leptin and Epilepsy

Epilepsy is a common and severe neurological disorder in which impaired glucose metabolism leads to changes in neuronal excitability that slow or promote the development of epilepsy. Leptin and adiponectin are important mediators regulating glucose metabolism in the peripheral and central nervous systems. Many studies have reported a strong association between epilepsy and these two adipokines involved in multiple signaling cascades and glucose metabolism. Due to the complex regulatory mechanisms between them and various signal activation networks, their role in epilepsy involves many aspects, including the release of inflammatory mediators, oxidative damage, and neuronal apoptosis. This paper aims to summarize the signaling pathways involved in leptin and adiponectin and the regulation of glucose metabolism from the perspective of the pathogenesis of epilepsy. In particular, we discuss the dual effects of leptin in epilepsy and the relationship between antiepileptic drugs and changes in the levels of these two adipokines. Clinical practitioners may need to consider these factors in evaluating clinical drugs. Through this review, we can better understand the specific involvement of leptin and adiponectin in the pathogenesis of epilepsy, provide ideas for further exploration, and bring about practical significance for the treatment of epilepsy, especially for the development of personalized treatment according to individual metabolic characteristics.

Topics: Adipokines; Adiponectin; Epilepsy; Glucose; Humans; Leptin; Signal Transduction

Adipose tissue is a dynamic organ with different effects on the body. Many of these effects are mediated by leptin, a hormone strongly involved in regulation of feeding and energy metabolism. It has an important role as a mediator of neuronal excitatory activity and higher brain functions. The aim of this study was to review the association between leptin and cerebral neuronal function, in particular its anticonvulsant or convulsant effects and the possible therapeutic role for treating epilepsy. For this purpose, the databases Pubmed, Science Direct, Elsevier, ResearchGate and Scielo were searched to identify experimental studies, reviews and systematic review articles, published in English, Spanish or Portuguese. Experimental studies and the presence of leptin receptors in nervous system sites other than the hypothalamus suggest an influence on higher brain functions. Indeed several animal studies have demonstrated a role of these channels in epileptiform activity as both anticonvulsive and convulsive effects have been found. The reason for these discrepancies is unclear but provides clear evidence of a potential role of leptin and leptin therapy in epileptiform activity. The association between leptin and brain function demonstrates the importance of peripheral metabolic hormones on central nervous system and opens a new way for the development of novel therapeutic interventions in diseases like epilepsy. Nevertheless further investigations are important to clarify the dynamics and diverse actions of leptin on excitatory regulation in the brain.

Topics: Animals; Central Nervous System; Epilepsy; Humans; Leptin

Treatment of epileptic patients with valproic acid (VPA) may be associated with substantial weight changes that may increase morbidity and impair adherence to the treatment regimen. VPA-induced weight gain seems to be associated with many metabolic disturbances; the most frequent are hyperinsulinemia and insulin resistance, hyperleptinemia and leptin resistance. Patients who gain weight during VPA therapy can develop dyslipidemia and metabolic syndrome that are associated with long-term vascular complications such as hypertension and atherosclerosis. Moreover, an elevation in the levels of uric acid and homocysteine, together with oxidative stress, may contribute to atherosclerotic risk in patients under long-term therapy with VPA. The aim of this review is to discuss the metabolic and endocrine effects of VPA chronic treatment in patients with epilepsy.

Topics: Anticonvulsants; Epilepsy; Humans; Hyperinsulinism; Insulin Resistance; Leptin; Metabolic Syndrome; Valproic Acid; Weight Gain

During managing patients with epilepsy, there is a great risk of weight changes, particularly weight gain with some antiepileptic medications. Weight gain is not only a cosmetic problem that leads to non-compliance to medications but also increases the risk for atherosclerosis and its related complications. The mechanisms underlying weight gain in epilepsy are multiple and controversial and have been attributed to the effect of epilepsy and more commonly the effect of antiepileptic medications on the central and peripheral mechanisms regulating weight homeostasis including the two main homeostatic hormones, leptin, a protein product of obesity gene secreted by adipocytes and insulin, a protein product of pancreatic beta-cells. Increased blood levels of leptin and insulin due to leptin and insulin resistance is observed in patients with epilepsy. Leptin forms an important link between weight gain, insulin resistance, epilepsy and atherosclerosis. The knowledge of the novel roles of leptin in patients with epilepsy will help identification of early markers for the related adverse weight changes, thus allowing proper characterization of suitable antiepileptic medication as initial step during management and follow up of patients.

Topics: Animals; Anticonvulsants; Body Weight; Epilepsy; Homeostasis; Humans; Insulin; Leptin; Valproic Acid

It is well established that the adipocyte-derived hormone leptin is an important circulating satiety factor that regulates body weight and food intake via its actions on specific hypothalamic nuclei. However, there is growing evidence that leptin and its receptors are widely expressed throughout the brain, in regions not generally associated with energy homeostasis, such as cortex, cerebellum, brainstem, basal ganglia, and hippocampus. In this review the author discusses recent advances made in leptin neurobiology, with particular emphasis on the role of this endocrine peptide in normal and pathophysiological hippocampal function.

Topics: Animals; Central Nervous System; Cognition; Epilepsy; Humans; Leptin; Phosphatidylinositol 3-Kinases; Receptors, Cell Surface; Receptors, Leptin; Receptors, N-Methyl-D-Aspartate; Signal Transduction; Synaptic Transmission

Patients with epilepsy may manifest metabolic adverse effects throughout the course of their management with antiepileptic drugs. Leptin is a hormone that plays a major role in the regulation of feeding and energy expenditure. Leptin has been expected to form a link to weight gain in epilepsy with the use of some antiepileptic drugs. The aim of this study is to evaluate the effect of carbamazepine on body weight and serum leptin levels. This study was conducted in Izmir Tepecik Training and Research Hospital, Neurology Department. 56 epileptic patients who were on continuous carbamazepine monotherapy for at least 6 months before the study and 42 control subjects were included. Serum leptin and insulin levels were measured. Body mass index, leptin and insulin were not significantly elevated in carbamazepine group compared to control subjects (p>0.05). Our study demonstrated that carbamazepine therapy does not affect significantly body mass index, leptin and insulin. Data regarding the effect of carbamazepine on serum leptin level is limited but the results of these recent studies are correlated with ours. It can be concluded that carbamazepine is a relatively low risky antiepileptic drug in terms of obesity and metabolic syndrome but further studies are needed.

Topics: Adolescent; Adult; Aged; Anticonvulsants; Body Mass Index; Carbamazepine; Epilepsy; Female; Humans; Insulin; Leptin; Male; Middle Aged; Young Adult

The aim of the study was to determine the influence of valproic acid (VPA) treatment on leptin, the soluble leptin receptor (sOB-R), the sOB-R/leptin ratio, body composition and insulin resistance in epileptic children.. A cross-sectional cohort study was conducted at the Medical University Innsbruck, Austria. Children >6 years with idiopathic epilepsy and antiepileptic drug therapy since at least six months were eligible. Leptin concentration, the sOB-R, the sOB-R/leptin ratio, body composition and glucose homeostasis were determined.. 87 children (median [range] age 12.8 years [6.0-18.6]) were on treatment with VPA, 55 (12.3 years [6.4-18.3]) on other AEDs, comprising the non-VPA group. VPA-treated children had higher leptin concentrations, body-mass-index standard-deviation score (SDS), body fat (each p<0.001), serum insulin concentrations (p=0.014) and homeostasis model assessment (HOMA) index (p=0.009), as well as a lower sOB-R/leptin ratio (p<0.001) when compared to the non-VPA group. Overweight VPA-treated children showed lower sOB-R concentrations and a lower sOB-R/leptin ratio (each p<0.001) as well as higher body fat and leptin levels (each p<0.001) compared to lean VPA-treated children.. VPA monotherapy was associated with higher body weight, body fat and serum leptin concentrations as well as impaired glucose homeostasis. Low sOB-R concentrations and a low sOB-R/leptin ratio in overweight VPA-treated patients might contribute to disturbances in glucose homeostasis and to the development of the metabolic syndrome in these children later in life.

Topics: Adolescent; Anthropology, Physical; Anticonvulsants; Body Composition; Body Mass Index; Child; Cross-Sectional Studies; Dose-Response Relationship, Drug; Epilepsy; Female; Humans; Leptin; Male; Receptors, Leptin; Sex Factors; Valproic Acid

Ghrelin is a major hormone, regulating the energy balance of the body. Weight gain is a significant side effect of valproic acid, which has not been clearly identified pathogenetically. The aim of this study was to investigate the effect of valproic acid on ghrelin and its potential effects on weight gain and growth. Each patient and control group consisted of 35 children aged 3 to 15 years. Fasting serum glucose, insulin, C-peptide, leptin, ghrelin, insulin-like growth factor-1, and insulin-like growth factor binding protein-3 levels were measured in patients treated with valproic acid before and at month 6 of treatment. A significant increase in body weight, body mass index, height, and height standard deviation scores was observed in all patients after 6 months of treatment. Significant increases in growth velocity and weight gain were observed in the patient group compared with controls at 6 months of therapy. A significant increase in serum ghrelin levels (P < .01) was detected at the same time in the study group. A negative correlation of ghrelin with insulin-like growth factor-1 and insulin-like growth factor binding protein-3 was detected. Serum ghrelin levels were significantly increased (P < .05), and insulin-like growth factor-1 and insulin-like growth factor binding protein-3 levels were significantly decreased (P < .01 and P < .05, respectively) in the prepubertal group at 6 months of treatment, but no significant change was observed in the pubertal group. Consequently, ghrelin levels significantly increase in the prepubertal children treated with valproic acid. The weight gain in using valproic acid may be associated with the increase in ghrelin level in the early treatment period.

Topics: Adolescent; Anticonvulsants; Blood Glucose; Body Height; Body Mass Index; Body Weight; C-Peptide; Child; Child, Preschool; Epilepsy; Female; Ghrelin; Humans; Insulin; Insulin Resistance; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Leptin; Male; Puberty; Valproic Acid; Weight Gain

Weight gain is a common side effect of valproate treatment. The potential mechanisms of valproate-associated weight gain are not yet clear. Decreased blood glucose level, impairment of beta-oxidation of fatty acids, and increased insulin levels are some of the possible mechanisms. The aim of the present study is to evaluate the role of insulin, leptin, and neuropeptide Y in valproate-related weight gain in epileptic children. In 20 epileptic children treated with valproate before treatment and after a follow-up period of 3 and 6 months, body mass index and fasting insulin glucose ratio were calculated and serum glucose, insulin, cortisol, leptin, and neuropeptide Y levels were measured. At the end of 3 months, the mean body mass index values and the mean serum insulin, fasting insulin glucose ratio, and neuropeptide Y levels increased, whereas the serum glucose levels decreased. After 6 months of treatment, the mean serum cortisol and leptin levels were high, in addition to the body mass index, neuropeptide Y, and fasting insulin glucose ratio. These results suggest that weight gain during valproate treatment might be related to low glucose and high insulin, cortisol, leptin, and neuropeptide Y levels.

Topics: Anticonvulsants; Blood Glucose; Body Mass Index; Child; Child, Preschool; Epilepsy; Female; Humans; Hydrocortisone; Hypoglycemic Agents; Insulin; Leptin; Male; Neuropeptide Y; Valproic Acid; Weight Gain

We examined predictors of weight loss with topiramate, an anticonvulsant associated with weight loss in adults.. In this uncontrolled, prospective clinical trial, topiramate was added to existing anticonvulsants in adults (40 to 110 kg) with partial-onset seizures. Primary measurements were change from baseline weight after 3 months and 1 year in patients completing 1 year of topiramate treatment (N = 38). Physiological and metabolic measures were analyzed for correlation with weight loss during topiramate treatment.. In patients who completed 1 year of topiramate treatment, baseline weight was reduced in 82% at 3 months and in 86% at 1 year. Mean body weight was reduced 3.0 kg (3.9% of baseline) at 3 months and 5.9 kg (7.3%) at 1 year. In obese patients [body mass index (BMI) >/= 30 kg/m(2)], mean weight loss was 4.2 kg (4.3%) at 3 months and 10.9 kg (11.0%) at 1 year. Weight loss was primarily caused by reduction in body fat mass. For all patients, weight loss at 3 months correlated most strongly with reduced caloric intake (p = 0.02). At 1 year, caloric intake had returned to baseline levels; weight loss correlated most strongly with higher baseline BMI (p = 0.0007).. Our results suggest that weight loss occurs in most adults treated with topiramate and is sustained for at least 1 year. Reduced caloric intake may account, in part, for weight loss during early treatment. The pattern of weight loss differs according to baseline BMI, with obese patients experiencing greater weight loss during continued therapy.

Topics: Adult; Anticonvulsants; Blood Glucose; Body Composition; Body Mass Index; Cholesterol; Energy Intake; Epilepsy; Female; Fructose; Glucose Tolerance Test; Humans; Leptin; Male; Middle Aged; Obesity; Prospective Studies; Regression Analysis; Topiramate; Weight Loss

The developing infant brain has a different response mechanism and repair potential for injury than the adult brain. There is an urgent need for new anticonvulsants to effectively control neonatal seizures while minimizing the drug's toxic damage to the developing brain. Leptin protects neuronal plasma membrane integrity, while it has clinical advantages in terms of anticonvulsant properties as well. This study aimed to evaluate the effect of immediate leptin treatment on the serum concentration of clusterin and vascular endothelial growth factor (VEGF), neuronal plasma membrane integrity-related proteins, and the neurobehavioral phenotypes following neonatal seizures. Leptin was injected i.p at a dose of 4 mg/kg 1 hour after daily 30 minutes prolonged seizures for consecutive 10 days. The serum biomarkers (clusterin and VEGF), and brain protein expression of ATF-4/GRP78/autophagy axis were measured by enzyme-linked immunosorbent assay and western blot in the acute phase (24 hours after the last seizures), respectively. Behavioral and histopathological phenotypes and seizure threshold were conducted from P23 to P34, respectively. There were rapid elevation of serum VEGF and clusterin as well as upregulated protein expression of ATF-4, GRP78, Beclin-1, and LC3 in the cerebral cortex and hippocampus following a neonatal seizure, which was restored by immediate treatment with leptin after seizures. In addition, leptin improved seizure-induced impaired neuropsychological, and cognitive functioning. Furthermore, leptin succeeded in ameliorating markers of neuronal excitability, including seizure threshold and hippocampal mossy fiber sprouting. In conclusion, this study verified that immediate treatment with leptin after neonatal seizures restored both rapid elevation of serum clusterin as well as upregulated protein expression of ATF-4/GRP78/autophagy axis in the cerebral cortex and hippocampus, which contributes to the recovery of neurological function.

Topics: Animals; Brain; Clusterin; Endoplasmic Reticulum Chaperone BiP; Epilepsy; Heat-Shock Proteins; Hippocampus; Leptin; Oxidative Stress; Phenotype; Rats; Rats, Sprague-Dawley; Seizures; Vascular Endothelial Growth Factor A

Comparison of cardiovascular risk factors, atherosclerosis, and psychological distress among adults with refractory versus well-controlled epilepsy.. The cross-sectional study consisted of two groups of 40 people each: Group I - People with well-controlled epilepsy, Group II - People with refractory epilepsy. Age- and gender-matched people of 20-50 years were recruited. People who were diabetic, smokers, hypertensive, alcoholic, pregnant, with infections, and lactating women were excluded from the study. Biochemical parameters, fasting glucose, lipid profile, fasting insulin, leptin, adiponectin, Lp[a], hsCRP, TyG INDEX, HOMA1-%S, HOMA1-IR, HOMA1-%B, QUICKI, FIRI, AIP, AC, CLTI, MLTI, CRI-I, CRI-II, and CIMT were estimated. Stress levels [PSS-10, GAD-7 & PHQ-9] were assessed based on the scoring system from the questionnaires.. The existence of metabolic syndrome, levels of triglycerides, TyG index, MDA, OSI, CIMT, AIP, and stress scores [PSS-10, GAD-7 & PHQ-9] were significantly higher in the refractory-epilepsy group in comparison to the well-controlled group. There were associations between LDL -C and CIMT as well as between GAD-7 and CIMT among all the study subjects. There were no significant differences in the levels of glucose homeostasis parameters, hsCRP, leptin, adiponectin, and Lp[a] between the two groups. Based on the ROC analysis, MDA [AUC = 0.853] and GAD-7 [AUC = 0.900] are useful in the differential diagnosis of the study groups.. People with refractory epilepsy had increased levels of vascular risk factors, atherosclerosis, and stress levels compared to people with well-controlled epilepsy. Suitable disease management and therapeutic approaches to address cardiovascular and psychological distress could be planned out among people with refractory epilepsy to improve their quality of life.

Topics: Adiponectin; Adult; Atherosclerosis; C-Reactive Protein; Cross-Sectional Studies; Drug Resistant Epilepsy; Epilepsy; Female; Glucose; Humans; Lactation; Leptin; Psychological Distress; Quality of Life; Risk Factors

The aim of this study was to investigate whether the modified Atkins diet (MAD), a variant of the ketogenic diet, has an impact on bone- and calcium (Ca) metabolism.. Two groups of adult patients with pharmacoresistant epilepsy were investigated. One, the diet group (n = 53), was treated with MAD for 12 weeks, whereas the other, the reference group (n = 28), stayed on their habitual diet in the same period. All measurements were performed before and after the 12 weeks in both groups. We assessed bone health by measuring parathyroid hormone (PTH), Ca, 25-OH vitamin D (25-OH vit D), 1,25-OH vitamin D (1,25-OH vit D), phosphate, alkaline phosphatase (ALP), and the bone turnover markers procollagen type 1 N-terminal propeptide (P1NP) and C-terminal telopeptide collagen type 1 (CTX-1). In addition, we examined the changes of sex hormones (estradiol, testosterone, luteinizing hormone, follicle-stimulating hormone), sex hormone-binding globulin, and leptin.. After 12 weeks of MAD, we found a significant reduction in PTH, Ca, CTX-1, P1NP, 1,25-OH vit D, and leptin. There was a significant increase in 25-OH vit D. These changes were most pronounced among patients <37 years old, and in those patients with the highest body mass index (≥25.8 kg/m²), whereas sex and type of antiseizure medication had no impact on the results. For the reference group, the changes were nonsignificant for all the analyses. In addition, the changes in sex hormones were nonsignificant.. Twelve weeks of MAD treatment leads to significant changes in bone and Ca metabolism, with a possible negative effect on bone health as a result. A reduced level of leptin may be a triggering mechanism. The changes could be important for patients on MAD, and especially relevant for those patients who receive treatment with MAD at an early age before peak bone mass is reached.

Topics: Adult; Biomarkers; Calcium; Diet, High-Protein Low-Carbohydrate; Epilepsy; Gonadal Steroid Hormones; Humans; Leptin; Parathyroid Hormone; Vitamin D

Recently, inflammation have been proposed as one of the mechanisms underlying the patology of drug-resistant epilepsy (DRE). Ketogenic diet (KD) is one of the therapeutic methods used in DRE. There are some data that adipokines may modulate inflammatory processes and their concentrations are influenced by KD. Therefore, the aim of this study was to evaluate the influence of KD on serum leptin, chemerin and resistin in children with DRE.. A cross-sectional observational study performed on 72 subjects aged 3-9 years, divided into 3 groups: 24 children with DRE treated with KD, 26 treated with valproic acid (VPA), and a control group of 22 children.. Anthropometric measurements (weight, heigth, BMI, waist to hip circumerences ratio) were performed in all participants. Biochemical tests included serum fasting glucose, insulin, beta-hydroxybutyric acid, lipid profile, alanine aminotransferase and aspartate aminotransferase activities and blood gasometry. Serum levels of leptin, chemerin and resistin were assayed using commercially available ELISA tests.. Serum levels of leptin and chemerin in the KD group were significantly lower and resistin - higher in comparison to patients receiving VPA and the control group. In children treated with the KD, leptin concentrations correlate with insulin levels and HOMA-IR scores. Chemerin levels in this group, in contrast, show negative correlation with body mass and height expressed as standard deviation scores from the mean for age and sex.. Modification of pro-inflammatory adipocytokine levels is potentially one of the mechanisms of anticonvulsant effects of KD in children with refractory epilepsy.

Topics: Adipokines; Adiponectin; Body Mass Index; Child; Cross-Sectional Studies; Diet, Ketogenic; Drug Resistant Epilepsy; Epilepsy; Humans; Insulin; Insulin Resistance; Leptin; Resistin

Weight gain is an important adverse effect of valproate (VPA) therapy. A number of mechanisms have been proposed for its pathophysiology. The aim of the present study is the evaluation of insulin, leptin and lipid levels in epileptic children on treatment with VPA.. Thirty epileptic children treated with VPA, and 20 age-sex-matched healthy children, were enrolled in this study. Blood samples were taken and the body mass index was calculated for all of the subjects. Serum insulin, leptin, and lipid levels were compared between the two groups.. Leptin levels were significantly higher in the patient group (P = 0.009) whereas body mass index values were comparable. There was a positive correlation between leptin and body mass index among both patient (r = 0.464, P = 0.01) and control groups (r = 0.734, P = 0.0001). Total cholesterol and low-density lipoprotein (LDL) cholesterol levels were lower in VPA-treated epileptic children than the control group (P = 0.008; P = 0.003, respectively). No significant difference was determined in insulin levels between the two groups. A negative correlation was observed between plasma VPA level and total cholesterol and LDL cholesterol levels in the patient group (r = -0.380, P = 0.03, r = -0.474, P = 0.008, respectively).. This study demonstrated higher leptin levels in the patient group despite similar BMI values. Hence, it seems likely that VPA causes leptin resistance. Unlike other anti-epileptics, VPA does not produce an increase in serum cholesterol levels. On the contrary, lower levels of total and LDL cholesterol levels in VPA-receiving patients have been observed in our study.

Topics: Anticonvulsants; Child; Epilepsy; Humans; Insulin; Leptin; Valproic Acid

Although some drugs used in the treatment of epilepsy are known to affect body weight, the hormonal factors responsible have not been sufficiently described. The purpose of this study was to compare insulin, leptin, neuropeptide Y and ghrelin levels in children with epilepsy receiving monotherapy with topiramate (TPM) and valproic acid (VPA), the drugs whose effects on body weight have been most discussed, with those of a control group.. 48 patients (25 VPA, 23 TPM) aged between 6 and 15.5 years, presenting to the Karadeniz Technical University Medical Faculty Pediatric Neurology Clinic, diagnosed with idiopathic epilepsy or location-related idiopathic epilepsy, and receiving VPA or TPM monotherapy for at least 6 months were included in the study. Twenty-five healthy subjects with similar demographic characteristics were enrolled as the control group. Blood samples were collected from the patient and control groups after fasting for at least 10-12 h and again 1 and 2 h postprandially. Body mass index (BMI) values were calculated for all cases. VPA levels, glucose, insulin, leptin, neuropeptide Y and ghrelin were investigated in all three separate blood samples.. Age, height, weight and BMI were similar between the patient and control groups. Significant weight gain was observed throughout treatment in the VPA group compared to the TPM group. High fasting and postprandial insulin levels were observed in the VPA group. VPA group leptin and neuropeptide Y (NPY) levels were also higher than in the TPM and control groups. No significant difference was determined in ghrelin levels in the patient groups compared to the controls.. Low blood sugar not being observed, even though insulin levels are high, after fasting and in the postprandial period in epileptic children receiving VPA is indicative of insulin resistance. The elevation in leptin and neuropeptide Y levels observed in the VPA group also suggest this.

Topics: Adolescent; Anticonvulsants; Biomarkers; Blood Glucose; Body Mass Index; Child; Epilepsy; Fructose; Ghrelin; Humans; Insulin; Leptin; Neuropeptide Y; Topiramate; Treatment Outcome; Valproic Acid; Weight Gain

Weight loss is one of the most frequent side effects of topiramate treatment. The aim of our study was to investigate the effect of topiramate on body mass index, serum glucose, insulin, cortisol, leptin, and neuropeptide-Y levels and the role of these variables on the pathogenesis of weight loss in prepubertal children with epilepsy.. Twenty prepubertal children with epilepsy who were treated with topiramate were enrolled in the study. Topiramate was used at a daily dose of 5 mg/kg. Body mass index and fasting insulin-to-glucose ratio were calculated. Serum glucose, insulin, leptin, neuropeptide-Y, ghrelin, and cortisol levels were measured for all patients before the treatment and at the third and sixth months of the treatment.. There were significant decreases in mean body mass index, fasting insulin-to-glucose ratio, and serum cortisol and leptin levels at the third and sixth months of the treatment compared with pretreatment levels. No significant changes were observed in serum glucose, ghrelin, neuropeptide-Y, or insulin levels.. The exact mechanism of topiramate on energy balance regulation is not clearly understood. Topiramate affects body mass index, fasting insulin-to-glucose ratio, and serum leptin and cortisol levels in prepubertal children. These changes may be key factors in weight loss due to topiramate.

Topics: Anticonvulsants; Blood Glucose; Body Mass Index; Body Weight; Child; Child, Preschool; Epilepsy; Female; Fructose; Ghrelin; Humans; Hydrocortisone; Insulin; Leptin; Male; Neuropeptide Y; Topiramate

Chronic treatment with valproate (VPA) is commonly associated with weight gain, which potentially has important health implications, in particular increased central fat distribution. We utilized a VPA-discordant same-sex, twin and matched sibling pair study design to primarily examine for differences in fat distribution between patients with epilepsy treated with VPA compared to their matched twin or sibling control. Weight, blood pressure, and leptin levels were assessed.. Height, weight, waist and hip measurements, exercise, blood pressure (BP), and serum leptin levels were measured. Body composition was measured using dual-energy x-ray absorptiometry (DXA). Abdominal fat was expressed as a percentage of the abdominal region (AFat%); and of whole body fat (WBF); (AFat%WBF). Mean within-pair differences were assessed (VPA-user and nonuser). Restricted maximum likelihood (REML) linear mixed model analysis was fitted to examine associations of anthropometrics, zygosity, gender, menopausal status, VPA dose and duration, with weight and AFat%.. We studied 19 pairs of VPA-discordant, gender-matched (five male, 14 female) twins and siblings. Mean (standard deviation, SD) duration of therapy for VPA users was 11.0 (7.4) years. There were no statistically significant within-pair differences in age, height, weight, body mass index (BMI), BP, leptin level, WBF, AFat%, or AFat%WBF. For pairs in which VPA-user was treated for >11 years there were statistically significant mean within-pair differences in AFat%, (+7.1%, p = 0.03, n = 10 pairs), mean BP (+11.0 mm Hg, p = 0.006, n = 8 pairs); but not in AFat%WBF. VPA duration was positively associated with weight (estimate +0.98 kg/per year of VPA, p = 0.03); VPA treatment duration and dose were not significantly associated with AFat%.. This study demonstrated a relationship between long-term VPA use and abdominal adiposity (AFat%), which could have significant health implications. We recommend ongoing monitoring of weight, BMI, and blood pressure for patients taking VPA.

Topics: Abdominal Fat; Absorptiometry, Photon; Adult; Anticonvulsants; Blood Pressure; Body Composition; Body Fat Distribution; Diseases in Twins; Epilepsy; Female; Humans; Leptin; Male; Sex Factors; Siblings; Twins, Dizygotic; Twins, Monozygotic; Valproic Acid; Weight Gain

Prior studies have demonstrated the involvement of leptin and cannabinoids in food intake and metabolism. However, the interaction between leptin and cannabinoids in epilepsy has not been studied. This study elucidated the relationship between leptin and cannabinoids in penicillin-induced epileptiform activity in rats.. The CB1 receptor agonist, arachidonyl-2-chloroethylamide (ACEA), at doses of 2.5 and 7.5 μg, the CB1 receptor antagonist, [N-(piperidine-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3 carboxamide] (AM-251), at doses of 0.125 and 0.25 μg, and leptin, at the dose of 1 μg, were administered intracerebroventricularly (i.c.v.) 30 min after intracortical penicillin (i.c.) application.. Leptin caused proconvulsant activity in all groups. The administration of AM-251, at a dose of 0.25 μg, increased the frequency of penicillin-induced epileptiform activity by producing status epilepticus-like activity, whereas AM-251, at a dose of 0.125 μg, was not effective when applied alone. ACEA, at a dose of 7.5 μg, decreased the frequency of epileptiform activity. Leptin reversed the anticonvulsant activity of ACEA and enhanced the proconvulsant activity of AM-251.. This study provides electrophysiological evidence that the proconvulsant activity of leptin is mediated, at least in part, by inhibition of cannabinoids in the experimental model of epilepsy.

Topics: Animals; Convulsants; Epilepsy; Infusions, Intraventricular; Leptin; Male; Penicillins; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1

Antiepileptic drugs may affect the endocrine system. We investigated the effects of valproic acid and topiramate on the levels of insulin, c-peptide and adipocytokines in pre-pubertal patients with idiopathic partial and generalized epilepsy.. Forty-one children with epilepsy were included. The patients were divided into two groups (valproic acid; n = 21, topiramate; n = 20). The weight, height, body mass index and homeostasis model assessment of insulin resistance (HOMA-IR) were recorded and insulin, c-peptide, leptin, neuropeptide Y, adiponectin, visfatin and resistin levels were determined at 0, 6 and 12 months of therapy.. In the valproate group, weight and height increased significantly. Seven of 21 patients were overweight at the end of one year. Leptin was higher in the overweight subgroup. Although insulin and HOMA-IR increased (p < 0.05), none of the patients showed hyperinsulinism or IR. Resistin had decreased at the 6th and 12th months (p < 0.05). In the topiramate group, some statistically nonsignificant changes were demonstrated.. The mechanisms behind valproate and topiramate-related weight control are still unclear, especially in children. Valproate and topiramate affect the weight, BMI, and insulin, leptin and adipocytokine levels in prepubertal children. We suggest that further studies including more patients with a long follow-up period are necessary to draw a firm conclusion regarding an association between the treatment with these drugs and the levels of leptin, insulin and adipocytokines.

Topics: Adiponectin; Anticonvulsants; Body Mass Index; Body Weight; C-Peptide; Child; Epilepsy; Female; Fructose; Humans; Insulin; Leptin; Male; Neuropeptide Y; Nicotinamide Phosphoribosyltransferase; Resistin; Topiramate; Valproic Acid

Both proconvulsive and anticonvulsive roles of leptin have been reported, suggesting cell-specific actions of leptin in different models of seizure and epilepsy. The goal of our study was to determine the regulation and function of astrocytic leptin receptors in a mouse model of epilepsy and glutamate-induced cytotoxicity. We show that in pilocarpine-challenged mice developing epilepsy with recurrent seizures after a latent period of 2 weeks, hippocampal leptin receptor (ObR) immunofluorescence was increased at 6 weeks. This was more pronounced in astrocytes than in neurons. In cultured astrocytes, glutamate increased ObRa and ObRb expression, whereas leptin pretreatment attenuated glial cytotoxicity by excess glutamate, reflected by better preserved adenosine triphosphate production. The protective role of astrocytic leptin signaling is further supported by the higher lethality of the astrocyte-specific leptin receptor knockout mice in the initial phase of seizure production. Thus, leptin signaling in astrocytes plays a protective role against seizure, and the effects are at least partially mediated by attenuation of glutamate toxicity. Astrocytic leptin signaling, therefore, may be a novel therapeutic target.

Topics: Animals; Astrocytes; Astrocytoma; Cell Line, Tumor; Convulsants; Epilepsy; Female; Gene Expression Regulation; Glial Fibrillary Acidic Protein; Gliosis; Glutamic Acid; Hippocampus; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nerve Tissue Proteins; Neurotoxins; Pilocarpine; Receptors, Leptin; Recurrence; Signal Transduction; Up-Regulation

Topics: Adiponectin; Anticonvulsants; Carotid Intima-Media Thickness; Epilepsy; Female; Ghrelin; Humans; Leptin; Male; Neuropeptide Y; Valproic Acid

Topics: Adiponectin; Anticonvulsants; Carotid Intima-Media Thickness; Epilepsy; Female; Ghrelin; Humans; Leptin; Male; Neuropeptide Y; Valproic Acid

Topics: Bacteremia; Epilepsy; History, 20th Century; Humans; Intelligence Tests; Leptin; United States

Because iatrogenic obesity may hinder medication compliance, it would be a reasonable approach to consider antiepileptic drugs (AEDs) that promote weight loss in overweight patients. We performed an open-label, observational study to assess the effects of zonisamide on weight in overweight female epilepsy patients. In particular, we studied how the basal serum leptin level is related to changes in the weight of these patients. We recruited female epilepsy patients with basal body mass index 25 or more. Laboratory findings including serum leptin level were measured and zonisamide was administered as a monotherapy at a dose of 200 to 400mg/day. Six months later, we measured changes in the body weight. Thirty-seven female epilepsy patients enrolled in the study, and 23 of them completed the treatment. Weight loss after zonisamide treatment was correlated with initial body weight (p=0.020), follow-up weight (p=0.010), and basal serum leptin level (p=0.008), but was not correlated with patients' age, results of lipid profile, and dosage of zonisamide. The correlation of the serum leptin level with weight loss was still significant after the effect of the initial weight was adjusted (p=0.042). Our study shows that low serum leptin level is associated with weight loss in overweight female epilepsy patients. This result may be beneficial for selecting AEDs and provide clues for the pathophysiology of zonisamide-induced weight loss.

Topics: Adolescent; Adult; Aged; Anticonvulsants; Epilepsy; Female; Follow-Up Studies; Humans; Isoxazoles; Leptin; Linear Models; Middle Aged; Obesity; Prospective Studies; Weight Loss; Young Adult; Zonisamide

Weight gain is a common side effect of valproate (VPA) treatment, although the mechanism is not clear. Abnormal weight gain and obesity are associated with dyslipidemia, hypertension, and atherosclerosis. Measurement of the common carotid artery intima media thickness (CAIMT) gives a picture of early arterial wall alterations and, currently, is considered a noninvasive marker of premature atherosclerosis. The aim of the present study was to evaluate plasma insulin, leptin, neuropeptide Y (NPY), ghrelin, and adiponectin levels in children with epilepsy treated with VPA and to evaluate these parameters for early atherosclerosis.. Twenty prepubertal children with idiopathic epilepsy treated with VPA were enrolled in this study. Body mass index (BMI) and fasting insulin glucose ratio (FIGR) were calculated, and the plasma insulin, leptin, NPY, ghrelin, and adiponectin levels; the lipid profiles; and CAIMT were measured for all subjects before the treatment and after a follow-up period of 6 and 12 months.. When pretreatment values were compared with those at the end of 6 and 12 months, the mean BMI values, plasma insulin, leptin, NPY levels, and FIGR were increased, whereas the plasma ghrelin and adiponectin levels, lipid profiles, and CAIMT did not change significantly at the end of 6 and 12 months.. These results suggest that weight gain during VPA treatment may be related to increases in insulin, leptin, and NPY levels. Additionally, in this study, no increase in the risk for early atherosclerosis was determined by CAIMT in children with epilepsy treated with VPA.

Topics: Adiponectin; Age Factors; Anticonvulsants; Blood Glucose; Body Mass Index; Carotid Intima-Media Thickness; Child; Epilepsy; Female; Follow-Up Studies; Ghrelin; Humans; Insulin; Leptin; Male; Neuropeptide Y; Valproic Acid

We investigated the mechanism of topiramate-related appetite loss and exposed its relationship to body weight, body mass index, body fat index, and serum insulin, lipid, leptin, neuropeptide-Y, cortisol, ghrelin, and adiponectin levels. Twenty children with epilepsy were evaluated at baseline and months 3 and 6 of treatment. Their body fat index, leptin, and neuropeptide-Y levels significantly decreased at month 3, whereas significant decreases occurred in body weight, body mass index, body fat index, neuropeptide-Y, cholesterol, and cortisol levels of patients at month 6 compared with baseline. Weight loss during topiramate treatment was attributed to loss of appetite and reduced food intake caused by reductions in neuropeptide-Y. To the best of our knowledge, this study is the first to describe reductions in neuropeptide-Y with topiramate use in humans.

Topics: Adiponectin; Adiposity; Anticonvulsants; Appetite; Body Mass Index; Body Weight; Child; Epilepsy; Female; Fructose; Ghrelin; Humans; Insulin; Leptin; Male; Neuropeptide Y; Topiramate

Topics: Animals; Autistic Disorder; Diet, Ketogenic; Disease Models, Animal; Epilepsy; Humans; Leptin; Receptors, Leptin; Rett Syndrome

Weight gain is a well-known unwanted effect of valproic acid (VPA) therapy. Studies on VPA-associated changes of homeostatic hormones remain limited and controversial. Allopregnanolone (AP) is a circulating neuroactive steroid involved in modulation of behavioral activities whose serum levels are increased in obese children. The aim of the present study was to determine whether VPA therapy affects leptin and AP circulating levels in prepubertal girls with epilepsy. One-hundred and one patients were divided into four groups: epileptic patients with VPA-associated obesity (n = 21); lean epileptic patients under VPA therapy (n = 35); healthy obese children (n = 23), and healthy lean children (n = 22). Patients with VPA-associated obesity had significantly enhanced blood concentrations of AP (p = 0.001) and leptin (p = 0.007) than lean subjects. There were no differences in leptin and AP plasma levels between patients with VPA-associated obesity and obese controls (p = 0.45 and p = 0.10, respectively), as there were no differences between lean patients under VPA therapy and lean healthy controls (p = 0.06). In patients under VPA therapy, both plasma leptin and AP levels were significantly correlated with BMI (r = 0.074, p = 0.02, and r = 0.084, p = 0.01, respectively). Plasma leptin concentrations were not correlated with AP levels (r = 0.023, p = 0.13). In conclusion, a correlation between obesity and neuroactive steroids was shown. It remains to be established whether the increased circulating level of AP is a secondary effect of anxiolytic-sedative processes occurring in subjects with obesity-related emotional and behavioral anomalies, or plays a central role in determining abnormal eating behaviors.

Topics: Anticonvulsants; Child; Epilepsy; Female; Humans; Immunoassay; Leptin; Male; Obesity; Pregnanolone; Valproic Acid; Weight Gain

The objective of this study was to investigate the cause of valproate (VPA)-associated weight gain in children.. Eighteen children (10.94 ± 3.78 years) with epilepsy were assigned to VPA therapy. Serum levels of glucose, insulin, cortisol, leptin, neuropeptide Y (NPY), galanin and ghrelin were assessed before (month 0) and after 18 months of therapy. Eighteen age- and gender-matched patients (10.78 ± 3.95 years) were enrolled as the control group.. Excess per capita weight of 2.3 kg was determined in the children receiving VPA over 18 months compared to the control group. In these patients, a statistically significant increase in standardized weight score, Homeostasis Model Assessment index, serum leptin, NPY and galanin values was determined at the 18th month compared to those before VPA treatment and in the control group, and there was also a significant decrease in ghrelin values.. Increased serum levels of leptin, NPY and galanin play an important role in VPA-associated weight gain in children. While ghrelin is not directly associated with weight gain, its serum levels decline as a response to weight gain.

Topics: Adolescent; Child; Child, Preschool; Epilepsy; Galanin; Ghrelin; Humans; Hydrocortisone; Insulin; Leptin; Neuropeptide Y; Valproic Acid; Weight Gain

Antiepileptic drugs (AED) had an effect on bone metabolism in children. This study was conducted in order to determine the relationships between serum leptin levels, bone mineral density (BMD) and bone turnover markers in epileptic children. Fifty-three patients were treated with valproic acid (VPA) and 23 with carbamazepine (CBZ) monotherapy; 50 healthy children were included in the study as controls. Serum alkaline phosphatase (ALP) and cross-linked C-telopeptide (CTx) levels were statistically significantly higher in the CBZ group than in the VPA group and the control group (p < 0.0001, p < 0.010, respectively). Serum osteocalcin and ALP levels were significantly lower in the VPA group than in the control group (P < 0.012, P < 0.030, respectively). Although we found slightly higher serum leptin levels in both the CBZ and VPA groups, they were not significantly different from the control group (P > 0.05). We demonstrated that the markers of bone formation and resorption increased with CBZ and decreased with VPA treatment without affecting BMD and vitamin D levels in prepubertal epileptic children.

Topics: Anticonvulsants; Biomarkers; Bone Density; Bone Remodeling; Carbamazepine; Child; Child, Preschool; Cross-Sectional Studies; Epilepsy; Female; Humans; Leptin; Male; Valproic Acid

We aimed to investigate the effects of topiramate monotherapy on anthropometric indexes, insulin resistance, and serum leptin and lipid levels in 33 premenopausal women (mean age+/-standard deviation: 26.7+/-7.1years) with cryptogenic epilepsy. Body mass index (BMI), waist circumference and serum leptin, insulin and lipid levels were measured at baseline and at 6months after initiation of topiramate. We found reductions in BMI (p<0.001), waist circumference (p<0.001) and serum high-density lipoprotein (HDL) cholesterol levels (p=0.011). We also found significant improvements in insulin resistance (p=0.023), but not in serum leptin levels (p=0.45). Our results suggest that topiramate treatment in women with epilepsy is associated with reduced BMI and waist circumference and improvement in insulin resistance; however, according to our data, topiramate treatment is also associated with lower HDL cholesterol levels, which may substantially increase vascular disease.

Topics: Adolescent; Adult; Anthropometry; Anticonvulsants; Body Mass Index; Body Weight; Enzyme-Linked Immunosorbent Assay; Epilepsy; Female; Fructose; Humans; Insulin Resistance; Leptin; Lipid Metabolism; Topiramate; Young Adult

Weight gain is an adverse metabolic effect in some children with epilepsy. The studies done to detect the effect of antiepileptic drugs and weight homeostatic hormones, insulin and leptin, were limited and controversial.. We evaluated the serum leptin and insulin as predictors of weight gain in children receiving long-term treatment with valproate (VPA), carbamazepine (CBZ), lamotrigine (LTG). This study included 90 patients (treated: 70; untreated: 20). Serum lipid profile, insulin and leptin were measured.. BMI, serum leptin and insulin were significantly elevated in VPA compared with controls, untreated patients and those treated with CBZ, LTG and combined therapy with LTG. Girls on VPA had higher BMI and leptin levels than boys. With VPA, serum insulin was correlated with BMI (r=0.625, p<0.01), leptin (r=0.823, p<0.001), treatment duration (r=0.775, p<0.01) and VPA dose (r=0.975, p<0.0001). Serum leptin was correlated with age (r=0.980, p<0.0001), BMI (r=0.704, p<0.01), serum insulin (r=0.823, p<0.001), LDL-c (r=0.630, p<0.01), HDL-c (r=-0.880, p<0.001), treatment duration (r=0.770, p<0.01) and VPA dose (r=0.970, p<0.001). BMI is correlated with serum insulin, leptin, LDL-c (r=0.835, p<0.001) and HDL-c (r=-0.955, p<0.0001).. Hyperinsulinemia and hyperleptinemia are common with VPA and marked among epileptic children who gained weight suggesting states of insulin and leptin resistances. These alterations were not demonstrated with CBZ or LTG. The relationship between VPA, leptin and weight seems to be gender specific. Serum leptin may serve as a sensitive parameter for weight gain and reduction with intervention programs during follow-up of girls with epilepsy.

Topics: Adolescent; Age Factors; Anticonvulsants; Body Mass Index; Carbamazepine; Case-Control Studies; Child; Epilepsy; Female; Humans; Hyperinsulinism; Insulin; Lamotrigine; Leptin; Lipids; Male; Predictive Value of Tests; Risk Assessment; Sex Factors; Triazines; Valproic Acid; Weight Gain

To explore the mechanism of topiramate-induced weight loss in epilepsy children by monitoring metabolism indices.. Children with epilepsy were treated with topiramate at their first clinical visit. Metabolism indices including body mass index (BMI) and its SD scores, leptin, adiponectin, leptin/adiponectin (L/A), lipid profile-insulin and Homeostasis Model Assessments (HOMA) index were collected before and after treatment.. Topiramate treatment significantly reduced L/A (t = 2.156, p = 0.031), and markedly increased the serum level of adiponectin (t = 3.124, p = 0.002). Moreover, there were no relationships between the metabolism indices and dosages of topiramate (p > 0.05).. Our studies find that topiramate treatment in epilepsy children increases energy metabolism, resulting in weight loss. It has been demonstrated that adiponectin play a significant role in metabolic regulations.

Topics: Adiponectin; Anti-Obesity Agents; Blood Glucose; Body Mass Index; Body Weight; Case-Control Studies; Child; Epilepsy; Female; Fructose; Homeostasis; Humans; Insulin; Insulin Resistance; Leptin; Lipids; Male; Metabolism; Statistics, Nonparametric; Topiramate

Chronic antiepileptic therapy with valproic acid (VPA) is associated with increased body weight and insulin resistance in adults and children. Attempts to determine the underlying pathophysiologic mechanisms have failed. Adipocytokines have recently been defined as a link between glucose and fat metabolism. We herein demonstrate that VPA-associated overweight is accompanied by lower adiponectin and higher leptin concentrations in children. The absence of any relationship with visfatin concentration does not suggest a role of this novel insulin-mimetic hormone in VPA-associated metabolic alterations. Therefore, adiponectin and leptin but not visfatin may be considered as potential regulators of glucose and fat metabolism during VPA-therapy.

Topics: Adiponectin; Adipose Tissue; Age Factors; Anticonvulsants; Blood Glucose; Child; Epilepsy; Female; Humans; Insulin Resistance; Leptin; Male; Nicotinamide Phosphoribosyltransferase; Valproic Acid; Weight Gain

To compare the incidence and magnitude of weight gain associated with valproic acid (VPA) monotherapy in male and female epilepsy patients and to determine possible gender-specific differences in frequency of carbohydrate craving, body-composition, glucose homeostasis and lipid metabolism.. Epilepsy patients on VPA monotherapy were consecutively recruited at the outpatient clinic of the Department of Neurology, Innsbruck Medical University. Weight gain during VPA-therapy, frequency of carbohydrate craving and physical exercise, sociopsychological problems and family history for diabetes were obtained from all patients. Clinical data also comprised body-impedance analysis, body mass index and waist-to-hip ratio. Morning fasting blood samples were drawn to determine serum leptin, glucose and lipid concentrations, as well as insulin, C-reactive protein and TNF-alpha.. One hundred and six patients (55 women) were enrolled in the study. Significant weight gain was seen during VPA-therapy in both genders (each p<0.001) with women experiencing increment of weight more frequently and more pronounced than did men. Analyses of patients who gained weight during VPA-therapy revealed significantly higher serum leptin concentrations in women than in men (p<0.001). Women also revealed significantly higher high-density lipoprotein-cholesterol and lower triglyceride concentrations than men (p=0.004 and 0.014, respectively). Frequency of carbohydrate craving was 25.8% in women and 14.3% in men. More women tried to lose or control weight through diet than did men (22.6% versus 7.1%). Moreover, weight gain as a sociopsychological problem was more numorous in women than in men.. Women are more prone to gain weight during VPA therapy though higher frequency of diet and sociopsychological burden than men, which might possibly be related to leptin-resitance and a higher frequency of carbohydrate craving.

Topics: Adult; Anticonvulsants; Appetite; Body Mass Index; Dietary Carbohydrates; Epilepsy; Female; Glucose; Homeostasis; Humans; Leptin; Male; Sex Factors; Valproic Acid; Weight Gain

Women with epilepsy (WWE) tend to have hormonal and metabolic abnormalities, raising concerns about an increased risk of cardiovascular disorders. This study was performed to determine whether epilepsy itself and/or antiepileptic drug (AED) medication cause metabolic abnormalities.. WWE in premenopausal state aged 18 to 45 years old, currently on AED monotherapy for more than six months, were recruited for this study. The subjects checked their oral temperature each morning, and tested serum levels for lipid profiles, insulin, glucose, and leptin. A HOMA-index was used as a marker for insulin resistance.. Of the 54 total patients, 18 women were diagnosed with primary generalized epilepsy (PGE) and the other 36 were diagnosed with localization-related epilepsy (LRE). Among the subjects, 19 women were on carbamazepine (CBZ), 12 on valproate (VPA), 12 on lamotrigine (LTG), and 11 on topiramate (TPM). Body mass index increased and HDL-cholesterol decreased in patients on VPA monotherapy compared with CBZ, LTG, or TPM (p=0.046 and 0.002). Metabolic syndrome was more frequently associated with VPA-treated patients (41.7%) than CBZ (5.3%), LTG (0%), or TPM group (0%) (p=0.005). There were no differences in hormonal and metabolic indices between PGE and LRE groups.. WWE on VPA monotherapy are more obese and more frequently suffer from metabolic syndrome. LTG or TPM may be safer when prescribed to the patients with high risk of cardiovascular disease.

Topics: Adolescent; Adult; Anticonvulsants; Blood Glucose; Body Mass Index; Carbamazepine; Comorbidity; Epilepsy; Female; Humans; Insulin; Insulin Resistance; Lamotrigine; Leptin; Lipids; Metabolic Syndrome; Obesity; Risk Factors; Sex Factors; Triazines; Valproic Acid

Leptin is an adipose tissue-derived peptide hormone, which acts as a satiety factor to reduce appetite by interactions with hypothalamic neurons. The other possible physiological functions of leptin are still unclear. In this study, we have evaluated dose-dependent effect of leptin on penicillin-induced epileptiform activity, analyzed by electrocorticogram (ECoG). The epileptiform activity was induced by microinjection of penicillin into the left sensorymotor cortex. Thirty minutes after penicillin injection, 1, 2 or 10 microg of leptin was administrated intracerebroventricularly (i.c.v.). Leptin (1, 2 or 10 microg) alone did not significantly change the spike amplitudes in non-penicillin pretreated control animals. One or two micrograms of leptin significantly increased the frequency of epileptiform activity in the penicillin-pretreated animals. The high dose of leptin (10 microg) did not significantly change either amplitude or frequency of epileptiform activity. One microgram i.c.v. leptin was the most effective dose in changing of frequency on penicillin-induced epileptiform activity. The proconvulsant effects of leptin appeared 90 min after leptin (1 and 2 microg) injection. These data indicate that leptin increases the frequency of penicillin-induced epileptic activity. We speculate that this action of leptin might suggest that leptin may be a proconvulsant substance.

Topics: Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Electroencephalography; Epilepsy; Female; Injections, Intraventricular; Leptin; Penicillins; Rats; Rats, Wistar

The authors studied 40 epileptic patients treated with valproate and 40 healthy controls for at least 2 years. At the end of follow-up, 15 epileptic patients (37.5%) had development of obesity. They showed circulating leptin and insulin levels significantly higher and ghrelin and adiponectin levels significantly lower than those of patients who did not gain weight.

Topics: Adiponectin; Adipose Tissue; Adolescent; Adult; Anticonvulsants; Appetite Regulation; Body Weight; Brain; Epilepsy; Female; Ghrelin; Humans; Insulin; Leptin; Obesity; Peptide Hormones; Up-Regulation; Valproic Acid

Topics: Adult; Anticonvulsants; Body Composition; Body Mass Index; Child; Epilepsy; Feedback; Female; Humans; Insulin; Leptin; Male; Obesity; Risk Factors; Valproic Acid

The obese gene product, leptin is an important circulating satiety factor that regulates energy balance via its actions in the hypothalamus. However, leptin receptors are also expressed in brain regions not directly associated with energy homeostasis, such as the hippocampus. Here, leptin inhibits hippocampal neurones via activation of large conductance Ca(2+)-activated K(+) (BK) channels, a process that may be important in regulating neuronal excitability. We now show that leptin receptor labelling is expressed on somata, dendrites and axons, and is also concentrated at synapses in hippocampal cultures. In functional studies, leptin potently and reversibly reduces epileptiform-like activity evoked in lean, but not leptin-resistant Zucker fa/fa rats. Furthermore, leptin also depresses enhanced Ca(2+) levels evoked following Mg(2+) removal in hippocampal cultures. The ability of leptin to modulate this activity requires activation of BK, but not K(ATP), channels as the effects of leptin were mimicked by the BK channel activator NS-1619, and inhibited by the BK channel inhibitors, iberiotoxin and charybdotoxin. The signalling mechanisms underlying this process involve stimulation of phosphoinositide 3-kinase (PI 3-kinase), but not mitogen-activated protein kinase (MAPK), as two structurally unrelated inhibitors of PI 3-kinase, LY294002 and wortmannin, blocked the actions of leptin. These data indicate that leptin, via PI 3-kinase-driven activation of BK channels, elicits a novel mechanism for controlling neuronal excitability. As uncontrolled excitability in the hippocampus is one underlying cause of temporal lobe epilepsy, this novel action of leptin could provide an alternative therapeutic target in the management of epilepsy.

Topics: Adenosine Triphosphate; Animals; Calcium; Cells, Cultured; Culture Media; Epilepsy; Hippocampus; Humans; Large-Conductance Calcium-Activated Potassium Channels; Leptin; Magnesium; Mitogen-Activated Protein Kinases; Neurons; Phosphatidylinositol 3-Kinases; Potassium Channels; Potassium Channels, Calcium-Activated; Rats; Receptors, Cell Surface; Receptors, Leptin; Recombinant Proteins

In this experiment, we studied the effect of valproate (VPA) on weight gain, and serum leptin levels in prepubertal epileptic children receiving VPA. Our purpose was to determine whether or not long-term use of VPA causes weight gain in childhood, and to evaluate serum leptin levels in a group of prepubertal children receiving VPA. Our study included 15 patients (9 males, 6 females) with new diagnosed epilepsy and 16 healthy age-matched controls (9 males, 7 females). The subjects' ages ranged from 9 months to 12 years. Weight gain was noted in 9 (60%) of 15 patients in the study group, and 8 (50%) of 16 subjects in the control group (p > .05). There was no difference between the groups for body mass index (BMI) and serum leptin levels. Although higher serum leptin levels were found in the patients treated with VPA weight gaining (5.65 +/- 3.06 ng/ml vs. 3.28 +/- 1.69 ng/ml), we did not find a difference between the patients weight gaining and nonweight gaining (p > .05). While a significant correlation between BMI and serum leptin levels was found in the study group (r = .704; p = .003), it was not significant in the control group (r = .330; p = .211). In conclusion, our findings showed that long-term use of VPA did not cause weight gain in a group of prepubertal children receiving VPA and, parallel to this, serum leptin levels were similar in both the control and study group.

Topics: Anticonvulsants; Body Mass Index; Child; Epilepsy; Female; Humans; Leptin; Male; Time; Valproic Acid; Weight Gain

Weight gain is an important adverse effect of valproate (VPA) therapy, and it is associated with hyperinsulinemia and hyperandrogenism in women with epilepsy. Leptin is considered a signaling factor regulating body weight and energy metabolism. In human subjects, obesity is in general associated with elevated serum leptin levels, suggesting decreased sensitivity to leptin. The present study aimed at evaluating the role of insulin and leptin in VPA-related obesity.. Body mass index (BMI) was calculated, and serum insulin and leptin levels were measured in 81 patients with epilepsy taking VPA and in 51 healthy control subjects.. Forty (49%) of the patients taking VPA and 25 (49%) of the control subjects were obese. The mean insulin levels were higher in VPA-treated patients than in the control subjects despite similar BMI values, when all subjects were included in the comparison. Both obese male and female patients taking VPA had higher serum insulin levels than the respective control subjects with similar BMI values. Serum insulin levels also were higher in lean male and lean female patients compared with the lean control subjects of same sex. Serum leptin levels did not differ between the VPA-treated patients and the control subjects.. Both obese and lean patients taking VPA for epilepsy have hyperinsulinemia, suggesting development of insulin resistance. This may be one of the factors leading to weight gain during VPA treatment. However, the results of the present study do not suggest an independent role for leptin in the pathogenesis of VPA-related obesity.

Topics: Adult; Body Mass Index; Body Weight; Epilepsy; Female; Humans; Insulin; Insulin Resistance; Leptin; Male; Obesity; Sex Factors; Valproic Acid

Weight gain has been recognized as an adverse effect of valproic acid therapy, but there are are no data about serum leptin levels in patients receiving this drug. To evaluate if valproic acid treatment in epileptic patients in whom obesity develops modifies serum levels of insulin and leptin, 40 female patients with epilepsy were evaluated before therapy and after 1 year of therapy. At the end of follow-up, 15 patients were obese and showed higher serum leptin and insulin levels than patients who did not gain weight. As in other types of obesity, elevation of serum leptin concentrations is related to the increase in body mass index.

Topics: Adolescent; Androgens; Anticonvulsants; Blood Glucose; Body Mass Index; Epilepsy; Female; Follicle Stimulating Hormone; Follow-Up Studies; Humans; Insulin; Leptin; Luteinizing Hormone; Proteins; Reference Values; Sex Hormone-Binding Globulin; Time Factors; Valproic Acid; Weight Gain