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)

Patients and experimental models of temporal lobe epilepsy display loss of somatostatinergic neurons in the dentate gyrus. To determine if loss of the peptide somatostatin contributes to epileptic seizures we examined kainate-evoked seizures and kindling in somatostatin knockout mice. Somatostatin knockout mice were not observed to experience spontaneous seizures. Timm staining, acetylcholinesterase histochemistry, and immunocytochemistry for NPY, calbindin, calretinin, and parvalbumin revealed no compensatory changes or developmental abnormalities in the dentate gyrus of somatostatin knockout mice. Optical fractionator counting of Nissl-stained hilar neurons showed similar numbers of neurons in wild type and somatostatin knockout mice. Mice were treated systemically with kainic acid to evoke limbic seizures. Somatostatin knockout mice tended to have a shorter average latency to stage 5 seizures, their average maximal behavioral seizure score was higher, and they tended to be more likely to die than controls. In response to kindling by daily electrical stimulation of the perforant path, to more specifically challenge the dentate gyrus, mean afterdischarge duration in somatostatin knockout mice was slightly longer, but the number of treatments to five stage 4-5 seizures was similar to controls. Although we cannot exclude the possibility of undetected compensatory mechanisms in somatostatin knockout mice, these findings suggest that somatostatin may be mildly anticonvulsant, but its loss alone is unlikely to account for seizures in temporal lobe epilepsy.
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PMID:Heightened seizure severity in somatostatin knockout mice. 1182 9

The results of several studies have contributed to the hypothesis that BDNF promotes seizure activity, particularly in adult hippocampus. To test this hypothesis, BDNF, vehicle (phosphate-buffered saline, PBS), or albumin was infused directly into the hippocampus for 2 weeks using osmotic minipumps. Rats were examined behaviorally, electrophysiologically, and anatomically. An additional group was tested for sensitivity to the convulsant pilocarpine. Spontaneous behavioral seizures were observed in BDNF-infused rats (8/32; 25%) but not in controls (0/20; 0%). In a subset of six animals (three BDNF, three albumin), blind electrophysiological analysis of scalp recordings contralateral to the infused hippocampus demonstrated abnormalities in all BDNF rats; but not controls. Neuronal loss in BDNF-treated rats was not detected relative to PBS- or albumin-treated animals, but immunocytochemical markers showed a pattern of expression in BDNF-treated rats that was similar to rats with experimentally induced seizures. Thus, BDNF-infused rats had increased expression of NPY in hilar neurons of the dentate gyrus relative to control rats. NPY and BDNF expression was increased in the mossy fiber axons of dentate gyrus granule cells relative to controls. The increase in NPY and BDNF expression in BDNF-treated rats was bilateral and occurred throughout the septotemporal axis of the hippocampus. Mossy fiber sprouting occurred in five BDNF-treated rats but no controls. In another group of infused rats that was tested for seizure sensitivity to the convulsant pilocarpine, BDNF-infused rats had a shorter latency to status epilepticus than PBS-infused rats. In addition, the progression from normal behavior to severe seizures was faster in BDNF-treated rats. These data support the hypothesis that intrahippocampal BDNF infusion can facilitate, and potentially initiate, seizure activity in adult hippocampus.
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PMID:Spontaneous limbic seizures after intrahippocampal infusion of brain-derived neurotrophic factor. 1192 62

Organotypic hippocampal slice cultures were treated with the muscarinic agonist pilocarpine to study induced seizure-like activity and changes in neurotrophin and neuropeptide expression. For establishment of a seizure-inducing protocol, 2-week-old cultures derived from 6-8-day-old rats were exposed to 0.1 mM to 5 mM of pilocarpine for 4 h to 7 days. Other cultures were treated with pilocarpine for 7 days and left for 7-14 days in normal medium. Age-matched, non-treated cultures served as controls. Intracellular recordings from CA1 pyramidal cells revealed increased spontaneous activity in 31 of 35 cultures superfused with 0.1 or 5 mM pilocarpine. Epileptiform discharges were recorded in 17 of the 31 cultures, and 19 displayed frequencies specifically in the 6-12-Hz (Theta rhythm) range when superfused with pilocarpine. The pilocarpine effect was blocked by simultaneous superfusion with the muscarinic receptor antagonist atropine (100 microM). Regardless of dose and exposure time, the pilocarpine treatment induced very limited neuronal cell death, recorded as cellular propidium iodide uptake. Cultures exposed to 5 mM pilocarpine for up to 7 days displayed increased BDNF expression when analyzed by Western blot and ELISA. This BDNF increase correlated with increased neuropeptide Y immunoreactivity, known to accompany seizure activity. Addition of BDNF (200 ng/ml) to otherwise untreated cultures also upregulated NPY expression. The pilocarpine-induced seizure-like activity in hippocampal slice cultures, with concomitant increase in BDNF and NPY expression, is compared with in vivo observations and discussed in terms of the potential use of the easily accessible slice cultures in experimental seizure research.
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PMID:Pilocarpine-induced seizure-like activity with increased BNDF and neuropeptide Y expression in organotypic hippocampal slice cultures. 1223 Dec 34

We compared the anticonvulsant actions of dynorphin A (1-13), galanin, neuropeptide Y and somatostatin in a model of self-sustaining status epilepticus (SSSE). SSSE was induced in adult Wistar rats by 30 min intermittent perforant path stimulation. Peptides or saline were injected into the hilus of the dentate gyrus 10 min after the end of perforant path stimulation. EEG was analyzed using Harmonie software (Stellate systems). While all neuropeptides showed significant seizure protecting effects, their anticonvulsant profiles followed different patterns: somatostatin and NPY induced strong, but transient suppression of spikes and seizures, while seizure suppression by dynorphin and galanin was more profound and irreversible.
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PMID:Anticonvulsant effects of four neuropeptides in the rat hippocampus during self-sustaining status epilepticus. 1236 56

Nitric oxide (NO) is a short-lived radical, which modulates synaptic plasticity, neuronal oscillations and cerebral blood flow. NOS-containing neurones can be detected anatomically by nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) histochemistry or by NOS immunohistochemistry. Neuropeptide Y(NPY) is the most abundant peptide in the brain. NPY is connected with several vital functions, such as a feeding behaviour, sexual maturation, regulation of circadian rhythms, body temperature, blood pressure and neuroendocrine secretions. Neuropeptide Y also modulates anxiety-related disorders, limbic epileptic seizures as well as learning and memory processes. The study was performed on 45 Wistar rats of various ages (PO, P4, P7, P10, P14, P21, P30, P60, and P120; P--postnatal day). The free-floating sections were stained with standard immunohistochemistry methods. Thereafter the histological sections were studied using the confocal laser microscope equipped. For 3D reconstruction the image analysis program LaserSharp 2000v. 2.0 (Bio-Rad, UK) was used. We found that in the newborn rat both NOS- and NPY-immunoreactivity was weak. It had been increasing gradually until the 7th day of postnatal life, after that until P14 it was maintained on the similar level, and then the number of immunolabelled cells deceased. The developmental changes concerned cell morphology as well--until the 10th day of life the immunoreactive cells were immature, with round or oval bodies and had only a few fibres. From P14 the cells' morphology became similar to that in adult.
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PMID:Distribution of nitric oxide synthase and neuropeptide Y neurones during the development of the hippocampal formation in the rat. 1272 88

The anticonvulsant effect of NPY may depend on Y(2) and/or Y(5) receptor-mediated inhibition of glutamate release in critical areas, such as the hippocampus. However, Y(2) and Y(5) receptor levels have been reported to increase and decrease, respectively, in the epileptic hippocampus, implicating that the profile of NPY effects may change accordingly. The aim of this study was to evaluate the differential effects of NPY on glutamate release in the normal and in the epileptic hippocampus. Thus, we pharmacologically characterized the effects of NPY on the release of [(3)H]D-aspartate, a valid marker of endogenous glutamate, from synaptosomes prepared from the whole hippocampus and from the three hippocampal subregions (dentate gyrus and CA1 and CA3 subfields) of control and kindled rats, killed 1 week after the last stimulus-evoked seizure. In the whole hippocampus, NPY does not significantly affect stimulus-evoked [(3)H]D-aspartate overflow. In synaptosomes prepared from control rats, NPY significantly inhibited 15 mM K(+)-evoked [(3)H]D-aspartate overflow only in the CA1 subfield (approx. -30%). Both Y(2) and Y(5) receptor antagonists (respectively, 1 microM BIIE0246 and 1 microM CGP71683A) prevented this effect, suggesting the involvement of both receptor types. In contrast, in synaptosomes prepared from kindled rats NPY significantly inhibited 15 mM K(+)-evoked [(3)H]D-aspartate overflow in the CA1 subfield and in the dentate gyrus (approx. -30%). Only the Y(2) (not the Y(5)) antagonist prevented these effects. These data indicate a critical role for the Y(2) receptor in the inhibitory control of glutamate release in the kindled hippocampus and, thus, suggest that the anticonvulsant effect of NPY in the epileptic brain is most likely Y(2), but not Y(5), receptor-mediated.
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PMID:Changes in NPY-mediated modulation of hippocampal [3H]D-aspartate outflow in the kindling model of epilepsy. 1274 Aug 67

The endogenous NPY system in the brain is centrally involved in seizure regulation. The present paper reviews the evidence that exogenously applied NPY receptor ligands can inhibit epileptic seizures in various rodent in vitro and in vivo models. Agonists at Y2 and/or Y5 receptors and antagonists at Y1 receptors appear to inhibit seizures, depending on the seizure model studied. Although progress has been made, further studies are needed using transgenic animals as well as novel selective agonists and antagonists to firmly identify the NPY receptors mediating antiepileptic effects. This may lead to the development of future antiepileptic drug treatments targeting the NPY system.
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PMID:Neuropeptide Y and seizures: effects of exogenously applied ligands. 1533 77

Neuropeptide Y inhibits neuronal excitability and seizures in various experimental models. This peptide delays kindling epileptogenesis but the receptors involved in this action are unknown. We have studied the role of Y5 receptors in kindling using the selective antagonist GW438014A (IC50=210 nM), a small heterocycle molecule that crosses the blood-brain barrier, and the selective peptide agonist Ala31Aib34 NPY (IC50=6.0 nM). Intraperitoneal injection of GW438014A (10 mg/kg), 30 min before the beginning of a rapid-kindling protocol, significantly accelerated the rate of kindling acquisition as compared to vehicle-injected rats. Thus, the number of electrical stimuli required to reach stages 3 and 4-5 of kindling were reduced by 50% and 25%, respectively. The average afterdischarge duration in the stimulated hippocampus was prolonged by 2-fold. Conversely, kindling rate was delayed by intracerebroventricular administration of 24 nmol Ala31Aib32 NPY. Thus, the number of stimuli necessary to reach stages 2 and 3 of kindling was increased by 3- and 4-fold, respectively. During the stimulation protocol (40 stimuli) none of the rats treated with the Y5 agonist showed stages 4-5 seizures. Twenty-four hours after the last kindling stimulation, thus during the re-test session, Y5 agonist- or antagonist-treated rats had stages 4-5 seizures as their controls. In rats treated with both the antagonist and the agonist, kindling rate was similar to vehicle-injected rats. These data indicate that Y5 receptors mediate inhibitory effects of NPY in kindling and display anticonvulsant rather then antiepileptogenic effects upon agonist stimulation.
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PMID:Neuropeptide Y Y5 receptors inhibit kindling acquisition in rats. 1558 17

Neuronal loss and irreversible brain damage often cause the worsening of symptoms and the decreased efficacy of pharmacological treatment occurring in epileptic patients and animal models of kindling. Recently we reported that the neurotransmitter/neuromodulatory peptide Cholecystokinin-8 (CCK-8) is able to induce the structural and functional neuronal recovery of chemical- and surgical-induced lesions when i.p. injected in rodents. The present study therefore, was aimed at verifying the hypothesis that treatment with a CCK-8 dose having a neuroprotective action might affect brain alterations and the development of kindling in adult rats receiving the convulsant agent pentylenetetrazole (PTZ). Compared to rats receiving Saline prior to PTZ, which manifested clonic-tonic seizures (Class 5 behavioural change scale) after three weeks of treatment, rats pre-treated with CCK-8 showed an improvement of behavioural score exhibiting myoclonus and occasionally tonic seizures (Class 3/4). This decreased susceptibility to develop convulsions was associated with the recovery of PTZ-induced reduction of ChAT levels in forebrain and GABA/GAD expression in the hippocampus. Furthermore, NPY immunoreactivity distribution and NPY mRNA levels were also increased in the hippocampus of rats receiving CCK-8 injection before each PTZ treatment. These data indicate that CCK-8 possesses the ability to prevent and/or suppress the convulsant effects of PTZ by stimulating the synthesis of neurotransmitters/peptides involved in the inhibition of hippocampal hyper-excitability. Our findings suggest that CCK-8 may have anticonvulsant and neuroprotective properties that merit further investigation.
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PMID:CCK-8 prevents the development of kindling and regulates the GABA and NPY expression in the hippocampus of pentylenetetrazole (PTZ)-treated adult rats. 1581 7

Major aspects of temporal lobe epilepsy (TLE) can be reproduced in mice following a unilateral injection of kainic acid into the dorsal hippocampus. This treatment induces a non-convulsive status epilepticus and acute lesion of CA1, CA3c and hilar neurons, followed by a latent phase with ongoing ipsilateral neuronal degeneration. Spontaneous focal seizures mark the onset of the chronic phase. In striking contrast, the ventral hippocampus and the contralateral side remain structurally unaffected and seizure-free. In this study, functional and neurochemical alterations of the contralateral side were studied to find candidate mechanisms underlying the lack of a mirror focus in this model of TLE. A quantitative analysis of simultaneous, bilateral EEG recordings revealed a significant decrease of theta oscillations ipsilaterally during the latent phase and bilaterally during the chronic phase. Furthermore, the synchronization of bilateral activity, which is very high in control, was strongly reduced already during the latent phase and the decrease was independent of recurrent seizures. Immunohistochemical analysis performed in the contralateral hippocampus of kainate-treated mice revealed reduced calbindin-labeling of CA1 pyramidal cells; down-regulation of CCK-8 and up-regulation of NPY-labeling in mossy fibers; and a redistribution of galanin immunoreactivity. These changes collectively might limit neuronal excitability in CA1 and dentate gyrus, as well as glutamate release from mossy fiber terminals. Although these functional and neurochemical alterations might not be causally related, they likely reflect long-ranging network alterations underlying the independent evolution of the two hippocampal formations during the development of an epileptic focus in this model of TLE.
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PMID:Epileptogenesis and chronic seizures in a mouse model of temporal lobe epilepsy are associated with distinct EEG patterns and selective neurochemical alterations in the contralateral hippocampus. 1589 45


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