Glutamate metabotropic receptors as targets for drug therapy in epilepsy

Moldrich, Randall X; Chapman, A. Chaston; Sarro, Giovambattista De; Meldrum, Brian S.

doi:10.1016/s0014-2999(03)02149-6

Cited by 165 publications

(112 citation statements)

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“…[297][298][299] Studies in animal models of epilepsy have provided a broadly consistent pattern of effects of selective agonists, antagonists, and allosterically acting compounds-although there are some puzzling anomalies. 300,301 Group I agonists such as DHPG [(R,S)-3,5-dihydroxyphenylglycine] and CHPG (2-chloro-5-hydroxyphenylglycine) are convulsant. 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).…”

Section: Metabotropic Glutamate Receptorsmentioning

confidence: 99%

“…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%

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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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Section: Metabotropic Glutamate Receptorsmentioning

confidence: 99%

Section: Metabotropic Glutamate Receptorsmentioning

confidence: 99%

Molecular Targets for Antiepileptic Drug Development

2007

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“…Group I metabotropic glutamate receptor (GI mGluR) activation is implicated in various synchronised neuronal processes, ranging from perception-pertinent 40 Hz oscillations (Whittington et al, 1995) to hypersynchronous neuronal activity as seen in seizures (Moldrich et al, 2003). Indeed, activation of GI mGluRs has been shown to produce epileptiform activity in hippocampal slices (Sayin and Rutecki, 2003;Taylor et al, 1995), seizures in vivo (Sacaan and Schoepp, 1992) and can lead to protein synthesis-dependent long-term modification of network excitability and the subsequent transition from inter-ictal activity to seizure-like events (Wong et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Pannexin-1-mediated ATP release from area CA3 drives mGlu5-dependent neuronal oscillations

2015

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The activation of Group I metabotropic glutamate receptors (GI mGluRs) in the hippocampus results in the appearance of persistent bursts of synchronised neuronal activity. Such activity is known to cause the release of the purines ATP and its neuroactive metabolite, adenosine.We have investigated the role of the purines in GI mGluR-induced oscillations in hippocampal areas CA3 and CA1 using pharmacological techniques and microelectrode biosensors for ATP and adenosine. The GI mGluR agonist DHPG induced both persistent oscillations in neuronal activity and the release of adenosine in areas CA1 and CA3. In contrast, the DHPG-induced release of ATP was only observed in area CA3. Whilst adenosine acting at adenosine A 1 receptors suppressed DHPG-induced burst activity, the activation of mGlu5 and P2Y 1 ATP receptors were necessary for the induction of DHPG-induced oscillations. Selective inhibition of pannexin-1 hemichannels with a low concentration of carbenoxolone (10 µM) or probenecid (1 mM) did not affect adenosine release in area CA3, but prevented both ATP release in area CA3 and DHPG-induced bursting. These data reveal key aspects of GI mGluR-dependent neuronal activity that are subject to bidirectional regulation by ATP and adenosine in the initiation and pacing of burst firing, respectively, and which have implications for the role of GI mGluRs in seizure activity and neurodevelopmental disorders.

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“…Glutamate, in contrast, is part of the principal excitatory pathway that interacts with both ionotropic receptors which open cationpermeable channels and G-protein-coupled metabotropic receptors [26,27]. It is well established that increased glutamate release can worsen or prolong seizure activity and plays a major role in the persistence of excitotoxicity [28][29][30].…”

Section: Introductionmentioning

confidence: 99%

Cross-species pharmacological characterization of the allylglycine seizure model in mice and larval zebrafish

Leclercq

Afrikanova

Langlois

et al. 2015

Epilepsy & Behavior

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Treatment-resistant seizures affect about a third of patients suffering from epilepsy. To fulfill the need for new medications targeting treatment-resistant seizures, a number of rodent models offer the opportunity to assess a variety of potential treatment approaches. The use of such models, however, has proven to be timeconsuming and labor-intensive. In this study, we performed pharmacological characterization of the allylglycine (AG) seizure model, a simple in vivo model for which we demonstrated a high level of treatment resistance. (D,L)-Allylglycine inhibits glutamic acid decarboxylase (GAD) -the key enzyme in γ-aminobutyric acid (GABA) biosynthesis -leading to GABA depletion, seizures, and neuronal damage. We performed a side-by-side comparison of mouse and zebrafish acute AG treatments including biochemical, electrographic, and behavioral assessments. Interestingly, seizure progression rate and GABA depletion kinetics were comparable in both species. Five mechanistically diverse antiepileptic drugs (AEDs) were used. Three out of the five AEDs (levetiracetam, phenytoin, and topiramate) showed only a limited protective effect (mainly mortality delay) at doses close to the TD 50 (dose inducing motor impairment in 50% of animals) in mice. The two remaining AEDs (diazepam and sodium valproate) displayed protective activity against AG-induced seizures. Experiments performed in zebrafish larvae revealed behavioral AED activity profiles highly analogous to those obtained in mice. Having demonstrated crossspecies similarities and limited efficacy of tested AEDs, we propose the use of AG in zebrafish as a convenient and high-throughput model of treatment-resistant seizures.

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Glutamate metabotropic receptors as targets for drug therapy in epilepsy

Cited by 165 publications

References 110 publications

Molecular Targets for Antiepileptic Drug Development

Molecular Targets for Antiepileptic Drug Development

Pannexin-1-mediated ATP release from area CA3 drives mGlu5-dependent neuronal oscillations

Cross-species pharmacological characterization of the allylglycine seizure model in mice and larval zebrafish

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