Effects of levetiracetam, a novel antiepileptic drug, on convulsant activity in two genetic rat models of epilepsy

Gower, Alma J.; Hirsch, Édouard; Boehrer, Any; Noyer, Michel; Marescaux, Christian

doi:10.1016/0920-1211(95)00077-1

Cited by 175 publications

(111 citation statements)

References 7 publications

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“…This antiepileptic profile of ONO-2506 is somewhat similar to that of levetiracetam (De Smedt et al, 2007). Levetiracetam did not affect MES and only weakly inhibited PTZ (Gower et al, 1992;Loscher and Honack, 1993;Mandhane et al, 2007)but it was effective against absence epilepsy in rats in two genetic models (Strasbourg and WAG/Rij rats) (Gower et al, 1995;Bouwman and van Rijn, 2004). Indirect comparisons based on meta-analysis indicated that add-on therapy with levetiracetam has a favourable response and/or withdrawal rate relative to several other antiepileptic drugs in patients with partial epilepsy with the doses used in clinical trials (Otoul et al, 2005).…”

Section: Antiepileptic Profile Of Ono-2506mentioning

confidence: 55%

ONO‐2506 inhibits spike–wave discharges in a genetic animal model without affecting traditional convulsive tests via gliotransmission regulation

Yamamura

Hoshikawa

Kato

et al. 2013

British J Pharmacology

102

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BACKGROUND AND PURPOSEAnticonvulsants have been developed according to the traditional neurotransmission imbalance hypothesis. However, the anticonvulsive pharmacotherapy currently available remains unsatisfactory. To develop new antiepileptic drugs with novel antiepileptic mechanisms, we have tested the antiepileptic actions of ONO-2506, a glial modulating agent, and its effects on tripartite synaptic transmission. EXPERIMENTAL APPROACHDose-dependent effects of ONO-2506 on maximal-electroshock seizure (MES), pentylenetetrazol-induced seizure (PTZ) and epileptic discharge were determined in a genetic model of absence epilepsy in mice (Cacna1a tm2Nobs/tm2Nobs strain). Antiepileptic mechanisms of ONO-2506 were analysed by examining the interaction between ONO-2506 and transmission-modulating toxins (tetanus toxin, fluorocitrate, tetrodotoxin) on release of L-glutamate, D-serine, GABA and kynurenic acid in the medial-prefrontal cortex (mPFC) of freely moving rats using microdialysis and primary cultured rat astrocytes. KEY RESULTS ONO-2506 inhibited spontaneous epileptic discharges in Cacna1atm2Nobs/tm2Nobs mice without affecting MES or PTZ. Given systemically, ONO-2506 increased basal release of GABA and kynurenic acid in the mPFC through activation of both neuronal and glial exocytosis, but inhibited depolarization-induced releases of all transmitters. ONO-2506 increased basal glial release of kynurenic acid without affecting those of L-glutamate, D-serine or GABA. However, ONO-2506 inhibited AMPA-induced releases of L-glutamate, D-serine, GABA and kynurenic acid. CONCLUSIONS AND IMPLICATIONSONO-2506 did not affect traditional convulsive tests but markedly inhibited epileptic phenomena in the genetic epilepsy mouse model. ONO-2506 enhanced release of inhibitory neuro-and gliotransmitters during the resting stage and inhibited tripartite transmission during the hyperactive stage. The results suggest that ONO-2506 is a novel potential glial-targeting antiepileptic drug. LINKED ARTICLEThis article is commented on by Onat, pp. 1086-1087 of this issue. To view this commentary visit http://dx

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Section: Antiepileptic Profile Of Ono-2506mentioning

confidence: 55%

ONO‐2506 inhibits spike–wave discharges in a genetic animal model without affecting traditional convulsive tests via gliotransmission regulation

Yamamura

Hoshikawa

Kato

et al. 2013

British J Pharmacology

102

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“…Its anticonvulsant activity was discovered in audiogenic seizures in susceptible mice, and it was subsequently found to have activity in a range of chemoconvulsant models, including seizures induced by submaximal PTZ doses (Gower et al, 1992), the 6-Hz model, a rat genetic model of absence epilepsy (Gower et al, 1995) and also various kindling models (Löscher and Hönack, 1993). Levetiracetam also seems to have "antiepileptogenic" activity, in that it retards the development of pentylenetetrazol-kindled seizures (Gower et al, 1992) as well as conventional amygdala-kindled seizures (Löscher et al, 1998).…”

Section: Levetiracetam Analogsmentioning

confidence: 99%

Diverse mechanisms of antiepileptic drugs in the development pipeline

2006

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There is a remarkable array of new chemical entities in the current antiepileptic drug (AED) development pipeline. In some cases, the compounds were synthesized in an attempt improve upon the activity of marketed AEDs. In other cases, the discovery of antiepileptic potential was largely serendipitous. Entry into the pipeline begins with the demonstration of activity in one or more animal screening models. Results from testing in a panel of such models provide a basis to differentiate agents and may offer clues as to the mechanism. Target activity may then be defined through cellbased studies, often years after the initial identification of activity. Some pipeline compounds are believed to act through conventional targets, whereas others are structurally novel and may act by novel mechanisms. Follow-on agents include the levetiracetam analogs brivaracetam and seletracetam that act as SV2A-ligands; the valproate-like agents valrocemide, valnoctamide, propylisopropyl acetamide, and isovaleramide; the felbamate analog flurofelbamate, a dicarbamate, and the unrelated carbamate RWJ-333369; the oxcarbazepine analog licarbazepine, which probably acts as a use-dependent sodium channel blockers, and its prodrug acetate BIA 2-093; and various selective partial benzodiazepine receptor agonists, including ELB139, which is a positive allosteric modulator of α3-containing GABA A receptors. A variety of AEDs that may act through novel targets are also in clinical development: lacosamide, a functionalized amino acid; talampanel, a 2,3-benzodiazepine selective noncompetitive AMPA receptor antagonist; NS1209, a competitive AMPA receptor antagonist; ganaxolone, a neuroactive steroid that acts as a positive modulator of GABA A receptors; retigabine, a KCNQ potassium channel opener with activity as a GABA A receptor positive modulator; the benzanilide KCNQ potassium channel opener ICA-27243 that is more selective than retigabine; and rufinamide, a triazole of unknown mechanism.

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“…LEV erwies sich als unwirksam in Tiermodellen fokaler und generalisierter Epilepsien, die üblicherweise zum Screening antikonvulsiv wirksamer Substanzen eingesetzt wurden; der Wirkmechanismus unterscheidet sich von dem anderer bislang bekannter Antikonvulsiva [22,38]. Tierexperimentell erwies sich LEV als wirksam in Kindling-Modellen fokaler Epilepsien und in genetischen Ratten-Modellen [19,22,28]; auch die bislang vorliegenden klinischen Erfahrungen legen ein breites Wirkspektrum nahe [3, 11,16]. Toxizitätsuntersuchungen ergaben einen ungewöhnlich großen therapeutischen Index [25].…”

Section: Levetiracetam (Lev Keppra) Ist Inunclassified