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Ashish Dhir - One of the best experts on this subject based on the ideXlab platform.
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Pentylenetetrazol ptz kindling model of epilepsy
Current protocols in protein science, 2012Co-Authors: Ashish DhirAbstract:This unit describes a protocol to perform chemical kindling in mice. Kindling is a chronic animal model of epilepsy that has been extensively studied to understand the process of epileptogenesis and discover novel anti-epileptic compounds. Kindling is a phenomenon where a sub-convulsive stimulus (either chemical or electrical), if applied repetitively and intermittently, will ultimately lead to the generation of full-blown convulsions. Kindling can be induced either by (1) electrical stimulation of different brain regions (electrical kindling) or (2) using various chemical agents (chemical kindling). This unit discusses in detail the methodology to execute Pentylenetetrazol (PTZ; a GABAA receptor antagonist)–induced chemical kindling in mice. PTZ is administered chronically at a sub-convulsive dose for a number of days. Seizure score is calculated after each PTZ injection. The effect of test/reference compounds can be tested by administering them either prior to the initiation of kindling (pre-kindling phase) or after animals are fully kindled (post-kindling phase). Curr. Protoc. Neurosci. 58:9.37.1-9.37.12. © 2012 by John Wiley & Sons, Inc. Keywords: epilepsy; chemical kindling; mice; Pentylenetetrazol
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nitric oxide signaling pathway in the anti convulsant effect of adenosine against Pentylenetetrazol induced seizure threshold in mice
European Journal of Pharmacology, 2008Co-Authors: Kiran Kumar Akula, Ashish Dhir, S K KulkarniAbstract:Abstract The present study was performed to examine the involvement of nitric oxide (NO) signaling pathway in the anti-convulsant effect of adenosine against Pentylenetetrazol seizure threshold in mice. Minimal dose of Pentylenetetrazol (i.v., mg/kg) needed to induce different phases (myoclonic jerks, generalized clonus and tonic extension) of convulsions was recorded as an index of seizure threshold. Adenosine (100 or 200 mg/kg i.p.) produced a significant increase in the seizure threshold for convulsions induced by Pentylenetetrazol i.v. infusion. The anti-convulsant effect of adenosine (100 mg/kg i.p.) was prevented by either l -arginine (50 mg/kg i.p.) [substrate for nitric oxide synthase (NOS)] or sodium nitroprusside (3 mg/kg i.p.) [a NO donor]. On the other hand, N(G)-nitro- l -arginine methyl ester (L-NAME, 2.5 mg/kg i.p.) [a non-selective NOS inhibitor] or 7-nitroindazole (7-NI) (25 mg/kg i.p.) [a specific neuronal nitric oxide synthase (nNOS) inhibitor] potentiated the anti-convulsant action of sub-effective dose of adenosine (50 mg/kg i.p.). Aminoguanidine (100 mg/kg i.p.) [a specific inducible NOS (iNOS) inhibitor] pre-treatment was not effective in inducing anti-convulsant effect with sub-effective dose of adenosine (50 mg/kg i.p.). Furthermore, the increase in seizure threshold elicited by adenosine (100 mg/kg i.p.) was also inhibited by concomitant administration with sildenafil (5 mg/kg i.p.) [phosphodiesterase 5 inhibitor]. In contrast, treatment of mice with methylene blue (1 mg/kg i.p.) [a direct inhibitor of both nitric oxide synthase (NOS) and soluble guanylate cyclase (sGC)] failed to induce anti-convulsant action with adenosine (50 mg/kg i.p.) against Pentylenetetrazol i.v. infusion. The results demonstrated that the anti-convulsant action of adenosine in the Pentylenetetrazol i.v. seizure threshold paradigm may possibly involve an interaction with the l -arginine-NO-cGMP pathway which may be secondary to the activation of adenosine receptors.
SJ Czuczwar - One of the best experts on this subject based on the ideXlab platform.
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Isobolographic and behavioral characterizations of interactions between vigabatrin and gabapentin in two experimental models of epilepsy
EUR J PHARMACOL, 2008Co-Authors: SJ CzuczwarAbstract:The aim of this study was to characterize the pharmacodynamic, pharmacokinetic and adverse-effect profiles of vigabatrin and gabapentin. Isobolographic analysis was used in two mouse experimental models of epilepsy: the maximal electroshock seizure threshold test and Pentylenetetrazole-induced seizures. In the maximal electroshock seizure threshold test, electroconvulsions were produced by a current with various intensities whilst in the Pentylenetetrazole test a CD97 dose (100 mg/kg) was used. Potential adverse-effect profiles of interactions of vigabatrin with gabapentin at three fixed-ratios of 1:3, 1:1 and 3:1 from both seizure tests were evaluated in the chimney (motor performance) and grip-strength (skeletal muscular strength) tests. Vigabatrin and gabapentin total brain concentrations were determined with high performance liquid chromatography. Vigabatrin and gabapentin administered singly increased the electroconvulsive threshold (TID20 - 226.2 and 70.0 mg/kg, respectively). With isobolography, the combination of vigabatrin with gabapentin at the fixed-ratio of 1:3 exerted supra-additive (synergistic) interactions whilst at 1:1 and 3:1 additivity occurred. Similarly. vigabatrin and gabapentin administered singly suppressed the Pentylenetetrazole-induced seizures (ED50 values - 622.5 and 201.1 mg/kg, respectively). Isobolography revealed that vigabatrin with gabapentin in combination at the fixed-ratio of 1:1 produced supra-additive (synergistic) interaction whilst at 1:3 and 3:1 additivity occurred. in combination neither motor coordination nor skeletal muscular strength was affected. Total vigabatrin and gabapentin brain concentrations revealed that neither drug affected the pharmacokinetics of the other. Vigabatrin and gabapentin have a favorable pharmacodynamic interaction in animal seizure models in the absence of acute adverse effects or concurrent pharmacokinetic changes. (C) 2008 Elsevier B.V. All rights reserved.
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N^G-nitro-L-arginine, a nitric oxide synthase inhibitor, and seizure susceptibility in four seizure models in mice
Journal of Neural Transmission, 1996Co-Authors: E. M. Urbańska, E. Drelewska, K. K. Borowicz, P. Błaszczak, Z. Kleinrok, SJ CzuczwarAbstract:Nitric oxide may be involved in seizure phenomena even though data often seem to be contradictory. This prompted us to study the influence of nitric oxide upon electrically and chemically induced seizures. The effects of nitric oxide synthase inhibitor, N^G-nitro-L-arginine (NNA), on Pentylenetetrazol-, aminooxyacetic acid-, aminophylline-induced seizures or electroconvulsive shock were evaluated. NNA was applied at 1, 10 and 40 mg/kg 0.5 and 2.0 h before chemical seizures and at 1 and 40 mg/kg 0.5 and 2.0 h prior to electroconvulsions. The nitric oxide synthase inhibitor (up to 40 mg/kg) did not affect the susceptibility of mice to Pentylenetetrazol, aminooxyacetic acid or electroconvulsions. However, NNA significantly enhanced the convulsive properties of aminophylline when applied at 40 mg/kg, 0.5 h before the test. The CD_50 value for aminophylline-induced clonus and tonus/mortality was decreased from 233 to 191 and from 242 to 212 mg/kg, respectively. However, this pretreatment also led to a significant increase in the plasma levels of theophylline. Our results suggest that differential effects of NNA on chemically-induced convulsions might in some cases be associated with a pharmacokinetic interaction.
Joao Jose Freitas Sarkis - One of the best experts on this subject based on the ideXlab platform.
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biochemical brain markers and purinergic parameters in rat csf after seizure induced by Pentylenetetrazol
Brain Research Bulletin, 2004Co-Authors: Jean Pierre Oses, Renata Leke, Luis Valmor Cruz Portela, Diogo Rizzato Lara, Andre Prato Schmidt, Emerson Andre Casali, Susana Tchernin Wofchuk, Diogo O Souza, Joao Jose Freitas SarkisAbstract:Abstract Cellular and molecular mechanisms involved in the generation of seizures and the magnitude of neural cells injury are not fully understood. We evaluated astrocyte and/or neuronal injury in rats in the Pentylenetetrazol model of acute seizures by measuring S100B and NSE levels in cerebrospinal fluid. Additionally, we determined ADP and GDP hydrolysis by soluble nucleoside triphosphate diphosphohydrolase in the cerebrospinal fluid, and the concentration of nucleosides adenosine, inosine and guanosine as putative markers of brain injury. After Pentylenetetrazol-induced seizures: (i) S100B values increased from 10 to 30 min, returning to control levels at 24 h; NSE levels presented a biphasic increase: an increase at 10 to 30 min returning to control levels , and again at 240 min followed by a decline at 24 h; (ii) nucleotidase activities increased from 10 min, returning to control levels at 240 min; (iii) guanosine and inosine levels increased exclusively after 30 min. In summary, this study showed biochemical changes in the cerebrospinal fluid occurring after seizures induced by Pentylenetetrazol. Such events may have a modulating effect upon seizure expression, particularly nucleoside triphosphate diphosphohydrolase activities and nucleoside concentrations, but are nevertheless followed by neural death as evidenced by the increase in NSE and S100B levels.
Diogo Rizzato Lara - One of the best experts on this subject based on the ideXlab platform.
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biochemical brain markers and purinergic parameters in rat csf after seizure induced by Pentylenetetrazol
Brain Research Bulletin, 2004Co-Authors: Jean Pierre Oses, Renata Leke, Luis Valmor Cruz Portela, Diogo Rizzato Lara, Andre Prato Schmidt, Emerson Andre Casali, Susana Tchernin Wofchuk, Diogo O Souza, Joao Jose Freitas SarkisAbstract:Abstract Cellular and molecular mechanisms involved in the generation of seizures and the magnitude of neural cells injury are not fully understood. We evaluated astrocyte and/or neuronal injury in rats in the Pentylenetetrazol model of acute seizures by measuring S100B and NSE levels in cerebrospinal fluid. Additionally, we determined ADP and GDP hydrolysis by soluble nucleoside triphosphate diphosphohydrolase in the cerebrospinal fluid, and the concentration of nucleosides adenosine, inosine and guanosine as putative markers of brain injury. After Pentylenetetrazol-induced seizures: (i) S100B values increased from 10 to 30 min, returning to control levels at 24 h; NSE levels presented a biphasic increase: an increase at 10 to 30 min returning to control levels , and again at 240 min followed by a decline at 24 h; (ii) nucleotidase activities increased from 10 min, returning to control levels at 240 min; (iii) guanosine and inosine levels increased exclusively after 30 min. In summary, this study showed biochemical changes in the cerebrospinal fluid occurring after seizures induced by Pentylenetetrazol. Such events may have a modulating effect upon seizure expression, particularly nucleoside triphosphate diphosphohydrolase activities and nucleoside concentrations, but are nevertheless followed by neural death as evidenced by the increase in NSE and S100B levels.
Laszlo Vecsei - One of the best experts on this subject based on the ideXlab platform.
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kynurenine administered together with probenecid markedly inhibits Pentylenetetrazol induced seizures an electrophysiological and behavioural study
Neuropharmacology, 2004Co-Authors: Hajnalka Nemeth, Hermina Robotka, Eva Rozsa, Tamas Janaky, Csaba Somlai, Mate Marosi, Tamas Farkas, Jozsef Toldi, Laszlo VecseiAbstract:Abstract The kynurenine pathway converts tryptophan into various compounds, including l -kynurenine, which in turn can be converted to the excitatory amino acid receptor antagonist kynurenic acid, which may therefore serve as a protective agent in such neurological disorders as epileptic seizures. Kynurenic acid, however, has a very limited ability to cross the blood-brain barrier, whereas kynurenine passes the barrier easily. In this study, we tested the hypothesis that kynurenine administered systemically together with probenecid, which inhibits kynurenic acid excretion from the cerebrospinal fluid, results in an increased level of kynurenic acid in the brain that is sufficiently high to provide protection against the development of pentylentetrazol-induced epileptic seizures. CA3 stimulation-evoked population spike activity was recorded from the pyramidal layer of area CA1 of the rat hippocampus, and in another series of behavioural experiments, water maze and open-field studies were carried out to test the presumed protective effect of kynurenine+probenecid pre-treatment against Pentylenetetrazol-induced seizures. This study has furnished the first electrophysiological proof that systemic kynurenine (300 mg/kg, i.p.) and probenecid (200 mg/kg, i.p.) administration protects against Pentylenetetrazol-induced (60 mg/kg, i.p.) epileptic seizures.
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kynurenine and probenecid inhibit Pentylenetetrazol and nmdla induced seizures and increase kynurenic acid concentrations in the brain
Brain Research Bulletin, 1992Co-Authors: Laszlo Vecsei, Joanne M Miller, Usha Macgarvey, Flint M BealAbstract:Kynurenine is a direct precursor of kynurenic acid, the only known endogenous antagonist of excitatory amino acid receptors in the brain. Kynurenine administered intraperitoneally (150, 450, 900 mg/kg) 2 h before Pentylenetetrazol injection dose-dependently increased the time to seizures, the time to death and the survivorship of mice. Kynurenine dose-dependently increased the time to seizures and the time to death in mice with NMDLA-induced seizures. Kynurenine, 900 mg/kg, was equally efficacious to diazepam, 2 mg/kg. Probenecid dose-dependently increased the time to seizures, the time to death and the survivorship of mice with Pentylenetetrazol-induced seizures. Probenecid had no significant effects on NMDLA-induced seizures, although the time to death was prolonged in the NMDLA 500 mg/kg group. Probenecid potentiated the effects of kynurenine in these tests. Both probenecid and kynurenine significantly increased kynurenine and kynurenic acid concentrations in mouse cerebral cortex and striatum. These findings suggest that kynurenine (metabolized to kynurenic acid) has anticonvulsant effects, and probenecid potentiates these effects in mice.