leptin and Seizures

Clozapine is, and will remain in the coming years, an irreplaceable drug in psychiatry which has elective indication in treatment-resistant schizophrenia, suicide risk in schizophrenia spectrum disorders, aggressiveness or violence in psychiatric patients, psychosis in Parkinson's disease, prevention and treatment of tardive dyskinesia. Unfortunately, the drug is largely underused for many and serious side effects. Only a good knowledge of these side effects and of the main strategies to prevent their occurrence or minimize their impact can allow overcoming the underutilization of this valuable therapy. The article describes the clinical and epidemiological features of the non-motor side effects of clozapine including blood dyscrasias, constipation, diabetes, enuresis, fever, hepatitis, hypersalivation, ileus, myocarditis, nephritis, priapism, seizures, serositis, weight gain and metabolic syndrome. The paper suggests several strategies, supported by scientific evidence, in the management of these side effects. The neuropsychiatric side effects of clozapine are not discussed in this review.

Topics: Antipsychotic Agents; Clozapine; Diabetes Mellitus, Type 2; Electroencephalography; Humans; Leptin; Metabolic Syndrome; Paraproteinemias; Receptor, Serotonin, 5-HT2C; Seizures; Weight Gain

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

The mechanism of linking neonatal seizures with long-term brain damage is unclear, and there is no effective drug to block this long-term pathological process. Recently, the fat-derived hormone leptin has been appreciated for its neuroprotective function in neurodegenerative processes, although less is known about the effects of leptin on neonatal seizure-induced brain damage. Here, we developed a "twist" seizure model by coupling pilocarpine-induced neonatal status epilepticus (SE) with later exposure to penicillin to test whether leptin treatment immediately after neonatal SE would exert neuroprotective effects on cognition, seizure threshold and hippocampal mossy fiber sprouting, as well if leptin had any influence on the expression of zinc transporter 3 (ZnT3) and calcium homeostasis-related CB-D28k in the hippocampus. Fifty Sprague-Dawley rats (postnatal day 6, P6) were randomly assigned to four groups: control (n = 10), control with intraperitoneal (i.p.) injection of leptin (Leptin, n = 10), pilocarpine-induced neonatal SE (RS), and RS i.p. leptin injection (RS+Leptin). At P6, all the rats in the RS group and RS+Leptin group were injected with lithium chloride i.p. (5 mEq/kg). Pilocarpine (320 mg/kg, i.p.) was administered 30 min after scopolamine methyl chloride (1 mg/kg) injection at P7 to block the peripheral effect of pilocarpine. From P8 to P14, the animals in the Leptin group and RS+Leptin group were given leptin (4 mg/kg, i.p.). The Morris water maze test was performed during P28-P33. Following routine seizure threshold detection and Timm staining procedures, Western blot analysis was performed for each group. Pilocarpine-induced neonatal SE severely impaired learning and memory abilities, reduced seizure threshold, and induced aberrant hippocampal CA3 mossy fiber sprouting. In parallel, there was a significantly down-regulated protein level of CB-D28k and an up-regulated protein level of ZnT3 in the hippocampus of the RS group. Furthermore, leptin treatment soon after neonatal SE for seven consecutive days counteracted these hyperexcitability-related alterations. These novel findings established that leptin has a neuroprotective role in the model of cholinergic neonatal SE and highlights ZnT3/CB-D28k associated-Zn (2+)/Ca (2+) signaling as a promising therapeutic target.

Topics: Animals; Animals, Newborn; Calbindin 1; Cation Transport Proteins; Disease Models, Animal; Hippocampus; Leptin; Maze Learning; Neuroprotective Agents; Random Allocation; Rats, Sprague-Dawley; Seizures

Metabolic disorders play an important role in the pathogenesis of many neurological diseases. Recent evidence suggests that leptin levels in peripheral blood and brain are lower in patients with epilepsy. Leptin is an energy-regulating hormone that plays a neuroprotective role in neurodegenerative diseases and brain trauma. However, little is known about the effects and molecular mechanisms of leptin treatment on long-term neurobehavioral impairment caused by developmental seizures. The present study evaluated whether chronic leptin treatment protected against neurobehavioral impairments induced by recurrent seizures in newborns treated with flurothyl. We also examined the effect of leptin on the expression of zinc/cPLA2-related autophagy signaling molecules and CaMKII in the cerebral cortex. Twenty Sprague-Dawley rats (6 days after birth, P6) were randomly divided into two groups, a neonatal seizure group and control group. Rats were subdivided on P13 into control, control + leptin (leptin, 2 mg/kg/day, continuous 10 days), seizure (RS), and seizure + leptin group (RS + leptin, 2 mg/kg/day for 10 consecutive days). Neurological behavioral parameters (negative geotaxis reaction reflex, righting reflex, cliff avoidance reflex, forelimb suspension reflex and open field test) were observed from P23 to P30. mRNA and protein levels in the cerebral cortex were detected using real-time RT-PCR and Western blotting, respectively. Flurothyl-induced seizures (RS group) produced long-term abnormal neurobehavior, which was improved with leptin treatment. Chronic leptin treatment restored several expression parameters affected by neonatal seizures, including seizure-induced up-regulated zinc transporter ZnT1/ZIP7, lipid membrane injury-related cPLA2, autophagy marker beclin-1/bcl2, LC3II/LC3I, and its execution molecule cathepsin-E, and down-regulated memory marker CaMK II alpha. Our results suggest that the early use of leptin after neonatal recurrent seizures may exert neuroprotective effects and antagonize the long-term neurobehavioral impairment caused by seizures. Autophagy-mediated Zn/cPLA2 and CaMK II signaling in the cerebral cortex may be involved in the neuroprotective effect of leptin. Our results provide new clues for anti-epileptogenetic treatment.

Topics: Animals; Animals, Newborn; Autophagy; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Carrier Proteins; Cerebral Cortex; Disease Models, Animal; Flurothyl; Group IV Phospholipases A2; Leptin; Male; Motor Activity; Neuroprotection; Neuroprotective Agents; Random Allocation; Rats, Sprague-Dawley; Seizures; Signal Transduction

The objective of this study is to examine the effects of the endogenous ligands leptin, ghrelin, and neuropeptide Y (NPY) on seizure generation, the oxidant/antioxidant balance, and cytokine levels, which are a result of immune response in a convulsive seizure model. With this goal, Wistar rats were divided into 5 groups-Group 1: Saline, Group 2: Saline+PTZ (65mg/kg), Group 3: leptin (4mg/kg)+PTZ, Group 4: ghrelin (80μg/kg)+PTZ, and Group 5: NPY (60μg/kg)+PTZ. All injections were delivered intraperitoneally, and simultaneous electroencephalography (EEG) records were obtained. Seizure activity was scored by observing seizure behavior, and the onset time, latency, and seizure duration were determined according to the EEG records. At the end of the experiments, blood samples were obtained in all groups to assess the serum TNF-α, IL-1β, IL-6, FGF-2, galanin, nitric oxide (NOֹ), malondialdehyde (MDA), and glutathione (GSH) levels. The electrophysiological and biochemical findings (p<0.05) of this study show that all three peptides have anticonvulsant effects in the pentylenetetrazol (PTZ)-induced generalized tonic-clonic convulsive seizure model. The reduction of the levels of the pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 caused by leptin, ghrelin, and NPY shows that these peptides may have anti-inflammatory effects in epileptic seizures. Also, leptin significantly increases the serum levels of the endogenous anticonvulsive agent galanin. The fact that each one of these endogenous peptides reduces the levels of MDA and increases the serum levels of GSH leads to the belief that they may have protective effects against oxidative damage that is thought to play a role in the pathogenesis of epilepsy. Our study contributes to the clarification of the role of these peptides in the brain in seizure-induced oxidative stress and immune system physiology and also presents new approaches to the etiology and treatment of tendency to epileptic seizures.

Topics: Animals; Cytokines; Disease Models, Animal; Fibroblast Growth Factor 2; Galanin; Ghrelin; Interleukin-1beta; Interleukin-6; Leptin; Malondialdehyde; Neuropeptide Y; Oxidative Stress; Pentylenetetrazole; Rats; Rats, Wistar; Seizures; Tumor Necrosis Factor-alpha

To evaluate the changes in serum CCK-8 and leptin levels in patients with refractory epilepsy treated with the ketogenic diet (KD).. In this prospective study, patients aged between one and 40 years with refractory epilepsy were included. CCK-8 and leptin were measured in serum at baseline and after three and 12 months of treatment with the KD using an enzyme-linked Immunoabsorbant Assay. Seizure frequency and responsiveness were calculated.. Fifty-four patients were included; 26 patients (48%) were still on the KD at 12 months. After three and 12 months, respectively, 39% and 26% were responders. CCK-8 values were statistically significantly increased at three months (p=0.005) and 12 months (p=0.012). In responders, at three months follow-up, this increase of CCK-8 was significant (p=0.020), whereas in the non-responders it was not (p=0.34). Leptin values were decreased at three and 12 months, the decrease at three months being statistically significant in post-pubertal men (p=0.028) and post-pubertal women (p=0.007).. In responders to the KD, serum CCK-8 increased statistically significantly during treatment at three months. Serum leptin decreased statistically significantly at three months in men and in post-pubertal women. It is plausible that the increase of CCK-8 and the decrease of leptin contribute to the anti-convulsive effect of the KD.

Topics: Adolescent; Adult; Biomarkers; Child; Child, Preschool; Cholecystokinin; Diet, Ketogenic; Drug Resistant Epilepsy; Enzyme-Linked Immunosorbent Assay; Female; Follow-Up Studies; Humans; Infant; Leptin; Male; Peptide Fragments; Prospective Studies; Seizures; Time Factors; Treatment Outcome; Young Adult

The aim of the present study was to investigate the role of NO as a mediator of leptin action at the penicillin-induced epileptiform activity in rat. Thirty minutes after penicillin injection, leptin, at a dose of 1 microg, significantly increased the mean frequency of epileptiform activity without changing the amplitude. The effects of systemic administration of nitric oxide synthase (NOS) inhibitors, non-selective NG-nitro-L-arginine methyl ester (L-NAME), selective neuronal NOS inhibitor, 7-nitroindazole (7-NI) and NO precursor, L-arginine on the effects of leptin were investigated. The occurrence of anticonvulsant activity of 7-NI (40 mg/kg, i.p.) was significantly delayed in the presence of leptin (1 microg). The administration of L-NAME (60 mg/kg, i.p.), 30 min before leptin (1 microg) application, did not influence proconvulsant activity of leptin. The administration of L-arginine (1000 mg/kg, i.p.) 30 min before the effective dose of leptin (1 microg, i.c.v.) reversed the proconvulsant effects of leptin whereas the same dose of its inactive enantiomer, D-arginine (1000 mg/kg, i.p.) failed to influence the proconvulsant effect of leptin. The electrophysiological evidence of the present study suggests that neuronal NOS/NO pathway is involved in mediating leptin effects on penicillin-induced epileptiform activity.

Topics: Animals; Anticonvulsants; Arginine; Brain; Convulsants; Electroencephalography; Enzyme Inhibitors; Indazoles; Leptin; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Penicillins; Rats; Rats, Wistar; Seizures; Signal Transduction

The metabolic-related hormone, leptin has been suggested for clinical use as an anticonvulsant based upon data generated from in vitro and in vivo non-human studies. However, a number of other non-human experiments have demonstrated proconvulsant activity for leptin. The current study investigated potential pro- and anticonvulsant effects of leptin during exposure to either glutamate (the major endogenous excitatory neurotransmitter) or three subtype-selective glutamate receptor agonists (N-methyl-d-aspartic acid [NMDA], alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA], and kainate). Male C57BL/6JRj mice were pretreated with leptin (0.1-10mg/kg, i.p.) and then administered doses of the glutamate receptor agonists (i.p.) that had been previously shown to result in clonic convulsions in approximately half of the animals tested. Leptin had no clear convulsant-related effects with either glutamate or AMPA, but it exhibited dose-related, proconvulsant activity (decreased latency to first occurrence of various convulsion-related signs, and increased percentage of animals exhibiting such signs) with both NMDA and kainate. The proconvulsant effects of leptin observed during the current study suggest that a cautious approach should be taken when administering leptin to individuals who may be prone to seizures.

Topics: Animals; Anticonvulsants; Convulsants; Dose-Response Relationship, Drug; Excitatory Amino Acid Agonists; Humans; Leptin; Male; Mice; Mice, Inbred C57BL; Receptors, Glutamate; Seizures

Topics: Antipsychotic Agents; Clozapine; Histamine Agonists; Histamine H1 Antagonists; Humans; Leptin; Psychotic Disorders; Receptors, Histamine H1; Seizures; Treatment Outcome

Women with epilepsy often suffer from weight gain. A similar phenomenon is seen in female rats that are kindled from the amygdala. Interestingly, it has been reported that kindling of the left amygdala causes more weight gain than kindling of the right amygdala. The present study was designed to confirm and extend that effect.. Female Wistar rats were kindled from the left or right basolateral amygdala to a criterion of 40 stage 5 seizures. Control subjects were handled but not stimulated. Subjects were weighed weekly for the duration of the study. Twenty-four hours following the last kindled seizure, kindled subjects and their yoked controls were sacrificed and their brains and serum were extracted.. Kindled subjects weighed significantly more than controls at the end of the kindling procedure and had significantly higher serum levels of leptin. No laterality effects were seen in either weight gain or leptin levels, however.. Amygdala kindling increases weight gain and serum leptin levels in rats, but in the present study no laterality effects were seen.

Topics: Amygdala; Analysis of Variance; Animals; Body Weight; Disease Progression; Electric Stimulation; Electrodes, Implanted; Estrous Cycle; Female; Functional Laterality; Kindling, Neurologic; Leptin; Rats; Rats, Wistar; Seizures; Weight Gain

Leptin plays a pivotal role in the regulation of energy homeostasis and metabolism, primarily by acting on neurons in the hypothalamus that control food intake. However, leptin receptors are more widely expressed in the brain suggesting additional, as yet unknown, functions of leptin. Here we show that both embryonic and adult hippocampal neurons express leptin receptors coupled to activation of STAT3 and phosphatidylinositol 3-kinase-Akt signaling pathways. Leptin protects hippocampal neurons against cell death induced by neurotrophic factor withdrawal and excitotoxic and oxidative insults. The neuroprotective effect of leptin is antagonized by the JAK2-STAT3 inhibitor AG-490, STAT3 decoy DNA, and phosphatidylinositol 3-kinase/Akt inhibitors but not by an inhibitor of MAPK. Leptin induces the production of manganese superoxide dismutase and the anti-apoptotic protein Bcl-xL, and stabilizes mitochondrial membrane potential and lessens mitochondrial oxidative stress. Leptin receptor-deficient mice (db/db mice) are more vulnerable to seizure-induced hippocampal damage, and intraventricular administration of leptin protects neurons against seizures. By enhancing mitochondrial resistance to apoptosis and excitotoxicity, our findings suggest that leptin signaling serves a neurotrophic function in the developing and adult hippocampus.

Topics: Animals; bcl-X Protein; Cell Survival; Enzyme Activation; Hippocampus; Janus Kinases; Leptin; Male; Membrane Potential, Mitochondrial; Mice; Mice, Inbred C57BL; Mitochondria; Neurons; Neuroprotective Agents; Neurotoxins; Oxidative Stress; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Receptors, Leptin; Seizures; Signal Transduction; STAT3 Transcription Factor; Superoxide Dismutase; Up-Regulation

Leptin is a hormone that reduces excitability in some hypothalamic neurons via leptin receptor activation of the JAK2 and PI3K intracellular signaling pathways. We hypothesized that leptin receptor activation in other neuronal subtypes would have anticonvulsant activity and that intranasal leptin delivery would be an effective route of administration. We tested leptin's anticonvulsant action in 2 rodent seizure models by directly injecting it into the cortex or by administering it intranasally. Focal seizures in rats were induced by neocortical injections of 4-aminopyridine, an inhibitor of voltage-gated K+ channels. These seizures were briefer and less frequent upon coinjection of 4-aminopyridine and leptin. In mice, intranasal administration of leptin produced elevated brain and serum leptin levels and delayed the onset of chemical convulsant pentylenetetrazole-induced generalized convulsive seizures. Leptin also reduced neuronal spiking in an in vitro seizure model. Leptin inhibited alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) receptor-mediated synaptic transmission in mouse hippocampal slices but failed to inhibit synaptic responses in slices from leptin receptor-deficient db/db mice. JAK2 and PI3K antagonists prevented leptin inhibition of AMPAergic synaptic transmission. We conclude that leptin receptor activation and JAK2/PI3K signaling may be novel targets for anticonvulsant treatments. Intranasal leptin administration may have potential as an acute abortive treatment for convulsive seizures in emergency situations.

Topics: 4-Aminopyridine; Administration, Intranasal; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Convulsants; Hypothalamus; Janus Kinase 2; Leptin; Male; Mice; Mice, Knockout; Neurons; Pentylenetetrazole; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Potassium Channel Blockers; Potassium Channels, Voltage-Gated; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Receptors, Leptin; Seizures; Synaptic Transmission

Secreted from adipose tissue at levels proportional to fat stores, the hormone leptin is a critical regulator of the hypothalamic machinery that controls feeding and energy metabolism. Despite the critical role of leptin in the maintenance of energy homeostasis, no leptin-based therapeutic approaches have emerged to combat metabolic disorders such as obesity or diabetes. In this issue of the JCI, Xu et al. report a robust influence of leptin, beyond its role in metabolism, on hippocampal neuronal processes implicated in the etiology of epileptic seizures, learning, and memory (see the related article beginning on page 272). They show, in two rodent seizure models, that leptin administered directly to the brain or nasal epithelium suppresses seizures via direct effects on glutamate neurotransmission in the hippocampus. These observations suggest that leptin may have therapeutic potential in the treatment of epilepsy and strengthen the notion that peripheral metabolic hormones such as leptin play important roles in the regulation of higher brain functions.

Topics: 4-Aminopyridine; Administration, Intranasal; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Convulsants; Hypothalamus; Janus Kinase 2; Leptin; Male; Mice; Mice, Knockout; Neurons; Pentylenetetrazole; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Potassium Channel Blockers; Potassium Channels, Voltage-Gated; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Receptors, Leptin; Seizures; Synaptic Transmission

Leptin modulates multiple ion channels making its net effect on brain excitability difficult to predict. One method of determining leptin's net effect on brain excitability is to examine brain excitability during chronic leptin deficiency. We compared the susceptibility of leptin deficient ob/ob and wild type mice to pentylenetetrazol (PTZ) induced seizures using continuous video electroencephalogram (EEG) recordings. We found that ob/ob mice were more likely to die and were more susceptible to generalized clonic and clonic-tonic seizures than wild type mice at submaximal PTZ doses. These findings suggest that chronic leptin deficiency in vivo increases seizure susceptibility.

Topics: Analysis of Variance; Animals; Dose-Response Relationship, Drug; Electroencephalography; Leptin; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Pentylenetetrazole; Reaction Time; Seizures; Severity of Illness Index

Recent studies conducted in our laboratory have demonstrated marked increases in both serum leptin levels and colony numbers in bone marrow progenitor cells following long-term kindled seizures in rats. The present study sought to determine whether such changes in hematopoietic functions following kindling are linked to increased serum leptin levels. Kindled stage V seizures were induced for 30 days in Sprague-Dawley rats by stimulation of the basal complex of amygdala. The results revealed colony numbers in colony forming units-granulocyte/macrophage (CFU-GM) cultures from kindled rats increased significantly, an effect that was blocked by the presence of an anti-leptin antibody. The results further demonstrated that the addition of serum obtained from kindled rats to CFU-GM cultures from control rats significantly increased the numbers of colonies relative to non-serum added cultures. Moreover, the proliferative effects of serum from kindled rats were also blocked by adding an anti-leptin antibody. These findings were confirmed from the observations that the long isoform of the leptin receptor, which is capable of signal transduction, was present only in kindled, but not in control rats. Thus, the results provide evidence that the hematopoietic changes observed following long-term kindling are directly associated with elevated serum leptin levels.

Topics: Analysis of Variance; Animals; Antibodies; Cell Count; Colony-Forming Units Assay; Female; Hematopoiesis; Hypoxanthine Phosphoribosyltransferase; Kindling, Neurologic; Leptin; Rats; Rats, Sprague-Dawley; Receptors, Cell Surface; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Seizures; Time Factors

The present study sought to determine the effects of kindled seizures generated from the left and right amygdala upon weight gain in rat. Seventy-five female Sprague-Dawley rats were implanted with electrodes in basal amygdala of the left and right hemispheres. A kindling paradigm was employed in which electrical stimulation was applied once per day for 30 days after Stage 5 seizures. An electrode was implanted into the basal amygdala of the control rats but no stimulation was applied. All rats were weighed daily during the course of the experiment and changes in weight during this period were recorded for all rats. The results demonstrated that kindling from either the left or right amygdala induced significant increases in weight gain relative to the control rats. However, kindling from the left basal amygdala induced increases in body weight that were four times greater than control rats and two times greater than the rats kindled from the right side of the basal amygdala. Likewise, serum leptin levels, which were highly correlated with weight gain, also showed significantly greater increases in left amygdaloid kindled rats relative to rats kindled from the right amygdala and control rats. These findings demonstrate that basal amygdaloid kindling induces significant increases in weight gain and that the magnitude of these effects is linked to the dominance of the left hemisphere.

Topics: Amygdala; Analysis of Variance; Animals; Dominance, Cerebral; Electric Stimulation; Energy Metabolism; Female; Kindling, Neurologic; Leptin; Rats; Rats, Sprague-Dawley; Seizures; Weight Gain

Neuropeptide Y (NPY), a 36-amino-acid transmitter distributed throughout the nervous system, is thought to function as a central stimulator of feeding behaviour. NPY has also been implicated in the modulation of mood, cerebrocortical excitability, hypothalamic-pituitary signalling, cardiovascular physiology and sympathetic function. However, the biological significance of NPY has been difficult to establish owing to a lack of pharmacological antagonists. We report here that mice deficient for NPY have normal food intake and body weight, and become hyperphagic following food deprivation. Mutant mice decrease their food intake and lose weight, initially to a greater extent than controls, when treated with recombinant leptin. Occasional, mild seizures occur in NPY-deficient mice and mutants are more susceptible to seizures induced by a GABA (gamma-aminobutyric acid) antagonist. These results indicate that NPY is not essential for certain feeding responses or leptin actions but is an important modulator of excitability in the central nervous system.

Topics: Animals; Body Weight; Eating; Feeding Behavior; Female; Food Deprivation; GABA Antagonists; Gene Targeting; Humans; Hyperphagia; Leptin; Male; Mice; Neuropeptide Y; Pentylenetetrazole; Proteins; Seizures