Emerging Benefits: Pathophysiological Functions and Target Drugs of the Sigma-1 Receptor in Neurodegenerative Diseases.

The sigma-1 receptor (Sig-1R) is encoded by the SIGMAR1 gene and is a nonopioid transmembrane receptor located in the mitochondrial-associated endoplasmic reticulum membrane (MAM). It helps to locate endoplasmic reticulum calcium channels, regulates calcium homeostasis, and acts as a molecular chaperone to control cell fate and participate in signal transduction. It plays an important role in protecting neurons through a variety of signaling pathways and participates in the regulation of cognition and motor behavior closely related to neurodegenerative diseases. Based on its neuroprotective effects, Sig-1R has now become a breakthrough target for alleviating Alzheimer's disease and other neurodegenerative diseases. This article reviews the most cutting-edge research on the function of Sig-1R under normal or pathologic conditions and target drugs of the sigma-1 receptor in neurodegenerative diseases.

[The effect of pectin of tansy, Tanacetum vulgare L., on anxiety and overeating food rich in fats and sugars in mice in modelling binge eating].

Binge eating is repeated episodes of eating large amounts of sweet and fatty food in short periods. Dietary fibers, including pectin, significantly reduce the subjective ratings of hunger, and the amount of food eaten. However, studies showing the effect of dietary fibers on satiety use juices or yoghurts with added dietary fiber, or a kissel-like food. Thus, there is a lack of data on the effect of dietary fibres on binge eating of palatable food. The aim of the study was to assess the effect of tansy pectin on anxiety and the binge eating of palatable food in mice. Material and methods. 64 mice weighing 33.3±0.6 g were divided into two groups. Binge eating was induced in forty mice of the first group by consumption of sunflower halva (SH) in addition to regular chow for 24 h once a week. The total energy intake and separately the consumption of regular chow (RC) and SH were monitored. Tansy pectin in the form of an aqueous solution was administered to the mice using a gastric feeding tube (50 mg/kg body weight) before the last presentation of SH. Blood was obtained by cardiac puncture at the end of the last 24 h SH access period. The concentration of insulin and ghrelin in plasma samples were determined by the enzyme immunoassay. In animals of the second group, 24 hours after the administration of pectin, the level of anxiety and depression of mice was assayed with an open field test, a light-dark box test, an elevated plus-maze test, and a forced swim test. Throughout the study, water was used as a negative control, and imipramine at a dose of 20 mg/kg was used as a positive control. Results. Mice treated with tansy pectin ate 2.6 fold less SH within 3 h and 1.4 fold less within 24 h after oral administration of tansy pectin compared to control (water administration). Consumption of RC did not differ within 3 or 24 h. The total energy intake was 1.9 fold lower within 3 h in mice treated with tansy pectin. Within 24 h after pectin oral administration the total energy intake did not differ from control. Insulin plasma level was 2.5 fold lower and ghrelin plasma concentration was 25% higher in the mice that received pectin compared to control, at the end of the 24 h SH access period. The administration of tansy pectin was found to decrease anxietyrelated behaviour in mice. Its administration significantly increased the time spent in the central sector of the open field apparatus by 87%, the time spent in the light area of the light-dark box by 31%, and the time spent on the open arms of the elevated plus maze by 22% compared with the control. Conclusion. Overall, tansy pectin reduced the binge eating of SH representing highly palatable, sweet, and fatty food. Reduced intake SH lead to a decrease in insulin concentration. Blood level of ghrelin was increased in mice treated with tansy pectin at the end of the sweet and fatty food presentation period. Tansy pectin reduced the level of anxiety in mice.

Severe and prolonged hypophosphatemia after intravenous iron administration in a malnourished patient.

Malnutrition may result in a phosphate-deficient state owing to a chronically insufficient phosphate intake. Concomitant iron deficiency is common and often supplemented by the intravenous route. It is not widely recognized that some parenteral iron formulations can induce hypophosphatemia. Herein we report a case of a severe and symptomatic hypophosphatemia (0.18 mM, normal range 0.8-1.4 mM) associated with an inappropriately reduced tubular reabsorption of phosphate (33%, norm >95%) in a malnourished patient with anorexia/bulimia who received 2 × 500 mg iron carboxymaltose (FCM) intravenously. Despite intravenous and oral phosphate supplements, it required 2 months to achieve a normal serum phosphate level. Our case demonstrates that in a chronically malnourished and phosphate-deficient state intravenous FCM could potentially be dangerous. If this form of iron application cannot be avoided, phosphate supplementation before and after iron infusion as well as close monitoring of phosphate levels are needed.

Effect of salidroside, active principle of Rhodiola rosea extract, on binge eating.

Stress is a key determinant of binge eating (BE). Since Rhodiola rosea is known to modulate stress responses, its effect in a model of BE was investigated. BE for highly palatable food (HPF) was evoked in female rats by three 8-day cycles of food restriction/re-feeding (for 4days 66% of the usual chow intake; for 4days food ad libitum) and acute stress on the test day (day 25). R. rosea dry extract (3% rosavin, 3.12% salidroside) or its active principles were given by gavage 1h before access to HPF. Only rats exposed to both food restrictions and stress exhibited BE in the first 15-60min after the stressful procedure. R. rosea extract 10mg/kg significantly reduced and 20mg/kg abolished the BE episode. R. rosea extract 20mg/kg abolished also stress-induced increase in serum corticosterone levels. The R. rosea active principle salidroside, but not rosavin, at doses present in the extract, dose-dependently reduced or abolished BE for the period in which it was elicited. In conclusion results indicate that R. rosea extracts may have therapeutic properties in bingeing-related eating disorders and that salidroside is the active principle responsible for this effect.

Acute methylphenidate treatments reduce sucrose intake in restricted-fed bingeing rats.

Recent evidence suggests that methylphenidate HCl may be effective at limiting the frequency and the amount of binge eating. The present study investigated if daily treatments with methylphenidate reduced the bingeing-like behavior observed in restricted-fed adult male rats. Three groups (n = 6) received peripheral injections of methylphenidate in doses of 1.5 or 0.75 mg/kg/day, or saline, 3 days prior and 7 days during a previously characterized intermittent feeding regimen that results in a gradual increase of sucrose and food intake. The higher, but not the lower, dose of methylphenidate reduced sucrose intake to an asymptotic level starting after 3 days of the feeding protocol and concurrently led to an increase in the intake of chow. The high dose methylphenidate group also had two-fold lower plasma insulin levels compared with the saline-treated animals at the time of sacrifice on the last day of the feeding regimen. Further histological assays revealed that the methylphenidate treatments, irrespective of the dose used, resulted in selectively higher dopamine transporter and D2-like receptor labeled bindings in the shell region of the nucleus accumbens. These results suggest that relatively low-dose methylphenidate treatments may be effective for the management of binge eating by reducing the intake of palatable foods and may not interfere with short-term regulation of energy balance. These findings further support the notion that the mesoaccumbens dopamine system plays an important role in restricted access-induced sucrose bingeing in this rat model.

The eating disorders medicine cabinet revisited: a clinician's guide to appetite suppressants and diuretics.

OBJECTIVE: This article explores the frequencies of use of alternative medications, available products, and their potential toxicities. METHOD: Survey data were gathered from 39 consecutive patients diagnosed with bulimia nervosa who were seeking treatment. A survey of area outlets (health food stores, pharmacies, grocery stores) was conducted to establish a database of available agents. Putative active ingredients were identified. MEDLINE literature searches, as well as reviews of specialized texts, were performed to identify the potential toxicities of the ingredients. RESULTS: Diet pill use was found in 64% of patients; 18 % reported use in the past month. The survey identified 167 products. Diuretic use was found in 31% of patients; 21% reported use in the past month. Twenty-five diuretic products were identified. DISCUSSION: Alternative medicines are frequently used in the population of patients seeking treatment for bulimia nervosa. An abundance of products are available with potentially significant toxicities.

Eating disorders: a review of the literature with emphasis on medical complications and clinical nutrition.

Eating disorders, including anorexia nervosa, bulimia nervosa, binge-eating disorder, and atypical eating disorder (eating disorder not otherwise specified or NOS), are estimated to occur in 5-10 million young and adult women and one million males in the United States. The etiology of eating disorders is complex and appears to include predisposing genetic factors and serotonin dysregulation, as well as psychological factors that include a history of trauma and childhood sexual abuse. Both anorexia nervosa and bulimia nervosa are medical conditions complicated by multiple neuroendocrine dysfunctions, nutritional deficiencies, and psychiatric diagnoses. Medical complications, specific nutritional deficiencies, and research involving the therapeutic use of inositol and zinc are reviewed.

Bulimia nervosa. A treatment concept implying an "integrative painting therapy".

At the Department of Psychiatry, University Hospital Graz, we have been applying a concept for treating bulimia nervosa, using a complementary method involving psychosocial and psychotherapeutic strategy as well as psychotropic medication. Thus we have been able to approach the patients from a holistic view. Painting and drawing as a creative method constitute another salient part of our concept. Between January 1995 and September 1999, 36 in-patients with bulimia were treated in the Psychotherapy Unit of the University Hospital's Department of Psychiatry in Graz; our concept focussed on "Integrative Painting Therapy". The wide variety of treatment methods comprised individual and group therapy, diet counselling and thymoleptics (SSRIs). Teamwork and close links within the team constituted an important part of our work, so that the different types of therapy are process-oriented and thus interrelated. In the initial phase of the symptom-oriented approach patients learn to control and ultimately normalise their eating habits. In the phase of acting out and/or conflict awareness, they try to cope with their disorder on a pictorial level. They gain access to their emotions and become aware of their problems, while their eating habits improve. Self-esteem is eventually stabilised and patients develop a sense of self-responsibility and work on effective strategies to cope with their disorder. This development also manifests itself in their pictorial expressions. "Integrative Painting Therapy" led to a marked improvement of the depressive moods initially prevalent in all patients. It also slightly elevated their Body Mass Index. Moreover, control capacity increased significantly, irregularities in eating habits were reduced and craving for food subsided.

Divergent responses to fluoxetine from two compulsive, food-related conditions: bulimia nervosa and compulsive water drinking.

BACKGROUND: The association of compulsive water drinking with bulimia nervosa is rarely encountered. Nevertheless similar behavior patterns could involve a common pathophysiological mechanism. METHODS: A case report with the association of those two disorders is described. Treatment with fluoxetine was introduced to alleviate the compulsive aspects of those disorders. RESULTS: Fluoxetine had a positive effect on bulimia nervosa but none on compulsive water drinking. CONCLUSIONS: The different response to pharmacologic treatment could mean that bulimia nervosa and compulsive water drinking are based on different physiological mechanisms.

Neurobiological and psychopharmacological basis in the therapy of bulimia and anorexia.

1. Eating disorders can be found in several psychiatric pathologies: schizophrenia, delusional disorder (somatic type), bipolar disorders, major depressive disorder, borderline personality disorder, generalized anxiety disorder, body dysmorphic disorder, somatization disorder and conversion disorder. 2. Although their clinical features have been defined, relatively little is known about the role of neurobiological patterns in the pathogenesis of these disorders. Several CNS neurotransmitters and neuromodulators are involved in the regulation of eating behavior in animals and have been implicated in symptoms such as depression and anxiety often observed in patients with eating disorders. The authors will review some studies on NA, DA, 5-HT, beta-endorphins, CRH, VP, OT, CCK, NPY and PYY involved in eating disorders. Furthermore, we will highlight some of the studies on drug therapy of eating disorders taking into account the effects of these agents on neurotransmitters and neuromodulators. 3. Antidepressant drugs have long been used for anorexia nervosa and bulimia, these disorders been claimed to be affective equivalent. Antidepressant agents seem to be effective in reducing the frequency of binge-eating episodes, purging behavior and depressive symptomatology. It is notable that antidepressant agents have been proved to be effective in patients with chronic bulimic symptoms, even in cases persisting for many years and in patients who had repeatedly failed courses of alternative therapeutic approaches. In all of the positive studies, antidepressant agents appeared effective even in bulimic subjects who did not display concomitant depression. 4. Few controlled studies on use of medications for anorexia nervosa have been published. Central serotonergic receptor-blocking compounds such as cyproheptadine cause marked increase in appetite and body weight. Zinc supplementation or cisapride could be a therapeutic option in addition to psychological and other approaches in anorexia nervosa. 5. There is no therapy as yet which is fully effective in alimentary disorders. Psychotropic drugs give some relief from symptoms, but they cannot cure the disorders. An integrated approach, either pharmacological or psychological, is still recommendable.

Combined cognitive-behavioral, psychopharmacological and nutritional therapy in eating disorders. 2. Anorexia nervosa--binge-eating/purging type.

Thirteen women with anorexia nervosa, binge-eating/purging type (AN-BP), 17-43 years old, were treated with a 4-month course of combined cognitive-behavioral, nutritional and antidepressant therapy (7 with amineptine and 6 with fluoxetine). Patients were monitored before and after 1, 2 and 4 months of treatment for body mass index (BMI), for eating disorder symptoms by the Eating Disorder Inventory (EDI) and the Bulimic Investigation Test (BITE) and for depression and anxiety by the Hamilton Rating Scales for Depression and for Anxiety. BMI, EDI scores, depression and anxiety improved significantly and equally in the two groups during the 4 months of therapy, while BITE scores did not change.

Combined cognitive-behavioral, psychopharmacological and nutritional therapy in bulimia nervosa.

Fifteen women with bulimia nervosa were treated with a 4-month course of combined cognitive-behavioral, nutritional and antidepressant therapy (5 with amineptine and 10 with fluvoxamine). Patients were monitored before and after 1, 2 and 4 months of therapy for body mass index (BMI), for eating disorder symptoms by the Eating Disorder Inventory (EDI) and the Bulimic Investigation Test (BITE), and for depression and anxiety by the Hamilton Rating Scale for Depression and for Anxiety (HRS-D and -A). BITE symptoms and gravity improved significantly and equally in the two groups during the 4 months of therapy. Global EDI scores, depression and anxiety decreased but not significantly. BMI was normal before therapy and did not change during treatment.

[The role of serotonin in normal appetite regulation and in the pathogenesis of anorexia/bulimia]. / Serotonins rolle i normal appetittregulering og i patogenesen ved anorexi/bulimi.

Evidence accumulated over the past two decades indicates the existence of several neurochemical systems that influence feeding behavior. The central region regulating appetite is thought to be in the hypothalamus, where different monoaminergic systems are localized. It has been suggested that altered function in these systems is taking part in the pathogenesis of anorexia and bulimia nervosa. According to these theoretical principles and to the development of specific monoaminergic and anti-monoaminergic drugs, the pharmacological treatment of eating disorders can become more successful in the future. This article discusses the role of serotonin in appetite regulation and presents new evidence that a dysfunction in hypothalamic serotonergic pathways can be an important part of the pathogenesis of anorexia and bulimia nervosa.