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)

The aim of our study was to assess abnormalities in 5-hydroxytryptamine-1A (5-HT1A) receptor density in patients suffering from refractory temporal lobe epilepsy (TLE). Experimental data in animals show that 5-HT1A receptors are predominantly located in limbic areas, and that serotonin, via these receptors, mediates an antiepileptic and anticonvulsant effect. In TLE patients, we quantified 5-HT1A receptor density in epileptogenic and non-epileptogenic areas, as defined by intracranial recordings with stereo-electroencephalography (SEEG). Nine TLE patients and 53 control subjects were studied by PET using a 5-HT1A receptor antagonist ([18F]MPPF). Anatomical regions of interest (ROIs) were drawn on patient and control MRIs co-registered with PET. PET data were quantified using a simplified model to assess binding potential (BP) values in each ROI, with cerebellum as reference. For each patient, a normalized percentage BP change was calculated as the relative variation of BP in each ROI compared with the corresponding ROI in control subjects. In patients, ROIs explored by SEEG were categorized according to their degree of epileptic activity (ictal onset, ictal spreading, interictal spikes, no epileptic activity) and according to their lesional aspect and volume (lesional with volume loss, lesional without volume loss, non-lesional). Compared with control values, the binding to 5-HT1A receptors in TLE patients was decreased in the epileptogenic temporal lobe. BP decrease was significantly greater in: (i) regions involved in the seizure onset than regions where only interictal paroxysms or no epileptic activity was recorded; and (ii) regions where the discharge propagated than regions where only interictal paroxysms or no epileptic activity was recorded. BP decrease was shown to be significantly influenced by the existence of a lesion on MRI. However, in the group of ROIs with normal quantitative and qualitative MRI aspect, BP decrease remained strongly correlated to the degree of epileptic activity. This study shows that in vivo availability of 5-HT1A receptors is decreased in epileptic patients compared with normal subjects. This decrease is highly correlated to the degree of epileptogenicity of cortical areas explored by intracerebral recordings, and does not reflect only pathological changes or neuronal loss in the epileptic focus.
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PMID:5-HT1A receptor binding and intracerebral activity in temporal lobe epilepsy: an [18F]MPPF-PET study. 1498 63

The reported increase in brain-derived neurotrophic factor (BDNF) mRNA expression after antidepressant treatment is a cornerstone of the BDNF hypothesis of antidepressant action. However, if this increase becomes manifest on the BDNF protein level is unknown. In the present study we performed parallel measurements of BDNF mRNA and protein expression in the frontal cortex and hippocampus of the rat after chronic treatment with electroconvulsive seizures (ECS), lithium, desipramine or escitalopram. ECS increased BDNF mRNA and protein in the hippocampus and BDNF protein in the frontal cortex. Desipramine moderately increased BDNF mRNA expression in the dentate gyrus but did not change BDNF protein in neither region. Escitalopram did not affect BDNF mRNA expression, but decreased BDNF protein in the frontal cortex and the hippocampus. Lithium increased BDNF protein levels in the hippocampus and frontal cortex, but overall decreased BDNF mRNA expression. Thus, here we report a striking non-correspondence between changes in BDNF mRNA and protein expression induced by the antidepressant treatments and lithium. Further, increased expression of BDNF mRNA or protein was not a common action of the treatments. We also investigated if treatment-induced modulations of the tissue contents of 5-hydroxytryptamine (5-HT) and its metabolite, 5-hydroxy-indoleacetic acid (5-HIAA), were related to changes in BDNF mRNA or protein expression. No correlation was found. However, all treatments increased 5-HT levels in the hippocampus.
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PMID:The effect of escitalopram, desipramine, electroconvulsive seizures and lithium on brain-derived neurotrophic factor mRNA and protein expression in the rat brain and the correlation to 5-HT and 5-HIAA levels. 1545 81

The antiepileptic drugs sodium valproate (VPA) and lamotrigine (LTG) are increasingly used in combination in patients in whom monotherapy has failed to control seizures. Although these drugs are known to interact pharmacokinetically, several authors have proposed a pharmacodynamic interaction between the two. In order to investigate this we have studied the effects of combined treatment with LTG and VPA on basal and stimulated extracellular aspartate (ASP), glutamate (GLU), taurine (TAU), gamma amino butyric acid (GABA), 5-hydroxytryptamine (5-HT) and dopamine (DA) release in the hippocampus of freely moving rats using microdialysis. Additionally, we measured the possible effect of VPA on LTG in plasma, whole brain and dialysates. Neither LTG (10 mg/kg) nor VPA (300 mg/kg) given alone significantly altered basal levels of ASP, GLU or TAU. When given together, however, the two drugs significantly reduced extracellular ASP and GLU while increasing TAU levels. In the case of GABA, LTG was without effect on basal levels of the transmitter, but these increased following VPA and this persisted with both drugs. When transmitter release was stimulated by 50 muM veratridine, marked increases in the release of all amino acids occurred and this was decreased by LTG in all cases. VPA alone only altered GABA release, increasing it by approximately the same extent as basal GABA. For all of the amino acids studied, however, VPA reversed the decreases in release seen after LTG. VPA and LTG increased and decreased respectively basal 5-HT and DA. When given together the increase in extracellular 5-HT was greatly prolonged, but no effect on DA release was seen. When 5-HT release was evoked by veratridine this was increased by VPA and no other treatment. With DA, however, neither drug alone altered evoked release, but the two combined led to a marked increase. Co-administration of VPA with LTG showed no significant effect of this combination on LTG in any of the three compartments studied indicating that in this case a significant pharmacokinetic contribution to our findings is unlikely, which suggests that there is a probable pharmacodynamic interaction of the two drugs.
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PMID:Effects of combined lamotrigine and valproate on basal and stimulated extracellular amino acids and monoamines in the hippocampus of freely moving rats. 1566 Feb 42

Neurosteroids represent a class of endogenous compounds that exert rapid, nongenomic effects through neurotransmitter receptor systems such as GABA(A). Two neurosteroids, allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one) and pregnanolone (3alpha-hydroxy-5beta-pregnan-20-one), possess anxiolytic and sedative properties and show substitution for ethanol, benzodiazepines, and barbiturates in drug discrimination assays. This study aimed to examine the effects of strain and sex on the discriminative stimulus effects of pregnanolone. Twelve male and female DBA/2J mice and 12 male and female C57BL/6J mice were trained to discriminate 10 mg/kg pregnanolone from saline. The male C57BL/6J mice had to be removed from the study due to increased seizures apparently associated with the chronic intermittent pregnanolone administration used in drug discrimination. GABA(A)-positive modulators, neuroactive steroids, N-methyl-d-aspartate (NMDA) antagonists, and 5-hydroxytryptamine (5-HT)(3) agonists were tested for pregnanolone substitution. In DBA/2J and C57BL/6J mice, a benzodiazepine, barbiturate, and GABAergic neuroactive steroids all substituted for the stimulus effects of pregnanolone. NMDA antagonists, 5-HT(3) agonists, and zolpidem failed to substitute for pregnanolone's discriminative stimulus in either sex or strain. Pentobarbital and midazolam were more potent in producing pregnanolone-like discriminative stimulus effects in DBA/2J mice. Differences in sensitivities to neurosteroids between the two strains were not evident. These results provide a comprehensive look at pregnanolone's discriminative stimulus effects in two commonly used strains of mice. The present data suggest that many of the previously documented neurosteroid-induced behavioral differences between the DBA/2J and C57BL/6J are acute effects and are not apparent in a drug discrimination procedure.
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PMID:Characterization of the discriminative stimulus effects of the neuroactive steroid pregnanolone in DBA/2J and C57BL/6J inbred mice. 1585 45

Since the correlation between the serotonin (5-hydroxytryptamine, 5-HT) system and seizure activity remains to be clarified, we investigated the 5-HT system in the hippocampus of seizure-resistant (SR) and seizure-sensitive (SS) gerbils. There was no difference of the 5-HT system in the hippocampi of young animals (predisposed and juvenile gerbils) in both SR and SS gerbils. 5-HT immunoreactivity in the dorsal raphe nucleus and the median raphe nucleus was also similarly detected in both animal groups. As compared to SR adult gerbils, only 5-HT1A receptor immunoreactivity was selectively reduced in CA1 interneurons within SS adult gerbils. (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (a 5-HT1A receptor agonist, 1 and 2 mg/kg) markedly reduced paired-pulse inhibition in the CA1 region of SS adult gerbils only. These findings suggest that the selective reduction in 5-HT1A receptor expression on CA1 interneurons of SS adult gerbil may not be developmental defects, but be an acquired compensatory change induced by repeated seizure activity.
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PMID:Seizure activity selectively reduces 5-HT1A receptor immunoreactivity in CA1 interneurons in the hippocampus of seizure-prone gerbils. 1749 97

The neuroprotective effects of pentoxifylline (PTX) against lithium-pilocarpine (Li-Pc)-induced status epilepticus (SE) in young rats are described. Animals treated with PTX (0, 20, 40, and 60 mg/kg) before induction of SE were examined for latency to and frequency of SE, behavioral changes, oxidative stress, neurochemical alterations in the hippocampus and striatum, and histological abnormalities in the hippocampus. Treatment with PTX significantly ameliorated the frequency and severity of epileptic seizures in a dose-dependent manner. Our behavioral studies using the elevated plus-maze, rotarod, and water maze tests suggested a significant reduction in anxiety, enhanced motor performance, and improved learning and memory in PTX-treated rats. Li-Pc-induced neuronal cell loss and sprouting of mossy fibers in the hippocampus were also attenuated by PTX. The neuroprotective activity of PTX was accompanied by reduction in oxidative stress and reversal of SE-induced depletion of dopamine and 5-hydroxytryptamine in hippocampus and striatum. The results of this study provide a good rationale to explore the prophylactic/therapeutic potential of PTX in SE.
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PMID:Pentoxifylline ameliorates lithium-pilocarpine induced status epilepticus in young rats. 1820 64

Whereas the entorhinal cortex (EC) receives profuse serotonergic innervations from the raphe nuclei in the brain stem and is critically involved in the generation of temporal lobe epilepsy, the function of serotonin (5-hydroxytryptamine, 5-HT) in the EC and particularly its roles in temporal lobe epilepsy are still elusive. Here we explored the cellular and molecular mechanisms underlying 5-HT-mediated facilitation of GABAergic transmission and depression of epileptic activity in the superficial layers of the EC. Application of 5-HT increased sIPSC frequency and amplitude recorded from the principal neurons in the EC with no effects on mIPSCs recorded in the presence of TTX. However, 5-HT reduced the amplitude of IPSCs evoked by extracellular field stimulation and in synaptically connected interneuron and pyramidal neuron pairs. Application of 5-HT generated membrane depolarization and increased action potential firing frequency but reduced the amplitude of action potentials in presynaptic interneurons suggesting that 5-HT still increases GABA release whereas the depressant effects of 5-HT on evoked IPSCs could be explained by 5-HT-induced reduction in action potential amplitude. The depolarizing effect of 5-HT was mediated by inhibition of TASK-3 K(+) channels in interneurons and required the functions of 5-HT(2A) receptors and Galpha(q/11) but was independent of phospholipase C activity. Application of 5-HT inhibited low-Mg(2+)-induced seizure activity in slices via 5-HT(1A) and 5-HT(2A) receptors suggesting that 5-HT-mediated depression of neuronal excitability and increase in GABA release contribute to its anti-epileptic effects in the EC.
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PMID:Serotonin increases GABA release in rat entorhinal cortex by inhibiting interneuron TASK-3 K+ channels. 1868 3

Pharmacological studies have been focused on the involvement of different neural pathways in the organization of antinociception that follows tonic-clonic seizures, including 5-hydroxytryptamine (5-HT)-, norepinephrine-, acetylcholine- and endogenous opioid peptide-mediated mechanisms, giving rise to more in-depth comprehension of this interesting post-ictal antinociceptive phenomenon. The present work investigated the involvement of 5-HT(1A/1B), 5-HT(6), and 5-HT(7) serotonergic receptors through peripheral pretreatment with methiothepin at doses of 0.5, 1.0, 2.0 and 3.0 mg/kg in the organization of the post-ictal antinociception elicited by pharmacologically (with pentylenetetrazole at 64 mg/kg)-induced tonic-clonic seizures. Methiothepin at 1.0 mg/kg blocked the post-ictal antinociception recorded after the end of seizures, whereas doses of 2.0 and 3.0 mg/kg potentiated the post-ictal antinociception. The nociceptive thresholds were kept higher than those of the control group. However, when the same 5-hydroxytryptamine receptors antagonist was microinjected (at 1.0, 3.0 and 5.0 microg/0.2 microL) in the dorsal raphe nucleus, a mesencephalic structure rich in serotonergic neurons and 5-HT receptors, the post-ictal hypo-analgesia was consistently antagonized. The present findings suggest a dual effect of methiothepin, characterized by a disinhibitory effect on the post-ictal antinociception when peripherally administered (possibly due to an antagonism of pre-synaptic 5-HT(1A) serotonergic autoreceptors in the pain endogenous inhibitory system) and an inhibitory effect (possibly due to a DRN post-synaptic 5-HT(1B), 5-HT(6), and 5-HT(7) serotonergic receptors blockade) when centrally administered. The present data also suggest that serotonin-mediated mechanisms of the dorsal raphe nucleus exert a key-role in the modulation of the post-ictal antinociception.
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PMID:5-HT1A/1B, 5-HT6, and 5-HT7 serotonergic receptors recruitment in tonic-clonic seizure-induced antinociception: role of dorsal raphe nucleus. 1941 88

Experimental studies suggest that 5-hydroxytryptamine (5-HT) receptors play a role in epileptogenesis and seizure propagation. Ondansetron, a 5-HT(3) receptor antagonist, has been reported to have proconvulsant and anticonvulsant effects in animals. We describe three patients who developed seizures after receiving ondansetron. There were two females and one male. Ages ranged from 38-56 years. None had a previous or family history of seizures. Four milligrams (mg) of ondansetron was given intravenously for severe nausea and vomiting in association with migraine, gastritis, and diabetic ketoacidosis. A generalized tonic-clonic seizure occurred in each patient--12, 15, and 22 min after injection. Brain magnetic resonance imaging (MRI) and electroencephalography (EEG) were normal in all patients. Although no antiepileptic drugs were given, none had seizure recurrence subsequently. The temporal relationship between ondansetron administration and seizures, lack of EEG or MRI abnormalities, and absence of seizure recurrence suggest that the seizures were causally related to ondansetron in our patients.
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PMID:Ondansetron and seizures. 1949 41

There is some evidence that epileptic seizures could be induced or increased by 5-hydroxytryptamine (5-HT) attenuation, while augmentation of serotonin functions within the brain (e.g. by SSRIs) has been reported to be anticonvulsant. This study was performed to determine the effect of selective 5-HT(3) channel/receptor antagonist granisetron and agonist SR57227 hydrochloride on the pentylenetetrazole (PTZ)-induced seizure threshold in mice. The possible interaction of this effect with nitrergic system was also examined using the nitric oxide (NO) synthase inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME) and the NO precursor l-arginine. SR57227 (10mg/kg, i.p.) significantly increased the seizure threshold compared to control group, while high dose granisetron (10mg/kg, i.p.) proved proconvulsant. Co-administration of sub-effective doses of the 5-HT(3) agonist with l-NAME (5 and 60mg/kg, i.p., respectively) exerted a significant anticonvulsive effect, while sub-effective doses of granisetron (3mg/kg) was observed to have a proconvulsive action with the addition of l-arginine (75mg/kg, i.p.). Our data demonstrate that enhancement of 5-HT(3) receptor function results in as anticonvulsant effect in the PTZ-induced seizure model, and that selective antagonism at the 5-HT(3) receptor yields proconvulsive effects. Furthermore, the NO system may play a role in 5-HT(3) receptor function.
Seizure 2010 Jan
PMID:Seizure susceptibility alteration through 5-HT(3) receptor: modulation by nitric oxide. 1994 58


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