Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Sensitivity to leptin and susceptibility to seizures of mice lacking neuropeptide Y. 870 Jan 97

Neuropeptide Y (NPY), a 36 amino acid neuromodulator that is secreted by neurons throughout the peripheral and central nervous system, has been implicated in the control of many physiological processes. We have begun to examine its role in regulation of appetite, behavior, and excitotoxicity by examining mice that are unable to produce NPY as a consequence of gene inactivation. These mutant mice are remarkably normal when reared under standard vivarium conditions. Despite considerable evidence that NPY plays a central role in stimulating appetite, NPY-deficient mice eat normally, grow normally, and refeed after a fast normally. Furthermore, all of their endocrine responses to fasting are normal. The response of NPY-null mice to diet-induced obesity, chemically induced obesity (monosodium glutamate and gold thioglucose), and genetic-based obesity (lethal yellow agouti, Ay; uncoupling protein-diphtheria toxin transgenics, UCP-DT) were all normal. However, NPY deficiency does partially ameliorate the obesity and all of the adverse endocrine effects of leptin deficiency in ob/ob mice. NPY-null mice as well as mice deficient in both NPY and leptin are more sensitive to leptin, suggesting that NPY may normally have a tonic inhibitory action on leptin-mediated satiety signals. NPY-null mice display the normal voracious feeding response to injected NPY. Thus, the only condition where we have observed a role for NPY in body-weight regulation is in the context of complete leptin deficiency--where absence of NPY is beneficial. The activity and general behavior of NPY-null mice are normal. They appear to have normal spatial and contextual learning ability; however, they manifest more anxiety under some conditions. NPY-null mice occasionally display spontaneous, seizure-like events. They also are less able to terminate seizures induced by GABA receptor antagonists or glutamate receptor agonists. These observations are consistent with previous data suggesting that NPY plays an important role in dampening excitotoxicity.
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PMID:Life without neuropeptide Y. 976 8

Insight into the mechanisms of action of neurotrophic growth factors has been obtained through the identification and characterization of gene products that are regulated or modified at the transcriptional, translational, and/or posttranslational level in response to neurotrophin treatment. VGF (non-acronymic) was identified approximately 15 years ago as a nerve growth factor (NGF)-regulated transcript in rat PC12 pheochromocytoma cells. Subsequent studies have demonstrated that neurotrophins such as NGF and brain-derived neurotrophic factor induce vgf gene expression relatively rapidly in PC12 cells and cultured cortical neurons, respectively, in comparison to less robust regulation by epidermal growth factor (EGF) and insulin, growth factors which do not trigger the neuronal differentiation of PC12 cells. vgf gene expression is stimulated in vitro by NGF and the ras/map kinase signaling cascade through a CREB-dependent mechanism, while in vivo, VGF mRNA levels are regulated by neuronal activity, including long-term potentiation, seizure, and injury. Both the mRNA and encoded approximately 68-kDa protein (VGF) are selectively synthesized in neuroendocrine and neuronal cells. The predicted VGF sequence is rich in paired basic amino acid residues that are potential sites for proteolytic processing, and VGF undergoes regulated release from dense core secretory vesicles. Although VGF mRNA is synthesized widely, by neurons in the brain, spinal cord, and peripheral nervous system, its expression is particularly abundant in the hypothalamus. In addition, VGF peptides are found in hypophysial, adrenal medullary, gastrointestinal, and pancreatic endocrine cells, suggesting important neuroendocrine functions. Recent analysis of VGF knockout mice indeed demonstrates that VGF plays a critical role in the control of energy homeostasis. VGF knockout mice are thin, small, hypermetabolic, hyperactive, and relatively infertile, with markedly reduced leptin levels and fat stores and altered hypothalamic pro-opiomelanocortin, neuropeptide Y, and agouti-related peptide expression. Coupled with the demonstration that VGF mRNA levels are induced in the normal mouse hypothalamic arcuate nuclei in response to fasting, important central and peripheral roles for VGF in the regulation of metabolism are suggested. Here we review previous studies of VGF in the broader context of its newly recognized role in the control of energy balance and propose several models and experimental approaches that may better define the mechanisms of action of VGF.
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PMID:VGF: a novel role for this neuronal and neuroendocrine polypeptide in the regulation of energy balance. 1088 40

Topiramate is currently used in the treatment of epilepsy, but this anticonvulsant drug has also been reported to exert mood-stabilizing effects and induce weight loss in patients. Neuropeptide Y (NPY) is abundantly and widely distributed in the mammalian central nervous system and centrally administered NPY markedly reduces pharmacologically induced seizures and induces antidepressant-like activity as well as feeding behavior. Two other peptides, galanin and corticotropin-releasing hormone (CRH), have also been proposed to play a modulatory role in mood, appetite, and seizure regulation. Consequently, we investigated the effects of single and repeated topiramate (10 days, once daily: 40 mg/kg i.p.) or vehicle treatment in 'depressed' flinders sensitive line (FSL) and control Flinders resistant line (FRL) rats on brain regional peptide concentrations of NPY, galanin, and CRH. The handling associated with repeated injections reduced hippocampal levels of NPY- and galanin-like immunoreactivities (LI) while NPY- and CRH-LI levels were increased in the hypothalamus, regardless of strain or treatment. In the hippocampus, concentrations of NPY-LI, galanin-LI, and CRH-LI were lower in FSL than FRL animals. Repeated topiramate treatment selectively normalized NPY-LI in this region in the FSL animals. In the hypothalamus, galanin-LI was reduced in FSL compared to FRL animals. Topiramate elevated the hypothalamic concentrations of NPY-LI, CRH-LI, and galanin-LI in both strains. Furthermore, topiramate elevated serum leptin but not corticosterone levels. The present findings show that topiramate has distinct effects on abnormal hippocampal levels of NPY, with possible implications for its anticonvulsant and mood-stabilizing effects. Furthermore, stimulating hypothalamic NPY-LI, CRH-LI and galanin-LI as well as serum leptin levels may be associated with the weight loss-inducing effects of topiramate.
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PMID:Topiramate normalizes hippocampal NPY-LI in flinders sensitive line 'depressed' rats and upregulates NPY, galanin, and CRH-LI in the hypothalamus: implications for mood-stabilizing and weight loss-inducing effects. 1270 Jun 90

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.
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PMID:Amygdaloid kindled seizures induce weight gain that reflects left hemisphere dominance in rats. 1527 25

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.
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PMID:Long-term kindled seizures induce alterations in hematopoietic functions: role of serum leptin. 1604 Feb 33

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.
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PMID:Leptin-mediated cell survival signaling in hippocampal neurons mediated by JAK STAT3 and mitochondrial stabilization. 1799 59

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.
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PMID:Leptin inhibits 4-aminopyridine- and pentylenetetrazole-induced seizures and AMPAR-mediated synaptic transmission in rodents. 1809 79

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.
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PMID:Anticonvulsant effects of leptin in epilepsy. 1809 72

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.
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PMID:Increased severity of pentylenetetrazol induced seizures in leptin deficient ob/ob mice. 1824 89


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