Impact of timing of the anorexigen sibutramine administration on reproductive end-points of male rats.

Sibutramine is a non-selective serotonin-norepinephrine reuptake inhibitor orally administered for weight loss. In a previous study, we showed pharmacological mechanisms involved in the reduction of sperm quality and fertility of rats exposed for 30 days to this anorexigen in the light phase of the light-dark (l/d) cycle. It is already known that rodents are nightlife animals, with higher metabolic activity during the dark phase than in the light phase of the light-dark (l/d) cycle. Thus, the present study aimed to investigate whether the deleterious effects on reproductive parameters after sibutramine administration would be enhanced after a shorter period of exposure during the dark phase of the l/d cycle. For this, adult male Wistar rats were treated with sibutramine (10 mg/kg/d) or vehicle for 15 days during the dark phase of the l/d cycle. Sibutramine treatment decreased final body and reproductive organ weights, as well as serum testosterone levels. Sperm transit time through the epididymis was accelerated, and sperm concentration and motility were diminished in the sibutramine-exposed rats. The decrease in sperm concentration was also verified in the epididymal histological sections. In conclusion, the deleterious effects of sibutramine on reproductive parameters of male rats were enhanced when the exposure occurred in the dark phase of the l/d cycle, even after a short exposure duration. Our results reinforce the impact of timing on drug therapeutic action.

Omega-3 fatty acids and mood stabilizers alter behavioral and oxidative stress parameters in animals subjected to fenproporex administration.

Studies have shown that oxidative stress is involved in the pathophysiology of bipolar disorder (BD). It is suggested that omega-3 (ω3) fatty acids are fundamental to maintaining the functional integrity of the central nervous system. The animal model used in this study displayed fenproporex-induced hyperactivity, a symptom similar to manic BD. Our results showed that the administration of fenproporex, in the prevent treatment protocol, increased lipid peroxidation in the prefrontal cortex (143%), hippocampus (58%) and striatum (181%), and ω3 fatty acids alone prevented this change in the prefrontal cortex and hippocampus, whereas the co-administration of ω3 fatty acids with VPA prevented the lipoperoxidation in all analyzed brain areas, and the co-administration of ω3 fatty acids with Li prevented this increase only in the prefrontal cortex and striatum. Moreover, superoxide dismutase (SOD) activity was decreased in the striatum (54%) in the prevention treatment, and the administration of ω3 fatty acids alone or in combination with Li and VPA partially prevented this inhibition. On the other hand, in the reversal treatment protocol, the administration of fenproporex increased carbonyl content in the prefrontal cortex (25%), hippocampus (114%) and striatum (91%), and in prefrontal coxter the administration of ω3 fatty acids alone or in combination with Li and VPA reversed this change, whereas in the hippocampus and striatum only ω3 fatty acids alone or in combination with VPA reversed this effect. Additionally, the administration of fenproporex resulted in a marked increase of TBARS in the hippocampus and striatum, and ω3 fatty acids alone or in combination with Li and VPA reversed this change. Finally, fenproporex administration decreased SOD activity in the prefrontal cortex (85%), hippocampus (52%) and striatum (76%), and the ω3 fatty acids in combination with VPA reversed this change in the prefrontal cortex and striatum, while the co-administration of ω3 fatty acids with Li reversed this inhibition in the hippocampus and striatum. In conclusion, our results support other studies showing the importance of ω3 fatty acids in the brain and the potential for these fatty acids to aid in the treatment of BD.

Anorexic action of deoxynivalenol in hypothalamus and intestine.

Although deoxynivalenol (DON) suppresses food intake and subsequent weight gain, its contribution to anorexia mechanisms has not been fully clarified. Thus, we investigated the anorexic actions of DON in the hypothalamus and intestine, both organs related to appetite. When female B6C3F1 mice were orally exposed to different doses of DON, a drastic anorexic action was observed at a dose of 12.5 mg/kg body weight (bw) from 0 to 3 h after administration. Exposure to DON (12.5 mg/kg bw) for 3 h significantly increased the hypothalamic mRNA levels of anorexic pro-opiomelanocortin (POMC) and its downstream targets, including melanocortin 4 receptor, brain-derived neurotrophic factor, and tyrosine kinase receptor B; at the same time, orexigenic hormones were not affected. In addition, exposure to DON significantly elevated the hypothalamic mRNA levels of proinflammatory cytokines (IL-1ß, TNF-α, and IL-6) and activated nuclear factor-kappa B (NF-κB), an upstream factor of POMC. These results suggest that DON-induced proinflammatory cytokines increased the POMC level via NF-κB activation. Moreover, exposure to DON significantly enhanced the gastrointestinal mRNA levels of anorexic cholecystokinin (CCK) and transient receptor potential ankyrin-1 channel (TRPA1), a possible target of DON; these findings suggest that DON induced anorexic action by increasing CCK production via TRPA1. Taken together, these results suggest that DON induces anorexic POMC, perhaps via NF-κB activation, by increasing proinflammatory cytokines in the hypothalamus and brings about CCK production, possibly through increasing intestinal TRPA1 expression, leading to anorexic actions.

Screening and determination of sibutramine in adulterated herbal slimming supplements by HPTLC-UV densitometry.

The adulteration of herbal supplements is of growing importance, especially when they contain undeclared compounds like sibutramine that are unsafe drugs. Sibutramine was withdrawn from US and European markets in 2010. In this study, an HPTLC-UV densitometric method was developed for the quantification of sibutramine in herbal diet foods. Sample extracts were directly applied onto HPTLC silica gel plates and separated with a mobile phase made of a toluene-methanol mixture. Sibutramine was quantified at 225 nm and its unequivocal identification was confirmed by MS using a TLC-MS interface. During two surveys, 52 weight loss supplements obtained via the Internet were screened. Half of those were adulterated with sibutramine at amounts reaching up to 35 mg per capsule. The results of this validated HPTLC method were compared with those obtained by HPLC-UV and HPLC-MS/MS. The results were not significantly different with the three methods.

Safety assessment of a hydroethanolic extract of Caralluma fimbriata.

This toxicological assessment evaluated the safety of a hydroethanolic extract prepared from Caralluma fimbriata (CFE), a dietary supplement marketed worldwide as an appetite suppressant. Studies included 2 in vitro genotoxicity assays, a repeated dose oral toxicity study, and a developmental study in rats. No evidence of in vitro mutagenicity or clastogenicity surfaced in the in vitro studies at concentrations up to 5000 µg of extract/plate (Ames test) or 5000 µg of extract/mL (chromosomal aberration test). No deaths or treatment-related toxicity were seen in the 6-month chronic oral toxicity study in Sprague-Dawley rats conducted at 3 doses (100, 300, and 1000 mg/kg body weight (bw)/d). The no observed effect level for CFE in this study was considered to be 1000 mg/kg bw/d. A prenatal developmental toxicity study conducted at 3 doses (250, 500, and 1000 mg/kg bw/d) in female Sprague-Dawley rats resulted in no treatment-related external, visceral, or skeletal fetal abnormalities, and no treatment-related maternal or pregnancy alterations were seen at and up to the maximum dose tested. CFE was not associated with any toxicity or adverse events.

Rats on a high-energy diet showing no weight gain present with ultrastructural changes associated with liver fibrosis.

Sibutramine is widely used as a weight-loss substance in the treatment of obesity and is a selective inhibitor of the neuronal reuptake of serotonin and noradrenaline. Although banned, it is often a hidden ingredient in herbal and dietary supplements that are widely used by the general public. Various weight loss products, including sibutramine, have successfully been tested in animal models of diet-induced obesity. In the female Sprague-Dawley rat model, fed a high-energy diet that did not produce a significant increase in BMI, the cellular structure of the liver was evaluated using transmission electron microscopy. Compared to controls showing no damage, the livers of rats fed a high-energy diet were found to have increased fibrosis without steatosis, while for rats fed high-energy diet with sibutramine, fibrosis was increased and steatosis had developed. In conclusion, in female rats fed a high-energy diet that does not result in weight gain hepatic fibrosis occurs without steatosis. In these rats the co-administration of sibutramine increases the degree of fibrosis and steatosis develops. Although it has been widely believed that sibutramine is not hepatotoxic, this study clearly shows that at an ultrastructural level, rats fed a high-energy diet treated with sibutramine show signs of hepatotoxicity.

The identification of neuropeptide Y receptor subtype involved in phenylpropanolamine-induced increase in oxidative stress and appetite suppression.

Hypothalamic neuropeptide Y (NPY) and superoxide dismutase (SOD) have been reported to participate in the regulation of appetite-suppressing effect of phenylpropanolamine (PPA), a sympathomimetic agent. This study explored whether Y1 receptor (Y1R) and/or Y5 receptor (Y5R) was involved in this regulation. Wistar rats were treated with PPA for 24 h. Changes in food intake and hypothalamic NPY, Y1R, Y5R, and SOD contents were assessed and compared. Results showed that food intake and NPY contents were decreased following PPA treatment, while Y1R and SOD contents were increased and Y5R contents remained unchanged. Moreover, although Y1R or Y5R knockdown by themselves could modify the food intake, Y1R but not Y5R knockdown could modify PPA-induced anorexia as well as NPY and SOD contents. In addition, selective inhibition of Y1R but not Y5R could modulate PPA-induced anorexia. It is suggested that Y1R but not Y5R participates in the anorectic response of PPA via the modulation of NPY and SOD. Results provide molecular mechanism of NPY-mediated PPA anorexia and may aid the understanding of the toxicology of PPA.

Safety profile of Hoodia gordonii extract: mouse prenatal developmental toxicity study.

Hoodia gordonii extract (0, 5, 15 or 50mg/kg body weight/day, n=24 mice/group) was orally administered by gavage to female CD-1 mice from gestation days 5-17. On gestation day 18 the females were euthanized and examined. Treatment at 50mg/kg/day caused a marked reduction in feed intake and body weight gain. Feed consumption was sporadically reduced at 15 mg/kg/day. At 50 or 15 mg/kg/day fetal weights, ossification of some bones and full and empty uterus weights were reduced. There were no clear maternal or fetal effects at 5mg/kg/day. Reproductive indices were unaffected at all doses and there were no treatment-related malformations, anomalies or variations. The overall study no-observed-adverse-effect level was set at 5mg/kg/day. In summary, at doses that reduced maternal feed consumption, H. gordonii extract delayed fetal development. The fetal effects seen could be consequent to reduced maternal feed consumption, the desired biological activity of the test item.

Safety profile of Hoodia gordonii extract: rabbit prenatal developmental toxicity study.

Hoodia gordonii extract was orally administered by gavage to groups of 22 female New Zealand white rabbits from day 3-28 after mating at doses of 0 (control), 3, 6 or 12 mg/kg bodyweight/day. These doses were reached by a dose escalation phase between days 3 and 7 after mating. As well as a vehicle control group, a control group pair-fed to the high dose was also included. On day 29 after mating the females were euthanized and examined. Treatment at 6 or 12 mg/kg/day was associated with a dose-related reduction in feed intake and bodyweight gain. Feed consumption and bodyweight gain was unaffected at 3mg/kg/day. In spite of marked maternal effects at 12 mg/kg/day, reproductive indices were unaffected at all doses and there were no effects on fetal or placental weights and no morphological changes in the fetuses. The no-observed-effect level (NOEL) for developmental effects was therefore 12 mg/kg/day, and the maternal NOEL was 3mg/kg/day. At doses that caused marked maternal effects, H. gordonii extract did not affect embryonic or fetal development in a species that is considered predictive of developmental toxicity in man.

Genotoxicity testing of a Hoodia gordonii extract.

Hoodia gordonii extract consists of a mixture of steroid glycosides, fatty acids, plant sterols and alcohols. As part of the overall safety assessment H. gordonii extract was assessed for genotoxicity in two assays in vitro: a bacterial mutation assay; and a gene mutation assay using mouse lymphoma cells. H. gordonii extract showed no evidence of genotoxic activity in either of these assays. In addition, H. gordonii extract was assessed for mutagenic activity in a bone marrow micronucleus (MN) assay in the mouse, with 400mg/kg selected as the high-dose group, based on observations in a dose-range-finding study. The group mean frequencies of micronucleated polychromatic erythrocytes of treated animals were similar to those of the vehicle control group, indicating H. gordonii extract to be non-genotoxic under the conditions of this test. All assays were performed in compliance with the Good Laboratory Practice Regulations and in accordance with standard guidelines for genotoxicity tests. H. gordonii extract was shown to be non-genotoxic in 3 independent assays (a bacterial mutation test, a gene mutation assay using mouse lymphoma cells and a bone marrow micronucleus assay in the mouse).

Drug-induced valvulopathy: an update.

Drug-induced valvulopathy is a serious liability for certain compound classes in development and for some marketed drugs intended for human use. Reports of valvulopathy led to the withdrawal of fenfluramines (anorexigens) and pergolide (antiparkinson drug) from the United States market in 1997 and 2007, respectively. The mechanism responsible for the pathogenesis of valvulopathy by these drugs is likely a result of an "off-target" effect via activation of 5-hydroxytryptamine (5-HT) 2B receptor (5-HT2BR) expressed on heart valve leaflets. Microscopically, the affected valve leaflets showed plaques of proliferative myofibroblasts in an abundant extracellular matrix, composed primarily of glycosaminoglycans. However, the valvular effects caused by fenfluramines and pergolide were not initially predicted from routine preclinical toxicity studies, and to date there are no specific validated animal models or preclinical/toxicologic screens to accurately predict drug-induced valvulopathy. This review covers the structure and function of heart valves and highlights major advances toward understanding the 5-HT2BR-mediated pathogenesis of the lesion and subsequently, development of appropriate animal models using novel techniques/experiments, use of functional screens against 5-HT2BR, and more consistent sampling and pathologic evaluation of valves in preclinical studies that will aid in avoidance of future drug-induced valvulopathy in humans.

Hepatotoxicidad inducida por el uso de hierbas y medicamentos para perder peso / Hepatotoxicity induced by herbs and medicines used to induce weight loss

En los últimos años ha aparecido un considerable númerode publicaciones en la literatura médica sobre la hepatotoxicidadasociada a productos herbarios a los que se ha atribuidoun efecto adelgazante. La expresión clínica de hepatotoxicidadha oscilado entre cuadros de hepatitis autolimitada,indistinguibles de los causados por los virus de la hepatitis,hasta formas de hepatitis fulminante que han causadomuerte o han requerido un trasplante hepático. Estos productos,que se venden como productos dietéticos o suplementosdietéticos, no pasan los controles de seguridad a quese somete a los fármacos antes de su comercialización, por loque la prevención de sus efectos tóxicos exige un mejor conocimientodel público para que evite su empleo, ya que susbeneficios nunca han sido comprobados, y una actuación decididade los médicos para que contribuyan a disuadir de suempleo a sus pacientes. Una regulación estricta de la autorizaciónde la comercialización de todos estos productos, denominadosnaturales, es muy necesaria para minimizar losdaños que pueden causar (AU)

In the last few years, a considerable number of reports havebeen published on hepatotoxicity associated with herbalproducts attributed with weight-reducing properties. Clinicalexpression of hepatotoxicity has ranged from symptomsof self-limiting hepatitis, indistinguishable from those causedby the hepatitis viruses, to forms of fulminant hepatitiscausing death or requiring liver transplantation.These products, which are sold as dietary products or supplements,do not undergo the safety tests required of drugsbefore their release on to the market. To prevent the toxiceffects of herbal products, the general public should bemade aware of their harmful effects and – since the benefitsof these products have not been demonstrated – avoid theiruse, while physicians should strongly discourage patientsfrom taking these products. Authorization of the commercializationof all these “natural” products should be strictlyregulated to minimize the harm they can cause (AU)

O uso de complexos emagrecedores por mulheres em idade reprodutiva e suas implicações na gravidez / The use of complexes to treat the obesityby women in reproductive age and its implications on gestation

Os padrões atuais de beleza têm estimulado o uso de complexos emagrecedores, principalmente por mulheres em idade reprodutiva. Como uma grande parte das gestações não é planejada, esta conduta pode resultar em dano para o embrião/feto. Este trabalho analisa os efeitos dos componentes dessas formulações na gravidez. Foi feita uma revisão da literatura, consultando a bibliografia da área e os bancos de dados PubMed, MedLine, ScienceDirect e Micromedex. Os complexos emagrecedores contêm estimulantes do sistema nervoso central- os anorexígenos (derivados da anfetamina, como femproporex) e os antidepressivos (fluoxetina); depressores do sistema nervoso central (benzodiazepínicos); diuréticos, e produtos de origem vegetal. Os fármacos derivados da anfetamina não devem ser teratogênícos, mas o femproporex demonstrou efeitos adversos na implantação. Já fluoxetina promove a síndrome de abstinência neonatal, enquanto o diazepam pode causar fendas orais, baixo peso ao nascer e mudanças neurocomportamentais. Diuréticos, como furosemida, provocaram anomalias esqueléticas em ratos pela depleção de potássio, e o hidroclorotiazida causa complicações na mãe e no feto. Atualmente, há poucos estudos sobre a segurança no uso das plantas medicinais. Por causa dos diversos efeitos sobre o embrião/feto, as mulheres que fazem uso de complexos emagrecedores devem ser alertadas para os riscos em caso de concepção.

Hepatotoxicidad inducida por el uso de hierbas y medicamentos para perder peso / Hepatotoxicity induced by herbs and medicines used to induce weight loss

En los últimos años ha aparecido un considerable númerode publicaciones en la literatura médica sobre la hepatotoxicidadasociada a productos herbarios a los que se ha atribuidoun efecto adelgazante. La expresión clínica de hepatotoxicidadha oscilado entre cuadros de hepatitis autolimitada,indistinguibles de los causados por los virus de la hepatitis,hasta formas de hepatitis fulminante que han causadomuerte o han requerido un trasplante hepático. Estos productos,que se venden como productos dietéticos o suplementosdietéticos, no pasan los controles de seguridad a quese somete a los fármacos antes de su comercialización, por loque la prevención de sus efectos tóxicos exige un mejor conocimientodel público para que evite su empleo, ya que susbeneficios nunca han sido comprobados, y una actuación decididade los médicos para que contribuyan a disuadir de suempleo a sus pacientes. Una regulación estricta de la autorizaciónde la comercialización de todos estos productos, denominadosnaturales, es muy necesaria para minimizar losdaños que pueden causar

In the last few years, a considerable number of reports havebeen published on hepatotoxicity associated with herbalproducts attributed with weight-reducing properties. Clinicalexpression of hepatotoxicity has ranged from symptomsof self-limiting hepatitis, indistinguishable from those causedby the hepatitis viruses, to forms of fulminant hepatitiscausing death or requiring liver transplantation.These products, which are sold as dietary products or supplements,do not undergo the safety tests required of drugsbefore their release on to the market. To prevent the toxiceffects of herbal products, the general public should bemade aware of their harmful effects and – since the benefitsof these products have not been demonstrated – avoid theiruse, while physicians should strongly discourage patientsfrom taking these products. Authorization of the commercializationof all these “natural” products should be strictlyregulated to minimize the harm they can cause

Transcript of protein kinase A knock-down modulates feeding behavior and neuropeptide Y gene expression in phenylpropanolamine-treated rats.

Neuropeptide Y (NPY) is an appetite-controlling neuromodulator that contributes to the appetite-suppressing effect of phenylpropanolamine (PPA). Aims of this study were to investigate whether protein kinase A (PKA) signaling is involved in regulating NPY gene expression and PPA-induced anorexia. Rats were given daily with PPA for 5 days. Changes in daily food intake and hypothalamic NPY, PKA, cAMP response element binding protein (CREB), and pro-opiomelanocortin (POMC) gene expression were measured and compared. To further determine if PKA was involved, intracerebroventricular infusions of antisense oligodeoxynucleotide were performed at 60 min before daily PPA treatment in freely moving rats. Results showed that daily PKA, CREB, and POMC expression were increased following PPA treatment, which showed a closely reverse relationship with alterations of decreased feeding behaviors and NPY mRNA levels. Results also showed that PKA knock-down could block PPA-induced anorexia as well as restore NPY mRNA level, indicating the involvement of PKA signaling in the regulation of NPY gene expression. It is suggested that hypothalamic PKA signaling may participate in the central regulation of PPA-mediated appetite suppression via the modulation of hypothalamic NPY gene expression. The present findings reveal that manipulations at the molecular level of PKA or cAMP may allow the development of therapeutic agents to improve the undesirable properties of PPA or other amphetamine-like anorectic drugs.

Safety assessment of (-)-hydroxycitric acid and Super CitriMax, a novel calcium/potassium salt.

(-)-Hydroxycitric acid (HCA) is a principle constituent (10-30%) of the dried fruit rind of Garcinia cambogia, a plant native to Southeastern Asia. The dried rind has been used for centuries throughout Southeast Asia as a food preservative, flavoring agent and carminative. Extensive experimental studies show that HCA inhibits fat synthesis and reduces food intake. The objective of this review is to systematically review the available safety/toxicity literature on HCA to determine its safety in-use. The primary mechanism of action of HCA appears to be related to its ability to act as a competitive inhibitor of the enzyme ATP-citrate lyase, which catalyzes the conversion of citrate and coenzyme A to oxaloacetate and acetyl coenzyme A (acetyl-CoA), primary building blocks of fatty acid and cholesterol synthesis. Super CitriMax, a novel calcium/potassium-HCA extract (HCA-SX), is considerably more soluble and bioavailable than calcium-based HCA ingredients. Acute oral toxicity studies in animals demonstrate that CitriMax (50% HCA as calcium salt) has a low acute oral toxicity. In a subchronic study in rats, the gavage administration of HCA-SX at doses up to 2500 mg/kg/day for a period of 90 days caused a significant decrease in body weight and reduction in feed consumption without any adverse effects. The structure, mechanism of action, long history of use of HCA and other toxicity studies indicate that HCA-SX is unlikely to cause reproductive or developmental effects. HCA-SX was not mutagenic in the presence or absence of metabolic activation in Ames genotoxicity assays in strains TA98 and TA102. HCA-SX-induced increases in number of revertants in other strains (TA100 and TA1535 in the absence of metabolic activation and in strain TA1537 in the presence of metabolic activation) but these were not considered as biologically indicative of a mutagenic effect. In several, placebo-controlled, double-blind trials employing up to 2800 mg/day HCA, no treatment-related adverse effects were reported. There is sufficient qualitative and quantitative scientific evidence, including animal and human data suggesting that intake of HCA at levels up to 2800 mg/day is safe for human consumption.

Safety and mechanism of appetite suppression by a novel hydroxycitric acid extract (HCA-SX).

A growing body of evidence demonstrates the efficacy of Garcinia cambogia-derived natural (-)-hydroxycitric acid (HCA) in weight management by curbing appetite and inhibiting body fat biosynthesis. However, the exact mechanism of action of this novel phytopharmaceutical has yet to be fully understood. In a previous study, we showed that in the rat brain cortex a novel HCA extract (HCA-SX, Super CitriMax) increases the release/availability of radiolabeled 5-hydroxytryptamine or serotonin ([3H]-5-HT), a neurotransmitter implicated in the regulation of eating behavior and appetite control. The aim of the present study was 2-fold: (a) to determine the effect of HCA-SX on 5-HT uptake in rat brain cortex in vitro; and (b) to evaluate the safety of HCA-SX in vivo. Isolated rat brain cortex slices were incubated in oxygenated Krebs solution for 20 min and transferred to buffer solutions containing [3H]-5-HT for different time intervals. In some experiments, tissues were exposed to HCA-SX (10 microM - 1 mM) and the serotonin receptor reuptake inhibitors (SRRI) fluoxetine (100 microM) plus clomipramine (10 microM). Uptake of [3H]-5-HT was expressed as d.p.m./mg wet weight. A time-dependent uptake of [3H]-5-HT occurred in cortical slices reaching a maximum at 60 min. HCA-SX, and fluoxetine plus clomipramine inhibited the time-dependent uptake of [3H]-5-HT. At 90 min, HCA-SX (300 microM) caused a 20% decrease, whereas fluoxetine plus clomipramine inhibited [3H]-5-HT uptake by 30%. In safety studies, acute oral toxicity, acute dermal toxicity, primary dermal irritation and primary eye irritation, were conducted in animals using various doses of HCA-SX. Results indicate that the LD50 of HCA-SX is greater than 5,000 mg/kg when administered once orally via gastric intubation to fasted male and female Albino rats. No gross toxicological findings were observed under the experimental conditions. Taken together, these in vivo toxicological studies demonstrate that HCA-SX is a safe, natural supplement under the conditions it was tested. Furthermore, HCA-SX can inhibit [3H]-5-HT uptake (and also increase 5-HT availability) in isolated rat brain cortical slices in a manner similar to that of SRRIs, and thus may prove beneficial in controlling appetite, as well as treatment of depression, insomnia, migraine headaches and other serotonin-deficient conditions.

Characteristics of BDNF-induced weight loss.

There is evidence that central infusion of brain-derived neurotrophic factor (BDNF) induces weight loss in rats. We have begun to investigate the physiological basis for BDNF-induced weight loss by assessing its relationship to (a) appetite, (b) serum indices of metabolic and renal toxicity, and (c) brain monoamine activity in areas associated with feeding or motor function. BDNF (0-6 microgram/day) was infused into the lateral ventricle (LV) of male Long-Evans rats for 14 days. Body weight and food intake were monitored throughout infusion and recovery periods. BDNF induced severe, dose-dependent appetite suppression and weight loss. Although appetite began to recover after the 10th infusion day, body weight had not returned to control values at the end of the recovery period. The weight loss observed in BDNF-infused rats was related to appetite suppression, since uninfused rats that were pair-fed to high dose BDNF-treated rats showed comparable weight loss. Despite severe weight loss, serum BUN, creatinine, thyroxine, glucose, and total protein were not affected by BDNF infusion. Striatal DO-PAC/DA was similarly unaffected by BDNF. In contrast, BDNF-infused rats showed a dose-dependent increase in hypothalamic 5-HIAA/5-HT that was not observed in pair-fed rats, suggesting that the observed increase in hypothalamic 5-HIAA/5-HT was a direct effect of BDNF infusion rather than a secondary effect of food restriction. These data suggest that BDNF may induce appetite suppression and weight loss through a central mechanism.