and sex-matched controls were assessed for dietary intake and fasting red blood cell (RBC) membrane concentrations of LCn-3PUFA. Fatty acid concentrations were compared between participants diagnosed with JBD and controls after controlling for dietary intake. RBC membrane concentrations of EPA and DHA were not significantly lower in participants diagnosed with JBD compared with healthy controls (M +/- sem EPA = 3.37 +/- 0.26 vs. 3.69 +/- 0.27 microg/mL, P = 0.458; M +/- sem DHA = 22.08 +/- 2.23 vs. 24.61 +/- 2.38 microg/mL, P = 0.528) after controlling for intake. Red blood cell DHA was negatively (r = -0.55; P = 0.044) related to clinician ratings of depression. Although lower RBC concentrations of LCn-3PUFA were explained by lower intakes in the current study, previous evidence has linked reduced LCn-3PUFA to the aetiology of BD. As RBC DHA was also negatively related to symptoms of depression, a randomised placebo-controlled study examining supplementation with LCn-3PUFA as an adjunct to standard pharmacotherapy appears warranted in this patient population.

Lipids. 2008 Nov;43(11):1031-8

Deficits in docosahexaenoic acid and associated elevations in the metabolism of arachidonic acid and saturated fatty acids in the postmortem orbitofrontal cortex of patients with bipolar disorder.

Previous antemortem and postmortem tissue fatty acid composition studies have observed significant deficits in the omega-3 fatty acid docosahexaenoic acid (DHA, 22:6n-3) in red blood cell (RBC) and postmortem cortical membranes of patients with unipolar depression. In the present study, we determined the fatty acid composition of postmortem orbitofrontal cortex (OFC, Brodmann area 10) of patients with bipolar disorder (n=18) and age-matched normal controls (n=19) by gas chromatography. After correction for multiple comparisons, DHA (-24%), arachidonic acid (-14%), and stearic acid (C18:0) (-4.5%) compositions were significantly lower, and cis-vaccenic acid (18:1n-7) (+12.5%) composition significantly higher, in the OFC of bipolar patients relative to normal controls. Based on metabolite:precursor ratios, significant elevations in arachidonic acid, stearic acid, and palmitic acid conversion/metabolism were observed in the OFC of bipolar patients, and were inversely correlated with DHA composition. Deficits in OFC DHA and arachidonic acid composition, and elevations in arachidonic acid metabolism, were numerically (but not significantly) greater in drug-free bipolar patients relative to patients treated with mood-stabilizer or antipsychotic medications. OFC DHA and arachidonic acid deficits were greater in patients plus normal controls with high vs. low alcohol abuse severity. These results add to a growing body of evidence implicating omega-3 fatty acid deficiency as well as the OFC in the pathoaetiology of bipolar disorder.

Psychiatry Res. 2008 Sep 30;160(3):285-99

Omega-3 fatty acids in bipolar disorder: a preliminary double-blind, placebo-controlled trial.

BACKGROUND: Omega-3 fatty acids may inhibit neuronal signal transduction pathways in a manner similar to that of lithium carbonate and valproate, 2 effective treatments for bipolar disorder. The present study was performed to examine whether omega-3 fatty acids also exhibit mood-stabilizing properties in bipolar disorder. METHODS: A 4-month, double-blind, placebo-controlled study, comparing omega-3 fatty acids (9.6 g/d) vs placebo (olive oil), in addition to usual treatment, in 30 patients with bipolar disorder. RESULTS: A Kaplan-Meier survival analysis of the cohort found that the omega-3 fatty acid patient group had a significantly longer period of remission than the placebo group (P = .002; Mantel-Cox). In addition, for nearly every other outcome measure, the omega-3 fatty acid group performed better than the placebo group. CONCLUSION: Omega-3 fatty acids were well tolerated and improved the short-term course of illness in this preliminary study of patients with bipolar disorder.

Arch Gen Psychiatry. 1999 May;56(5):407-12

Omega-3 fatty acid treatment and T(2) whole brain relaxation times in bipolar disorder.

OBJECTIVE: The authors hypothesized that changes in brain membrane composition resulting from omega-3 fatty acid administration in patients with bipolar disorder would result in greater membrane fluidity, as detected by reductions in T(2) values. METHOD: Women with bipolar disorder (N=12) received omega-3 fatty acids for 4 weeks. A cohort of bipolar subjects (N=9) and a group without bipolar disorder (N=12) did not receive omega-3 fatty acids. T(2) values were acquired at baseline and after 4 weeks. RESULTS: Bipolar subjects who received omega-3 fatty acids had significant decreases in T(2). There was a dose-dependent effect when the bipolar omega-3 fatty acid group was subdivided into high- and low-dose cohorts. CONCLUSIONS: Omega-3 fatty acids lowered T(2) values, consistent with the hypothesis that the fluidity of cell membranes was altered. Further studies are needed to clarify the significance of alterations in brain physiology induced by omega-3 fatty acids, as reflected in T(2) values.

Am J Psychiatry. 2004 Oct;161(10):1922-4

Omega-3 eicosapentaenoic acid in bipolar depression: report of a small open-label study.

INTRODUCTION: Epidemiologic studies have suggested that consumption of cold water fish oils may have some protective function against depression. This proposition is supported by a series of biochemical and pharmacologic studies that have suggested that fatty acids may modulate neurotransmitter metabolism and cell signal trans-duction in humans and that abnormalities in fatty acid and eicosanoid metabolism may play a causal role in depression. Aware of the critical need for antidepression treatments that might not carry the risk of precipitating a manic episode in bipolar patients, we decided to conduct an open-label add-on trial of eicosapentaenoic acid (EPA) in bipolar depression. METHOD: Twelve bipolar I outpatients with depressive symptoms diagnosed by DSM-IV were treated with 1.5 to 2 g/day of the omega-3 fatty acid EPA for up to 6 months. The study was conducted between September 2001 and January 2003. RESULTS: Eight of the 10 patients who completed at least 1 month of follow-up achieved a 50% or greater reduction in Hamilton Rating Scale for Depression scores within 1 month. No patients developed hypomania or manic symptoms. No significant side effects were reported. LIMITATIONS: This study is limited both by the open-label design and by the small sample size. As in all previous reported studies, patients in this study were treated in an outpatient setting, so that the most severely depressed bipolar patients (requiring hospitalization) are not represented. CONCLUSIONS: Although the ultimate utility of omega-3 fatty acids in bipolar depression is still an open question, we believe that these initial results are encouraging, especially for mild to moderate bipolar depression, and justify the continuing exploration of its use.

J Clin Psychiatry. 2005 Jun;66(6):726-9

Omega-3 fatty acids for bipolar disorder.

BACKGROUND: Bipolar disorder is a complex psychiatric disorder and is amongst the top thirty causes of worldwide disability. Mood stabilisers are the primary pharmacological intervention, both in the treatment of acute episodes and in prophylaxis. There is, however, mounting evidence that dietary supplementation with omega-3 fatty acids may be beneficial in psychiatric conditions, particularly those involving disturbances of mood. OBJECTIVES: To review the efficacy of omega-3 fatty acids as either a monotherapy or an adjunctive treatment for bipolar disorder. SEARCH STRATEGY: Electronic searches of the following databases were performed: CCDANCTR-Studies and CCDANCTR-References were searched on 12/2/2008, Supplementary searches were carried out on Biological Abstracts, CINAHL, The Cochrane Library, CCDAN Register, EMBASE, MEDLINE, and PsycINFO. The search strategy also included cited reference searching, personal contact with all authors of studies initially included and contact with the omega-3 producing pharmaceutical companies. SELECTION CRITERIA: All relevant randomised controlled trials were included in the review. Studies involving males and females of all ages with a diagnosis of bipolar disorder qualified for inclusion. Studies using any type or dose of omega-3 fatty acid treatment as monotherapy or in addition to standard pharmacotherapy were eligible. The primary outcome was symptom severity; and secondary outcomes were adverse effects, dropout and satisfaction with treatment. DATA COLLECTION AND ANALYSIS: Two review authors independently inspected the citations identified from the search. Potentially relevant abstracts were identified and full papers ordered and reassessed for inclusion and methodological quality. All relevant data were extracted. The weighted mean difference (WMD) was used for continuous outcome data, with 95% confidence intervals (CI). MAIN RESULTS: Five studies met inclusion criteria for the review, however, methodological quality was highly variable. Only one study, involving 75 participants, provided data for analysis, and showed a benefit of active treatment over control for depression symptom levels (WMD -3.93, 95% CI -7.00 to -0.86)and Clinical Global Impression scores (WMD -0.75, 95% CI -1.33 to -0.17) but not for mania (WMD -2.81, 95% CI -7.68 to 1.90). No serious adverse effects were reported in the five studies. The pattern of dropout was highly variable between studies. AUTHORS’ CONCLUSIONS: Results from one study showed positive effects of omega-3 as an adjunctive treatment for depressive but not manic symptoms in bipolar disorder. These findings must be regarded with caution owing to the limited data available. There is an acute need for well-designed and executed randomised controlled trials in this field.

Cochrane Database Syst Rev. 2008 Apr 16;(2):CD005169

Efficacy of omega-3 Fatty acids in mood disorders - a systematic review and metaanalysis.

Objectives: Existing efficacy trials of Omega-3 (omega-3) fatty acids in mood disorders have yielded inconsistent results. The current paper is an effort to provide a systematic review and meta-analysis to evaluate efficacy of omega-3 fatty acids in treatment of mood disorders. Design:We searched Medline, Embase, PsychInfo, and the Cochrane Controlled Trials registry up to June 2008 for randomized trials investigating efficacy of omega-3 fatty acids in mood disorders.We conducted random effects meta-analyses.We used the I2 statistic to quantify between-study inconsistency, and conducted pre-specified subgroup analyses to explore potential explanations for inconsistency. Observations:We included 21 trials in our systematic review and found 13 trials to be eligible for meta-analysis. The pooled standardized mean difference in depressed mood states (n = 554 in 12 trials) was -0.47 (95% CI:-0.92,-0.02; I2 = 82.7; p = 0.07) and in manic mood states (n = 126 in 4 trials) was 0.22 (95% CI: -0.21, 0.65; I2 = 40.5; p = 0.31).We did not identify any treatment- subgroup interaction across forms of omega-3 fatty acids preparations (P = 0.99) or patient diagnosis (bipolar vs. unipolar depressive disorder; P = 0.96); there was a significant correlation between omega-3 fatty acids dose and treatment effect on depressive symptoms (r = 0.5, p = 0.04), but not on manic symptoms (P = 0.3). Conclusions: The available evidence suggests that omega-3 fatty acids are a potential treatment of depressive disorders, but not mania. The unexplained between-study inconsistency and imprecision of the pooled estimates mitigate this suggestion. Large randomized placebo-controlled trials are needed to better estimate the value of this intervention for patients with depression.

Psychopharmacol Bull. 2009;42(3):39-54

Reduced mania and depression in juvenile bipolar disorder associated with long-chain omega-3 polyunsaturated fatty acid supplementation.

Long-chain omega-3 polyunsaturated fatty acid (LCn-3PUFA) supplementation may improve symptoms of depression in children and bipolar disorder (BD) in adults. No studies have examined the effectiveness of LCn-3PUFA supplementation in the treatment of mania and depression in juvenile BD (JBD) when given as an adjunct to standard pharmacological

treatment. Eighteen children and adolescents with JBD received supplements containing 360 mg per day eicosapentaenoic acid (EPA) and 1,560 mg per day docosahexaenoic acid (DHA) for 6 weeks in an open-label study. Intake and fasting red blood cell (RBC) LCn-3PUFA, mania, depression and global function were assessed before and after supplementation. RBC EPA and DHA were significantly higher following supplementation. Clinician ratings of mania and depression were significantly lower and global functioning significantly higher after supplementation. Parent ratings of internalizing and externalizing behaviours were also significantly lower following supplementation. A larger randomized controlled trial appears warranted in this participant population.

Eur J Clin Nutr. 2009 Aug;63(8):1037-40

Efficacy of omega-3 fatty acid supplementation on improvement of bipolar symptoms: a systematic review.

The purpose of this review was to examine the current level of evidence regarding the efficacy of omega-3 fatty acid supplementation in improving bipolar disorder symptoms. Of 99 articles meeting initial search criteria, 5 randomized control trials and 2 quasi-experimental studies were selected for review. Omega-3 fatty acid supplementation was effective in 4 of 7 studies. Those using an omega-3 combination of eicosapentaenoic acid and docosahexanoic acid demonstrated a statistically significant improvement in bipolar symptoms, whereas those using a single constituent did not. Dosage variations did not demonstrate statistically significant differences. Due to its benign side effect profile and some evidence supporting its usefulness in bipolar illness, omega-3 may be a helpful adjunct in treatment of selected patients. Future studies are needed to conclusively confirm the efficacy of omega-3s in bipolar disorder, uncovering a new well-tolerated treatment option.

Arch Psychiatr Nurs. 2008 Oct;22(5):305-11

Radioprotection of Swiss albino mice by Emblica officinalis.

The fruit pulp of Emblica officinalis (EO) is an important drug used in Indian systems of medicine for several diseases and as a tonic. In view of its multifarious uses, the plant extract (aqueous) was tested for its radioprotective properties against sublethal gamma radiation (9 Gy) in Swiss albino mice. Animals were divided into two groups and irradiated with gamma radiation externally, with or without EO extract, which was given orally at different doses before irradiation. The dose of fruit pulp extract found to be most effective against radiation was 100 mg/kg b.wt. This dose increased the survival time and reduced the mortality rate of mice significantly. Furthermore, body weight loss in EO administered irradiated animals was significantly less in comparison with animals who were given radiation only.

Phytother Res. 2005 May;19(5):444-6

Inhibitory effect of ascorbic acid post-treatment on radiation-induced chromosomal damage in human lymphocytes in vitro.

In the present study, the effect of exposure to ascorbic acid (vitamin C) after gamma-ray-induced chromosomal damage in cultured human lymphocytes was examined to explore the mechanism by which this antioxidant vitamin protects irradiated cells Non-irradiated lymphocytes were exposed to increasing concentrations of ascorbic acid (1-100 micro g/ml) and DNA damage was estimated using chromosomal aberration analysis and the comet assay. The results showed that ascorbic acid did not influence the frequency of chromosomal aberrations in non-irradiated cells, except at the highest concentration (20 micro g/ml), which induced breakage-type chromosomal aberrations. Vitamin C at the concentration of 50 micro g/ml caused DNA damage detected by the comet assay. A significant (34%) decrease in the frequency of chromosomal aberrations was observed in lymphocytes exposed to gamma-radiation and then cultured in the presence of ascorbic acid (1 micro g/ml). The removal of DNA breaks in cells exposed to 2 Gy of gamma-radiation was accelerated in the presence of ascorbic acid as determined by the comet assay, suggesting that it may stimulate DNA repair processes.

Teratog Carcinog Mutagen. 2002;22(6):443-50

Radioprotective-antimutagenic effects of rosemary phenolics against chromosomal damage induced in human lymphocytes by gamma-rays.

The radioprotective effects of carnosic acid (CA), carnosol (COL), and rosmarinic acid (RO) against chromosomal damage induced by gamma-rays, compared with those of L-ascorbic acid (AA) and the S-containing compound dimethyl sulfoxide (DMSO), were determined by use of the micronucleus test for antimutagenic activity, evaluating the reduction in the frequency of micronuclei (MN) in cytokinesis-blocked cells of human lymphocytes before and after gamma-ray irradiation. With treatment before gamma-irradiation, the most effective compounds were, in order, CA > RO > or = COL > AA > DMSO. The radioprotective effects (antimutagenic) with treatment after gamma-irradiation were lower, and the most effective compounds were CA and COL. RO and AA presented small radioprotective activity, and the sulfur-containing compound DMSO lacked gamma-ray radioprotection capacity. Therefore, CA and COL are the only compounds that showed a significant antimutagenic activity both before and after gamma-irradiation treatments. These results are closely related to those reported by other authors on the antioxidant activity of the same compounds, and the degree of effectiveness depends on their structure. Furthermore, the results for treatments before and after gamma-ray irradiation suggest the existence of different radioprotective mechanisms in each case.

J Agric Food Chem. 2006 Mar 22;54(6):2064-8

Radioprotective effect of melatonin assessed by measuring chromosomal damage in mitotic and meiotic cells.

This study was taken to evaluate the radioprotective effects of melatonin. Male adult albino mice were treated (intraperitoneal, i.p.) with 10 mg/kg melatonin either 1 h before or 1/2 h after exposure to 1.5 Gy of gamma-irradiation. Control, melatonin, irradiated and melatonin plus irradiation groups were sacrificed 24 h following treatment. The incidence of micronuclei (MN) in bone marrow cells was determined in all groups. The results show that melatonin caused a significant reduction in micronuclei polychromatic erythrocytes (MNPCE) when animals were treated with melatonin before and not after exposure to radiation. Mitotic and meiotic metaphases were prepared from spermatogonial and primary spermatocytes, respectively. Examination and analysis of metaphases showed no mutagenic effect of melatonin on chromosomal aberration (CA) frequency in spermatogonial chromosomes. Administration of one single dose of melatonin to animals before irradiation lowered total CA from 46 to 32%. However, no significant effect was observed when melatonin was given after irradiation. Similarly, the frequency of CA in meiotic metaphases decreased from 43.5% in the irradiated group to 31.5% in the irradiated group treated with melatonin 1 h before irradiation, but no change was observed when melatonin was administered after irradiation. The data obtained in this study suggest that melatonin administration confers protection against damage inflicted by radiation when given prior to exposure to irradiation and not after, and support the contention that melatonin radioprotection is achieved by its ability as a scavenger for free radicals generated by ionizing radiation.

Mutat Res. 1999 Aug 18;444(2):367-72

Liposoluble antioxidants provide an effective radioprotective barrier.

Ionising radiation causes the massive generation of reactive oxygen species and induces cellular DNA damage. The antioxidant, protective effects of several compounds against gamma-ray-induced chromosomal damage were determined by the micronucleus test, evaluating the reduction in the frequency of micronuclei in cytokinesis-blocked human lymphocytes. The compounds studied were added to human blood at 25 microM, 5 min before or after irradiation with 2 Gy of caesium-137. The results suggest that different protective mechanisms are operating in each case. When the phenolic compounds are added before gamma-irradiation, their protective antimutagenic activity is based on their scavenging capacity against superoxide anion (O(2)(.-)) and, especially, hydroxyl radical ((.)OH), regardless of whether they are oil- or water-soluble compounds. When the phenolic compounds are added after gamma-irradiation treatment, the protective effect relies on activity against reactive oxygen species present in cells, i.e. lipoperoxy radicals (R(-)OO(.)), which are mainly responsible for continuous chromosomal oxidative damage. In addition, ionising radiation enhances lysosomal enzyme secretion and arachidonate release from membranes through lipo-oxygenase, cyclo-oxygenase and phospholipase activities, thus increasing the inflammatory cell response. Only oil-soluble compounds, such as carnosic acid, carnosol and delta-tocopherol, provide a significant protective antimutagenic activity. The most powerful water-soluble antioxidants lack the capacity to protect against gamma-ray-induced damage. The difference between anti-radical and anti-lipoperoxidant activities could explain the different behaviour of the compounds tested in terms of protecting against the lipid peroxidative processes. This anti-lipoperoxidant activity depends on several factors, but it is clear that only the lipo-antioxidants are effective in protecting human cells against oxidative damage, even when administered after exposure to ionising radiation.

Br J Radiol. 2009 Jul;82(979):605-9

Ionizing radiation-induced E-selectin gene expression and tumor cell adhesion is inhibited by lovastatin and all-trans retinoic acid.

E-selectin mediated tumor cell adhesion plays an important role in metastasis. Here we show that ionizing radiation (IR) induces E-selectin gene and protein expression in human endothelial cells at therapeutically relevant dose level. E-selectin expression is accompanied by an increase in the adhesion of human colon carcinoma cells to primary human umbilical vein endothelial cells (HUVEC). The HMG-CoA reductase inhibitor lovastatin impairs IR-stimulated E-selectin expression as analyzed at the level of the protein, mRNA and promoter. Inactivation of Rho GTPases either by use of Clostridium difficile toxin A or by co-expression of dominant-negative Rho blocked IR-induced E-selectin gene induction, indicating Rho GTPases to be essential. Radiation-induced expression of E-selectin was also blocked by all-trans retinoic acid (at-RA), whereas 9-cis retinoic acid was ineffective. Abrogation of IR-stimulated E-selectin expression by lovastatin and at-RA reduced tumor cell adhesion in a dose-dependent manner. Combined treatment with lovastatin and at-RA exerted additive inhibitory effects on radiation-induced E-selectin expression and tumor cell adhesion. Therefore, application of statins and at-RA might have clinical impact in protecting against E-selectin-promoted metastasis, which might arise as an unwanted side effect from radiation treatment.

Carcinogenesis. 2004 Aug;25(8):1335-44

Retinoids and TIMP1 prevent radiation-induced apoptosis of capillary endothelial cells.

Radiation-induced changes in capillaries constitute a basic injury in the pathogenesis of chronic radiation damage to the heart, lung, liver, kidney and brain. It is important to identify new radioprotectors for capillary endothelial cells for use during radiotherapy to minimize normal tissue damage and possibly to increase the deliverable dose. Previously we demonstrated that exposure to ionizing radiation (10 Gy) results in death of bovine adrenal capillary endothelial cells in confluent monolayers by apoptosis. We also showed that retinoids inhibit the growth of endothelial cells, induce their differentiation, down-regulate matrix metalloproteinase (MMP) production, and up-regulate tissue inhibitors of matrix metalloproteinases (TIMPs). In the present studies, we demonstrated that radiation (10 Gy) induced an immediate increase in the amounts and activation of MMP1 and MMP2 in the cell fraction and medium of bovine capillary endothelial cells followed by an incidence of apoptosis. We also obtained data indicating that radiation-induced apoptosis can be inhibited by exposing bovine capillary endothelial cells to all-trans-retinol or all-trans-retinoic acid for 6 days before irradiation, even when the vitamins were removed 24 h before irradiation. Finally, we determined that inhibition of MMPs by TIMP was sufficient to block radiation-induced apoptosis, suggesting that the mechanism of protection by retinoids is through the alteration of levels of MMPs and TIMPs produced by the cells.

Radiat Res. 2004 Feb;161(2):174-84

Antioxidant vitamins C, E, and beta-carotene reduce DNA damage before as well as after gamma-ray irradiation of human lymphocytes in vitro.

The protective effect of vitamins C, E, and beta-carotene against gamma-ray-induced DNA damage in human lymphocytes in vitro was investigated. Cultured lymphocytes were exposed to increasing concentration of these vitamins either before or after irradiation with 2Gy of gamma-rays and DNA damage was estimated using micronucleus assay. A radioprotective effect was observed when antioxidant vitamins were added to cultured cells before as well after irradiation; the strongest effect was observed when they were added no later than 1h after irradiation. The radioprotective effect of vitamins also depended on their concentration; vitamins C added at low concentration (1 microg/ml) before exposure of the cells to radiation prevented induction of micronuclei. Vitamin E at the concentration above 2 microg/ml decreased the level of radiation-induced micronuclei when compared to the cells irradiated without vitamin treatment. beta-Carotene was effective at all tested concentrations from 1 to 5 microg/ml and reduced the number of micronuclei in irradiated cells. The vitamins had no effect on radiation-induced cytotoxicity as measured by nuclear division index. The radioprotective action of antioxidant vitamins C, E, and beta-carotene was dependent upon their concentration as well as time and sequence of application.

Mutat Res. 2001 Apr 5;491(1-2):1-7

Radioprotective role of zinc following single dose radioiodine (131I) exposure to red blood cells of rats.

BACKGROUND & OBJECTIVES: Irradiation with 131I is used for the treatment of various thyroid disorders. It is likely that radioiodine while in systemic circulation may cause some adverse effects on antioxidative enzymes present in red blood cells (RBCs). Zinc, on the other hand, has been reported to maintain the integrity of cells under certain toxic conditions. The present study was conducted to evaluate the adverse effects of 131I on RBCs and also to assess the protection provided by zinc under these conditions. METHODS: Female Wistar rats (n=32) were divided into four groups. Animals in group I served as normal controls; group II animals were administered a dose of 3.7 Mbq of 131I (carrier-free) intraperitoneally, group III animals were supplemented with zinc (227 mg/l drinking water) and animals in group IV were given a combined treatment of zinc as well as 131I. Activities of antioxidant enzymes were assessed in erythrocyte lysates after two days of treatments. RESULTS: An increase in the activity of glutathione reductase (GR), superoxide dismutase (SOD), reduced glutathione (GSH) and malondialdehyde (MDA) in the lysates of erythrocytes was seen after two days of exposure from 131I radiations. However, the activity of catalase was found to be significantly decreased. Interestingly, zinc supplementation to 131I treated rats resulted in attenuating the adverse effects caused by 1,31I on the levels of antioxidative enzymes. INTERPRETATION & CONCLUSION: 131I can induce significant oxidant/antioxidant changes in RBCs and zinc may prove to be a candidate with great promise for radioprotection.

Indian J Med Res. 2005 Oct;122(4):338-42

Zinc as an antiperoxidative agent following iodine-131 induced changes on the antioxidant system and on the morphology of red blood cells in rats.

Iodine-131 ((131)I) irradiation is the first line treatment for Graves’ disease and thyroid carcinoma. In such cases, (131)I gets accumulated in the thyroid, and is released in the form of radioiodinated triiodothyronine (T3) and tetraiodothronine (T4). Various reports describe changes in the blood picture after radioiodine treatment. Zinc, on the other hand, has been reported to maintain the integrity of red blood cells (RBC) under certain toxic conditions. The present study was conducted to evaluate the adverse effects of (131)I on the antioxidant defense system and morphology of RBC and also to assess the possible protection by zinc under irradiation by (131)I. Thirty two female Wistar rats were equally segregated into four main groups. Animals with Group I served as normal controls; Group II animals were administered a dose of 3.7 MBq of (131)I (carrier free) intraperitoneally, Group III rats were supplemented with zinc (227 mg/L drinking water) and Group IV rats were given a combined treatment of (131)I and zinc, in a similar way as in Group II and IV rats. After seven days of (131)I treatment, RBC lysate was prepared and its antioxidant status assessed. The activity of superoxide dismutase (SOD), reduced glutathione (GSH) and malondialdehyde (MDA) in the lysate of RBC was increased. On the contrary, the activity of catalase was found to be significantly decreased. The activity of glutathione reductase (GR) remained unchanged. Marked changes in the shape of RBC from normal discocytes to echinocytes, spherocytes, stomatocytes and acanthocytes were also observed in the blood of the rats treated with (131)I. Zinc supplementation to (131)I treated rats, significantly attenuated the adverse effects caused by (131)I on the levels of MDA, GSH, SOD and catalase. In conclusion, the study revealed significant oxidant/antioxidant changes in RBC following (131)I administration in rats, while zinc was shown to act as a radioprotector agent.

Hell J Nucl Med. 2006 Jan-Apr;9(1):22-6

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