Chemical Kindling: Implications for Antiepileptic Drugs‐Sensitive and Resistant Epilepsy Models

Шандра, А. А.; Mazarati, Andréy; Godlevsky, L. S.; Vastyanov, R. S.

doi:10.1111/j.1528-1157.1996.tb00024.x

Cited by 35 publications

(15 citation statements)

References 10 publications

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“…8) (see Dhir et al, 2005) and is also obtained with other GABA A receptor antagonists including picrotoxin (Shandra et al, 1996). Moreover, there was no persistent enhanced seizure susceptibility when animals treated with repeated doses of TETS were exposed to a subthreshold challenge dose of PTZ 7 days after the last dose of TETS.…”

mentioning

confidence: 94%

“…Moreover, TETS and picrotoxin have similar potencies for inhibition of GABA A receptor-mediated GABA-activated 36 Cl Ϫ uptake by membrane vesicles from rat cerebral cortex (IC 50 for TETS is 1.75 M; Obata et al, 1988). Although TETS and picrotoxin have similar potencies on GABA A receptors, TETS is 30-to 100-fold more potent as a convulsant and lethal toxin in the mouse than picrotoxin (Lamanna and Hart, 1968;Duka et al, 1979;Shandra et al, 1996;Vogel, 2008). The basis for the high in vivo convulsant potency of TETS is not well understood.…”

Section: Introductionmentioning

confidence: 99%

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Characterization of Seizures Induced by Acute and Repeated Exposure to Tetramethylenedisulfotetramine

Żółkowska

Banks

Dhir

et al. 2012

J Pharmacol Exp Ther

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Tetramethylenedisulfotetramine (tetramine; TETS) is a potent convulsant poison that is considered to be a chemical threat agent. To provide a basis for the investigation of antidotes for TETS-induced seizures, we characterized the convulsant activity of TETS in mice and rats when administered by the intraperitoneal, intravenous, oral, and intraventricular routes as a single acute dose and with repeated sublethal doses. In mice, parenteral and oral TETS caused immobility, myoclonic body jerks, clonic seizures of the forelimbs and/or hindlimbs, tonic seizures, and death. The CD 50 values for clonic and tonic seizures after oral administration were 0.11 and 0.22 mg/kg, respectively. Intraventricular administration of TETS (5-100 g) in rats also caused clonic-tonic seizures and death. In mice, repeated sublethal doses of TETS at intervals of 2, 24, and 48 h failed to result in the development of persistent enhanced seizure responsivity ("kindling") as was observed with repeated pentylenetetrazol treatment. In mice, sublethal doses of TETS that produced clonic seizures did not cause observable structural brain damage as assessed with routine histology and Fluoro-Jade B staining 7 days after treatment. However, 1 to 3 days after a single convulsant dose of TETS the expression of glial fibrillary acidic protein, an astrocyte marker, and ionized calcium binding adaptor molecule 1, a microglia marker, were markedly increased in cortex and hippocampus. Although TETS doses that are compatible with survival are not associated with overt evidence of cellular injury or neurodegeneration, there is transient reactive astrocytosis and microglial activation, indicating that brain inflammatory responses are provoked.

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mentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Characterization of Seizures Induced by Acute and Repeated Exposure to Tetramethylenedisulfotetramine

Żółkowska

Banks

Dhir

et al. 2012

J Pharmacol Exp Ther

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“…This means that drug effects can be modified by preliminary ES of brain structures and can explain the resistance of ES-kindling to antiepileptic agents [6,7].…”

Section: Resultsmentioning

confidence: 99%

Increasing the efficacy of antiepileptic effect of diazepam by cerebellar cortex electrostimulation

Brusentsov¹

1998

Bull Exp Biol Med

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Diazepam effects on epileptic foci induced by benzylpeniciUin application to the posterior sigmoid gyrus were studied in acute experiments on cats. Diazepam more effectively decreased the activity of the foci after preliminary electrostimulation of the IX and X lobules of the vermis than without such a pretreatment. Our purpose was to assess the opposite effect: stimulation of antiepileptic action of diazepam by preliminary ES of the cerebellar cortex. MATERIALS AND METHODSThe study was performed on 27 cats of both sexes weighing 2.5-3.5 kg. Tracheostomy, trephination, implantation of constantan bipolar electrodes (0.12-0.15 ~t, distance between the electrodes 0.25 mm) in the cerebellar cortex (IX-X lobules of the vermis according to [5]), and catheterization of the femoral vein were carried out under ether rausch narcosis. Electrodes were f'Lxed to the skull bones by rapidly hardened Noracryl. The animals were transferred to forced respiration after intraperitoneal injection of 0.25 mg/kg d-tubocurarine (Orion). Follow-up started from 22.5 h after the end of ether narcosis. Twenty sessions of ES of cerebellar cortex (rectangular pulses, 100-300 Hz, 300-400 ~tA, pulse duration 0.25 msec, ES duration 5-7 see) were performed every 3 min with an ESU-2 electrostimulator. To Odessa State Medical University control animals, electrodes were similarly implanted, but no ES was performed.After opening the dura mater, a focus of epileptic activity (EpA) was created by applying a filter paper (2x2 mm) moistened with fresh-prepared benzylpenicillin sodium solution (10,000 U/ml) onto the posterior sigmoid gyrus. Activity of EpA was recorded through monopolar electrodes by an electroencephalograph (Medicor) with indifferent electrodes f'Lxed in the nasal bones.EpA of the foci was expressed in arbitrary units: a mean amplitude of 1 mV at 1 charge/min generation was taken for one unit. A 1-min Bpoque of charge generation was taken for estimating the level of EpA, and the life span of foci was determined as the period from the first to the last spike [3]. Diazepam (Gedeon Richter) was injected intravenously in doses 0.5 and 1.5 mg/kg during generation of stable activity in the foci. Controls were injected with 0.5 ml normal saline.Results were statistically processed using ANOVA tests with subsequent processing by the NeumannKeuls test. Differences were considered significant at p<0.05. RESULTSAfter application of benzylpenicillin (in 3-7 min), the first spike charges were generated in the focus. The amplitude and frequency of these charges in-

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“…These reports, in conjunction with previous data using Homer1b/c targeted siRNA to protect neurons form traumatic injury [9] and our own in vivo Homer1b/c knockdown data in two different seizure models, support the application of a Homer1b/c lowering therapy to regulate hyperexcitability. PTX and PTZ kindling are the most widely-accepted animal models used to study seizure mechanisms and to discover novel treatments for seizures [16,17]. Given that the compounds that provide protection against PTZ seizures in vivo have generally been successful in subsequent human clinical trials [18], our findings of Homer1b/c knockdown using two different GABA antagonists will also apply broadly to epilepsy in vivo models and to human epilepsy.…”

Section: Cellular Physiology and Biochemistrymentioning

confidence: 97%

Down-Regulation of Homer1b/c Protects Against Chemically Induced Seizures Through Inhibition of mTOR Signaling

Cao

Tian²,

Jiang³

et al. 2015

Cell Physiol Biochem

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Background: Homer is a family of post synaptic density proteins functionally and physically attached to target proteins at proline-rich sequences. Reducing Homer1b/c expression has been shown in previous studies to be protective against excitotoxic insults, implicating Homer1b/c in the physiological regulation of aberrant neuronal excitability. Methods: To test the efficacy of a Homer1b/c reducing therapy for disorders with a detrimental hyperexcitability profile in mice, we used small interfere RNA (siRNA) to decrease endogenous Homer1b/c expression in mouse hippocampus. The baseline motor and cognitive behavior was measured by sensorimotor tests, Morris water maze and elevated plus maze tasks. The anti-epileptic effects of Homer1b/c knockdown were determined in two chemically induced seizure models induced by Picrotoxin (PTX) or pentylenetetrazole (PTZ) administration. Results: The results of sensorimotor tests, Morris water maze and elevated plus maze tasks showed that Homer1b/c reduction had no effect on baseline motor or cognitive behavior. In two chemically induced seizure models, mice with reduced Homerb/c protein had less severe seizures than control mice. Total Homer1b/c protein levels and seizure severity were highly correlated, such that those mice with the most severe seizures also had the highest levels of Homer1b/c. In addition, the phosphorylation of mammalian target of rapamycin (mTOR) and its target protein S6 was significantly inhibited in Homer1b/c down-regulated mice. Homer1b/c knockdown-induced inhibition of mTOR pathway was partially ablated by the metabotropic glutamate receptor 5 (mGluR5) agonist CHPG. Conclusion: Our results demonstrate that endogenous Homer1b/c is integral for regulating neuronal hyperexcitability in adult animals and suggest that reduction of Homer1b/c could protect against chemically induced seizures through inhibition mTOR pathway.

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Chemical Kindling: Implications for Antiepileptic Drugs‐Sensitive and Resistant Epilepsy Models

Cited by 35 publications

References 10 publications

Characterization of Seizures Induced by Acute and Repeated Exposure to Tetramethylenedisulfotetramine

Characterization of Seizures Induced by Acute and Repeated Exposure to Tetramethylenedisulfotetramine

Increasing the efficacy of antiepileptic effect of diazepam by cerebellar cortex electrostimulation

Down-Regulation of Homer1b/c Protects Against Chemically Induced Seizures Through Inhibition of mTOR Signaling

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