Tetrahydrobiopterin modulates the behavioral neuroinflammatory response to an LPS challenge in mice.

Tetrahydrobiopterin (BH4) is a necessary cofactor for the synthesis of monoamines from essential amino-acids, phenylalanine, tyrosine and tryptophan. The BH4 synthesis pathway is induced by inflammatory factors but highly regulated processes maintain levels in a physiological range. However, BH4 activity can be durably altered in inflammation-related pathologies, such as certain types of depression, potentially involving impairment of dopaminergic neurotransmission. The purpose of this study was to investigate the response of the brain BH4 pathway to the inflammatory stimulus induced by lipopolysaccharide (LPS) in mice. Brain expression of genes related to BH4 synthesis, levels of BH4, changes in L-aromatic amino acid precursors of monoamines and dopamine levels were determined. As secondary aim, the effect of acute BH4 supply under the inflammatory challenge was tested on these parameters and on the expression of inflammatory cytokines. Mice were also submitted to the sucrose preference test and to the open-field in order to asses hedonic and locomotor responses to LPS, in addition to their modulation by BH4 supply. The LPS challenge resulted in decreased striatal DA levels and increased Phenylalanine/Tyrosine ratio, suggesting reduced BH4 activity. BH4 supply was effective to increase striatal BH4 levels, to restore the LPS-induced decreased in DA levels in striatum and to dampen the LPS-induced expression of inflammatory cytokines. At the behavioral level, BH4 supply was able to restore the loss of locomotor response to amphetamine in the LPS treated mice, suggesting a modulation of the dopaminergic neurotransmission. These data suggest that BH4 can be considered as a potential add-on molecule, helping to maintain or restore dopaminergic neurotransmission in neuroinflammatory conditions..

Tetrahydrobioterin (BH4) Pathway: From Metabolism to Neuropsychiatry.

Tetrahydrobipterin (BH4) is a pivotal enzymatic cofactor required for the synthesis of serotonin, dopamine and nitric oxide. BH4 is essential for numerous physiological processes at periphery and central levels, such as vascularization, inflammation, glucose homeostasis, regulation of oxidative stress and neurotransmission. BH4 de novo synthesis involves the sequential activation of three enzymes, the major controlling point being GTP cyclohydrolase I (GCH1). Complementary salvage and recycling pathways ensure that BH4 levels are tightly kept within a physiological range in the body. Even if the way of transport of BH4 and its ability to enter the brain after peripheral administration is still controversial, data showed increased levels in the brain after BH4 treatment. Available evidence shows that GCH1 expression and BH4 synthesis are stimulated by immunological factors, notably pro-inflammatory cytokines. Once produced, BH4 can act as an anti- inflammatory molecule and scavenger of free radicals protecting against oxidative stress. At the same time, BH4 is prone to autoxidation, leading to the release of superoxide radicals contributing to inflammatory processes, and to the production of BH2, an inactive form of BH4, reducing its bioavailability. Alterations in BH4 levels have been documented in many pathological situations, including Alzheimer's disease, Parkinson's disease and depression, in which increased oxidative stress, inflammation and alterations in monoaminergic function are described. This review aims at providing an update of the knowledge about metabolism and the role of BH4 in brain function, from preclinical to clinical studies, addressing some therapeutic implications.

Tetrahydrobiopterin administration facilitates amphetamine-induced dopamine release and motivation in mice.

Dopamine (DA) is a critical neurotransmitter involved in motivational processes. Tetrahydrobiopterin (BH4) is an essential cofactor for tyrosine hydroxylase, the rate-limiting enzyme in DA synthesis. Decreases in BH4 levels are observed in several DA-related neuropsychiatric diseases involving impairment in motivation. Yet, whether BH4 could be used to treat motivational deficits has not been comprehensively investigated. To investigate the effects of exogenous BH4 administration on the dopaminergic system and related behaviors, we acutely injected mice with BH4 (50 mg/kg). Passage of BH4 through the blood brain barrier and accumulation in brain was measured using the in situ brain perfusion technique. DA release was then recorded using in-vivo micro-dialysis and motivation was evaluated through operant conditioning paradigms in basal condition and after an amphetamine (AMPH) injection. First, we showed that BH4 crosses the blood-brain barrier and that an acute peripheral injection of BH4 is sufficient to increase the concentrations of biopterins in the brain, without affecting BH4- and DA-related protein expression. Second, we report that this increase in BH4 enhanced AMPH-stimulated DA release in the nucleus accumbens. Finally, we found that BH4-induced DA release led to improved performance of a motivational task. Altogether, these findings suggest that BH4, through its action on the dopaminergic tone, could be used as a motivational enhancer.

How French subjects describe well-being from food and eating habits? Development, item reduction and scoring definition of the Well-Being related to Food Questionnaire (Well-BFQ©).

Providing well-being and maintaining good health are main objectives subjects seek from diet. This manuscript describes the development and preliminary validation of an instrument assessing well-being associated with food and eating habits in a general healthy population. Qualitative data from 12 groups of discussion (102 subjects) conducted with healthy subjects were used to develop the core of the Well-being related to Food Questionnaire (Well-BFQ). Twelve other groups of discussion with subjects with joint (n = 34), digestive (n = 32) or repetitive infection complaints (n = 30) were performed to develop items specific to these complaints. Five main themes emerged from the discussions and formed the modular backbone of the questionnaire: "Grocery shopping", "Cooking", "Dining places", "Commensality", "Eating and drinking". Each module has a common structure: items about subject's food behavior and items about immediate and short-term benefits. An additional theme - "Eating habits and health" - assesses subjects' beliefs about expected benefits of food and eating habits on health, disease prevention and protection, and quality of ageing. A preliminary validation was conducted with 444 subjects with balanced diet; non-balanced diet; and standard diet. The structure of the questionnaire was further determined using principal component analyses exploratory factor analyses, with confirmation of the sub-sections food behaviors, immediate benefits (pleasure, security, relaxation), direct short-term benefits (digestion and satiety, energy and psychology), and deferred long-term benefits (eating habits and health). Thirty-three subscales and 14 single items were further defined. Confirmatory analyses confirmed the structure, with overall moderate to excellent convergent and divergent validity and internal consistency reliability. The Well-BFQ is a unique, modular tool that comprehensively assesses the full picture of well-being related to food and eating habits in the general population.

Nutritional omega-3 modulates neuronal morphology in the prefrontal cortex along with depression-related behaviour through corticosterone secretion.

Understanding how malnutrition contributes to depression is building momentum. In the present study we unravel molecular and cellular mechanisms by which nutritional disturbances lead to impaired emotional behaviour in mice. Here we report that nutritional n-3 polyunsaturated fatty acids (PUFA) deficiency induces a chronic stress state reflected by disrupted glucocorticoid receptor (GR)-mediated signalling pathway along with hypothalamic-pituitary-adrenal (HPA) axis hyperactivity. This hyperactivity in turn resulted in neuronal atrophy in the dorsolateral (dl)- and dorsomedial (dm)- prefrontal cortex (PFC) and subsequent mood-related behaviour alterations, similarly to chronic social defeat stress. Supplementation of n-3 PUFA prevented detrimental chronic social defeat stress-induced emotional and neuronal impairments by impeding HPA axis hyperactivity. These results indicate a role for dietary n-3 PUFA in the prevention of HPA axis dysfunction associated with the development of some neuropsychiatric disorders including depression.

Quality of life after Roux-en-Y gastric bypass and changes in body mass index and obesity-related comorbidities.

AIM: Dynamics of improvement in health-related quality of life (QoL) after bariatric surgery have never been fully assessed, and neither has the potential influence of body mass index (BMI) and comorbidity modification. The objective of this study was to investigate early and medium-term changes in QoL following Roux-en-Y gastric bypass (RYGB), and their relationship to BMI and comorbidity variations. METHODS: A total of 71 obese subjects (80% women, mean age 42.1±11.2 years, mean baseline BMI 47.6±6.2kg/m(2)) undergoing RYGB filled in QoL questionnaires (SF-36) before and 3, 6 and 12 months after surgery. QoL was assessed using repeated-measures Anova, with associations between its changes and changes in BMI and comorbidities (diabetes, hypertension, dyslipidaemia, sleep apnoea, knee pain) assessed by mixed-effects models. RESULTS: Physical QoL scales (physical component summary, PCS) significantly increased over time (from 38.9±9.3 to 52.6±7.9; P<0.001) as did other physical SF-36 scales (all P<0.001), whereas mental QoL summary scale did not vary significantly (from 45.7±9.5 to 48.6±11.5; P=0.072). Major changes in QoL occurred at 3 months after surgical intervention to reach values comparable to those in the general population. PCS was mostly associated with changes in either BMI or comorbidity status except for diabetes, dyslipidaemia and sleep apnoea. CONCLUSION: Results show that improvements in physical QoL after RYGB are observed as early as 3 months after intervention, and are independently associated with weight loss and improvements in comorbidities.

Relationship between adiposity, emotional status and eating behaviour in obese women: role of inflammation.

BACKGROUND: Obesity is characterized by chronic low-grade inflammation that may lead to emotional distress and behavioural symptoms. This study assessed the relationship between adiposity, low-grade inflammation, eating behaviour and emotional status in obese women awaiting gastric surgery and investigated the effects of surgery-induced weight loss on this relationship. METHOD: A total of 101 women with severe or morbid obesity awaiting gastric surgery were recruited. Assessments were performed before and at 1 year post-surgery and included the measurement of neuroticism and extraversion using the revised Neuroticism-Extraversion-Openness personality inventory (NEO-PI-R) and eating behaviour using the Three-Factor Eating Questionnaire (TFEQ). Blood samples were collected for the measurement of serum inflammatory markers [interleukin-6 (IL-6), high-sensitive C-reactive protein (hsCRP)] and adipokines (leptin, adiponectin). RESULTS: At baseline, body mass index (BMI) was positively correlated with inflammatory markers and adipokines. Regression analyses adjusting for age and diabetes revealed that baseline concentrations of IL-6 and hsCRP were associated with the depression and anxiety facets of neuroticism, with higher inflammation predicting higher anxiety and depression. This association remained significant after adjusting for BMI. Gastric surgery induced significant weight loss, which correlated with reduced inflammation. After controlling for BMI variations, decreases in inflammatory markers, notably hsCRP, were associated with reduced anxiety and TFEQ-cognitive restraint scores. CONCLUSIONS: These findings indicate strong associations between adiposity, inflammation and affectivity in obese subjects and show that surgery-induced weight loss is associated concomitantly with reduced inflammation and adipokines and with significant improvement in emotional status and eating behaviour. Inflammatory status appears to represent an important mediator of emotional distress and psychological characteristics of obese individuals.

Association between decreased serum tryptophan concentrations and depressive symptoms in cancer patients undergoing cytokine therapy.

Cytokine therapy for cancer or viral diseases is accompanied by the development of depressive symptoms in a significant proportion of patients. Despite the increasing number of studies on the neurotoxic effects of cytokines, the mechanisms by which cytokines induce depressive symptoms remain largely unknown. In view of the relationship between neurotransmitter precursors and mood, the present study aimed at assessing the relationship between serum concentrations of the amino acids tryptophan and tyrosine, major precursors of serotonin and norepinephrine respectively, and depressive symptoms in cancer patients undergoing cytokine therapy. Sixteen cancer patients eligible to receive immunotherapy with interleukin-2 and/or interferon-alpha participated in the study. At baseline and after one week and one month of therapy, depressive symptoms were assessed using the Montgomery-Asberg Depression Rating Scale (MADRS), and blood samples were collected for the determination of the large neutral amino acids (LNAA) (tryptophan, tyrosine, valine, leucine, isoleucine, phenylalanine) which compete for transport across the blood-brain barrier. Serum concentrations of tryptophan as well as the tryptophan/LNAA ratio significantly decreased between baseline, one week and one month of therapy. The development and severity of depressive symptoms, especially anorexia, pessimistic thoughts, suicidal ideation and loss of concentration were positively correlated with the magnitude of the decreases in tryptophan concentrations during treatment. These findings indicate that the development of depressive symptoms in patients undergoing cytokine therapy could be mediated by a reduced availability of the serotonin relevant amino acid precursor, tryptophan.

Association between immune activation and early depressive symptoms in cancer patients treated with interleukin-2-based therapy.

The relationship between immune activation and the development of early depressive symptoms were studied in 33 cancer patients undergoing cytokine therapy. Patients were treated either with subcutaneous IL-2 administered alone (n=13) or in association with IFN-alpha (n=5), or with IFN-alpha alone administered subcutaneously at low doses (n=5) or intravenously at high doses (n=10). The intensity of depressive symptoms was assessed during a clinical interview carried out before the start of cytokine therapy and five days later using the Montgomery and Asberg Depression Rating Scale (MADRS). On the same days, blood samples were collected for each patient to measure serum concentrations of cytokines (IL-6, IL-10, IL-1ra) and cytokine-receptors (sIL-2R, LIF-R). Results showed that patients treated with IL-2 or IL-2+IFN-alpha displayed concomitant mood symptoms and increased serum cytokine levels during treatment. In these patients, the intensity of depressive symptoms at endpoint was positively correlated with the increases measured in serum levels of IL-10 between baseline and endpoint. IL-10 is an anti-inflammatory cytokine that is produced in response to the production of pro-inflammatory cytokines, and thereby reflects an inflammatory response. These results support the hypothesis of close relationship between depressive symptoms and the activation of the cytokine network.

Timing and specificity of the cognitive changes induced by interleukin-2 and interferon-alpha treatments in cancer patients.

OBJECTIVE: Neuropsychological changes develop in patients treated by cytokine immunotherapy with interleukin-2 (IL-2) and interferon-alpha (IFN-alpha). However, the time course of appearance of these effects remains unclear, and their precise nature is still incompletely characterized. The objective of this study was to assess and characterize the early cognitive changes induced by IL-2 and IFN-alpha in cancer patients at the end of the first week of treatment and to investigate the subsequent evolution of these changes. METHODS: The study was conducted in 47 cancer patients who received subcutaneous IL-2, administered alone (N = 17) or with IFN-alpha (N = 7), or IFN-alpha alone, administered subcutaneously at low doses (N = 7) or intravenously at high doses (N = 16). An automated battery of neuropsychological tests (Cambridge Neuropsychological Test Automated Battery) was used to measure reaction time, spatial working memory, and planning tasks. Cognitive tests were performed before treatment (day 1) and after 5 days (day 5) and 1 month of treatment. RESULTS: On day 5, patients treated with IL-2 alone had impaired spatial working memory and lower accuracy of planning abilities. In contrast, patients treated with IFN-alpha did not show any impairment in performance accuracy in these tasks but showed longer latencies in the test of reaction time. Most of these early alterations persisted at the end of the first month of treatment without any obvious sign of worsening. CONCLUSIONS: These findings suggest the existence of early differential neuropsychological changes in patients treated with IL-2 and IFN-alpha.

Lowered serum dipeptidyl peptidase IV activity is associated with depressive symptoms and cytokine production in cancer patients receiving interleukin-2-based immunotherapy.

There is some evidence that treatment with interleukin-2 (IL-2) and interferon-alpha (IFNalpha) frequently induces depressive symptoms and activation of the inflammatory response system (IRS). There is evidence that major depression is accompanied by lowered serum activity of dipeptidyl peptidase IV (DPP IV; EC 3.4.14.5), a membrane-bound serine protease which catalyses the cleavage of some cytokines and neuro-active peptides and which modulates T cell activation and the production of cytokines, such as IL-2. This study was carried out to examine the effects of immunochemotherapy with IL-2 and IFNalpha, alone and together, in cancer patients on serum DPP IV activity in relation to changes in depressive symptoms and the IRS. The Montgomery and Asberg Rating Scale (MADRS), serum DPP IV activity, and the serum IL-6, and IL-2 receptor (IL-2R) concentrations were measured in 26 patients with metastatic cancers before and three and five days after treatment with IL-2 and IFNalpha, alone or together. Treatment with IL-2 with or without IFNalpha significantly suppressed serum DPP IV activity. The MADRS scores were significantly elevated by treatment with IL-2 with or without IFNalpha, but not IFNalpha alone. The immunochemotherapy-induced decreases in serum DPP IV were significantly and inversely correlated with the increases in the MADRS. Treatment with IL-2 alone or combined with IFNalpha also elevated serum IL-6 and IL-2R. There were significant and inverse correlations between the immuchemotherapy-induced decreases in serum DPP IV and the elevations in serum IL-6 or IL-2R. In conclusion, treatment with IL-2/IFNalpha decreases serum DPP IV activity within 3-5 days and the immunochemotherapy-induced decreases in serum DPP IV activity are significantly and inversely related to treatment-induced increases in severity of depression and signs of activation of the IRS.

Early depressive symptoms in cancer patients receiving interleukin 2 and/or interferon alfa-2b therapy.

PURPOSE: Depressive symptomatology is frequently associated with interleukin (IL)-2 and interferon alfa-2b (INFalpha-2b) therapy in cancer patients. The objective of the present study was to evaluate the depressive and anxiety symptoms induced by IL-2 and/or INFalpha-2b in cancer patients during the first days of cytokine immunotherapy. PATIENTS AND METHODS: The study included 48 patients with renal cell carcinoma or melanoma. Patients were treated either with subcutaneous IL-2, alone (n = 20) or in combination with INFalpha-2b (n = 6); or with INFalpha-2b alone, administered subcutaneously at a low dose (n = 8) or intravenously at a high dose (n = 14). Depressive symptoms were evaluated using the Montgomery and Asberg Depression Rating Scale (MADRS), and anxiety symptoms were evaluated using the Covi scale. Evaluations were performed just before initiation of treatment (day 1) and on days 3 and 5 of treatment. RESULTS: Patients treated with IL-2 alone or in association with INFalpha-2b had significantly higher MADRS scores after 5 days of cytokine therapy, and patients who received both cytokines had increased scores on day 3. In contrast, patients treated with INFalpha-2b alone did not have varying MADRS scores during the course of treatment. Cytokine therapy had no effect on anxiety, except in patients treated with IL-2 in combination with INFalpha-2b. In these patients, the enhancement in anxiety scores that was observed on day 5 was mainly attributable to increased somatic complaints. CONCLUSION: IL-2 and INFalpha-2b have differential effects on mood, and IL-2 therapy induces depressive symptoms early in treatment.

Attentional and mnemonic deficits associated with infectious disease in humans.

BACKGROUND: Infectious diseases are accompanied by behavioural and psychological changes that suggest the implication of the central nervous system. Among them, cognitive alterations have been reported, but their specificity and implication in everyday life are still largely unclear. The purpose of the present study was to evaluate and specify the everyday memory disturbances in sick human subjects and to determinate the role of fever in the appearance of these alterations. METHODS: The study was carried out in a military training centre for naval recruits. Ninety-one volunteer subjects, healthy (N = 30) or suffering from flu-like syndrome, with (N = 29) or without fever (N = 32), participated in this experiment and were administered a cognitive test (the ERBMT) according to a cross-sectional design for assessing various aspects of everyday memory. RESULTS: Sick subjects were specifically impaired in daily memory tasks that require the temporary management of a large amount of information. This impairment was similar for the feverish and apyretic sick subjects who both differed from the controls. CONCLUSION: These findings suggest that infectious disease disturbs the complex cognitive processes that might be associated with attentional functions. Moreover, these results show that fever is not a necessary condition for the appearance of these cognitive disturbances.

Cognitive sequelae of propofol anaesthesia.

As with any substance that interferes with nervous system functioning, anaesthetics are likely to have neural effects the duration of which extend beyond the acute loss of consciousness. Studies of recovery after anaesthesia have shown that physiological effects and psychomotor functions return to pre-anaesthesia levels within at most 90 min of the cessation of propofol administration. To date no report has been published concerning the possible longer term effects of propofol anaesthesia on higher cognitive functions such as learning, language, reasoning and planning. We evaluated a range of cognitive tasks (short and long-term memory, attention, language comprehension and planning) up to 6 h after cessation of Propofol administration, and found that this set of cognitive functions was still depressed after 3 h, but had recovered by 6 h. The results suggest that, for their security, patients should be remain in a supervised environment for at least 3 h after propofol anaesthesia, and that oral information to patients within those 3 h should be avoided.