Anticonvulsant actions of LY 367385 ((+)-2-methyl-4-carboxyphenylglycine) and AIDA ((RS)-1-aminoindan-1,5-dicarboxylic acid)

Chapman, A. Chaston; Yip, Ping K.; Yap, Joan S; Quinn, Leann P.; Tang, Ellen; Harris, J.; Meldrum, Brian S.

doi:10.1016/s0014-2999(99)00014-x

Cited by 75 publications

(40 citation statements)

References 16 publications

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“…This data set was divided across the 3 phases in which Y-maze learning occurred since there were intervals with varying length between the learning sessions. Our within-subjects factor was day (day 1 to 5, day 6 to 10, day [11][12][13] and the between-subjects factor was drug (ETX, control). As mentioned, the dependent variables were the percentage correct choices made in the Y-maze and the amount of completed trials.…”

Section: Discussionmentioning

confidence: 99%

The anti-absence effect of mGlu5 receptor amplification with VU0360172 is maintained during and after antiepileptogenesis

D'Amore

Raaijmakers

Santolini

et al. 2016

Pharmacology Biochemistry and Behavior

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Ethosuximide (ETX) has become the drug of choice in the treatment of patients with absence seizures taking into account both its efficacy, tolerability and antiepileptogenic properties. However, 47% of subjects treated with ETX failed in therapy, and most antiepileptic drugs have cognitive side effects. VU0360172, a positive allosteric modulator (PAM) of mGluR5, acutely and chronically administered decreased seizures dose dependently in rats of the WAG/Rij strain, a genetic absence model. Here it is investigated whether anti-epileptogenesis induced by ETX alters the sensitivity of VU0360172 as an anti-absence drug, and cognition is affected during and after chronic ETX treatment.Method: Male WAG/Rij rats were chronically treated with ETX for 4 months. EEG's were recorded during and after treatment as well as challenged with VU0360172. Rats were also periodically exposed to a cue discrimination learning task in a Y-maze. mGlu5 receptors were quantified with Western Blot.Results: Antiepileptogenesis was successfully induced by ETX and VU0360172 showed a time and dose dependent anti-absence action. However, chronic ETX treated rats showed a decrease in absences both during and after the end treatment, without clear time and dose related effects. The decrease of sensitivity for VU0360172 was not accompanied by a change in mGluR5 expression in cortex and thalamus. Chronic ETX enhanced motivation to collect sucrose pallets and this was followed by an increase in cued discrimination learning.It is concluded that VU0360172 keeps its antiabsence effects after chronic treatment. Moreover, its differential effects in the two groups cannot be explained by a simple receptor down regulation suggesting a more downstream interaction between ETX and mGluR5. The cognitive enhancing effects of ETX, as found at the end of the experiment might be mediated to the antidepressant action of ETX as expressed by an increase in the rewarding properties of sucrose pallets.

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Section: Discussionmentioning

confidence: 99%

The anti-absence effect of mGlu5 receptor amplification with VU0360172 is maintained during and after antiepileptogenesis

D'Amore

Raaijmakers

Santolini

et al. 2016

Pharmacology Biochemistry and Behavior

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“…Group I antagonists such as AIDA (1-aminoindan-1,5-dicarboxylic acid), LY367385, LY456236, MPEP [2-methyl-6-(phenylethynyl)-pyridine], and SIB-1893 are anticonvulsant in a variety of animal models, including generalized convulsive and absence-like seizures, and in models of complex partial seizures (6 Hz, MES, and amygdalakindled seizures). 300,[302][303][304] A lack of anticonvulsant efficacy has, however, been reported for the potent mGluR1 antagonist EMQMCM [3-ethyl-2-methylquinolin-6-yl-(4-methoxy-cyclohexyl)-methanone methanesulfonate] and the potent mGluR5 antagonist MTEP {[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine} in the 6-Hz electroshock model and the amygdala-kindled rat, 305 suggesting that group I antagonists are unlikely to be effective in the largest group of pharmacotherapyresistant patients.…”

Section: Metabotropic Glutamate Receptorsmentioning

confidence: 99%

Molecular Targets for Antiepileptic Drug Development

2007

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Summary:This review considers how recent advances in the physiology of ion channels and other potential molecular targets, in conjunction with new information on the genetics of idiopathic epilepsies, can be applied to the search for improved antiepileptic drugs (AEDs). Marketed AEDs predominantly target voltage-gated cation channels (the ␣ subunits of voltagegated Na ϩ channels and also T-type voltage-gated Ca 2ϩ channels) or influence GABA-mediated inhibition. Recently, ␣2-␦ voltage-gated Ca 2ϩ channel subunits and the SV2A synaptic vesicle protein have been recognized as likely targets. Genetic studies of familial idiopathic epilepsies have identified numerous genes associated with diverse epilepsy syndromes, including genes encoding Na ϩ channels and GABA A receptors, which are known AED targets. A strategy based on genes associated with epilepsy in animal models and humans suggests other potential AED targets, including various voltage-gated Ca 2ϩ channel subunits and auxiliary proteins, A-or M-type voltage-gated K ϩ channels, and ionotropic glutamate receptors. Recent progress in ion channel research brought about by molecular cloning of the channel subunit proteins and studies in epilepsy models suggest additional targets, including G-protein-coupled receptors, such as GABA B and metabotropic glutamate receptors; hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel subunits, responsible for hyperpolarization-activated current I h ; connexins, which make up gap junctions; and neurotransmitter transporters, particularly plasma membrane and vesicular transporters for GABA and glutamate. New information from the structural characterization of ion channels, along with better understanding of ion channel function, may allow for more selective targeting. For example, Na ϩ channels underlying persistent Na ϩ currents or GABA A receptor isoforms responsible for tonic (extrasynaptic) currents represent attractive targets. The growing understanding of the pathophysiology of epilepsy and the structural and functional characterization of the molecular targets provide many opportunities to create improved epilepsy therapies.

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“…Group I mGluR antagonists protect against the onset of sound-induced seizures in mice genetically prone to audiogenic seizures: mGlu1 and mGlu5 receptor antagonists protect against sound-induced generalized motor seizures in DBA/2 mice (Chapman et al, 1999(Chapman et al, , 2000; mGlu1 receptor antagonists protect against sound-induced seizures in genetically epilepsy-prone rats (Chapman et al 1999); and mGlu5 receptor antagonist protects against sound-induced seizures in a mouse model of Fragile X syndrome . Group I mGluR antagonists also prevent the onset of seizures induced by intrahippocampal injection of the muscarinic agonist pilocarpine (Smolders et al, 2004).…”

Section: Group I Mglur and Epileptiform Activitymentioning

confidence: 99%

“…Group I metabotropic glutamate receptor (mGluR) activation has been implicated as a mediator of epileptiform activity in several different models both in vitro (Arvanov et al, 1995;Burke and Hablitz, 1995;Taylor et al, 1995;Merlin and Wong, 1997;Martín et al, 2001;Lee et al, 2002) and in vivo (Tizzano et al, 1995;Camón et al, 1998;Thomsen and Dalby, 1998;Chapman et al, 1999;Chapman et al, 2000;Smolders et al, 2004;Yan et al 2005). In some of these models group I mGluR antagonists block the emergence of the epileptiform activity but do not block established epileptiform activity (Arvanov et al, 1995;Martín et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

“…In some of these models group I mGluR antagonists block the emergence of the epileptiform activity but do not block established epileptiform activity (Arvanov et al, 1995;Martín et al, 2001). Both the mGlu1 and mGlu5 subtypes of group I mGluR have been shown to play a role in the generation of epileptiform activity (Chapman et al, 1999;Chapman et al, 2000;Merlin, 2002;Smolders et al, 2004), with possible differential roles in induction and maintenance of the activity (Merlin, 2002). These experiments and others have generated interest in group I mGluRs as possible targets for antiepileptic and even antiepileptogenic drug development (Merlin, 2002;Moldrich et al, 2003;Wong et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

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Effects of subtype-selective group I mGluR antagonists on synchronous activity induced by 4-aminopyridine/CGP 55845 in adult guinea pig hippocampal slices

Salah

Perkins

2008

Neuropharmacology

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Co-application of the convulsant 4-aminopyridine (4-AP) and the GABA B receptor antagonist CGP 55845 to adult guinea pig hippocampal slices elicits giant GABA-mediated postsynaptic potentials (GPSPs) and epileptiform discharges. Here we tested the effects of the group I metabotropic glutamate receptor (mGluR) subtype-selective antagonists LY 367385 (mGlu1, 100 µM), MPEP (mGlu5, 10 µM), and MTEP (mGlu5, 500 nM) on this synchronous activity. Electrophysiological field recordings were performed in the CA3 region of hippocampal slices from adult guinea pigs. The mGlu5 receptor antagonists increased GPSP rate, but the mGlu1 receptor antagonist did not. This ability of mGlu5 receptor antagonists to increase the rate of GPSPs indicates that enough endogenous glutamate is released under these conditions to activate group I mGluR; nevertheless, co-application of a mGlu1 receptor antagonist (LY 367385 or JNJ 16259685) and MPEP did not decrease pre-existing epileptiform activity. Furthermore, co-application of LY 367385 and MPEP did not prevent the emergence of epileptiform activity. When ionotropic glutamate receptor (iGluR) antagonists were present, neither MPEP nor the group I mGluR agonist DHPG changed GPSP rate, suggesting that pyramidal cell-to-interneuron iGluR-mediated synaptic connections are involved in the rate change mechanism. In contrast to the lack of effect of group I mGluR antagonists on epileptiform activity in the 4-AP/CGP 55845 model, group I mGluR antagonists blocked the emergence of longer epileptiform events and decreased the overall amount of synchronous activity in the GABA A antagonist/4-AP model. In conclusion, in the 4-AP/CGP 55845 model, enough glutamate was released to activate group I mGluRs and affect GPSP rate via mGlu5 receptors; however, this group I mGluR activation was not required for the generation of the epileptiform activity.

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Anticonvulsant actions of LY 367385 ((+)-2-methyl-4-carboxyphenylglycine) and AIDA ((RS)-1-aminoindan-1,5-dicarboxylic acid)

Cited by 75 publications

References 16 publications

The anti-absence effect of mGlu5 receptor amplification with VU0360172 is maintained during and after antiepileptogenesis

The anti-absence effect of mGlu5 receptor amplification with VU0360172 is maintained during and after antiepileptogenesis

Molecular Targets for Antiepileptic Drug Development

Effects of subtype-selective group I mGluR antagonists on synchronous activity induced by 4-aminopyridine/CGP 55845 in adult guinea pig hippocampal slices

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