Two new actions of topiramate: inhibition of depolarizing GABAA-mediated responses and activation of a potassium conductance

Herrero, Ana; Olmo, Nuria Del; González-Escalada, J. R.; Solı́s, José M.

doi:10.1016/s0028-3908(01)00171-x

Cited by 159 publications

(95 citation statements)

References 41 publications

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“…Fifth, HCO 3 − dependent depolarization may lead to the activation of voltage-gated Ca 2+ channels (Autere et al, 1999). In line with this view, it has been reported that antiepileptic drugs such as topiramate inhibit the cytosolic carbonic anhydrase (Dodgson et al, 2000) thus decreasing or abolishing GABA A receptor-mediated depolarizing responses (Herrero et al, 2002). In addition, it has been proposed that inhibiting NKCC1 with bumetanide can reduce and even abolish seizures in rodent models of neonatal seizures (Dzhala et al, 2005(Dzhala et al, , 2010Nardou et al, 2009) and in human neonates (Kahle et al, 2009).…”

Section: Gaba a Receptor-mediated Depolarizing Actionsmentioning

confidence: 93%

GABAergic synchronization in the limbic system and its role in the generation of epileptiform activity

Avoli¹,

Curtis²

2011

Progress in Neurobiology

227

253

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GABA is the main inhibitory neurotransmitter in the adult forebrain, where it activates ionotropic type A and metabotropic type B receptors. Early studies have shown that GABA A receptormediated inhibition controls neuronal excitability and thus the occurrence of seizures. However, more complex, and at times unexpected, mechanisms of GABAergic signaling have been identified during epileptiform discharges over the last few years. Here, we will review experimental data that point at the paradoxical role played by GABA A receptor-mediated mechanisms in synchronizing neuronal networks, and in particular those of limbic structures such as the hippocampus, the entorhinal and perirhinal cortices, or the amygdala. After having summarized the fundamental characteristics of GABA A receptor-mediated mechanisms, we will analyze their role in the generation of network oscillations and their contribution to epileptiform synchronization. Whether and how GABA A receptors influence the interaction between limbic networks leading to ictogenesis will be also reviewed. Finally, we will consider the role of altered inhibition in the human epileptic brain along with the ability of GABA A receptor-mediated conductances to generate synchronous depolarizing events that may lead to ictogenesis in human epileptic disorders as well.

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Section: Gaba a Receptor-mediated Depolarizing Actionsmentioning

confidence: 93%

GABAergic synchronization in the limbic system and its role in the generation of epileptiform activity

Avoli¹,

Curtis²

2011

Progress in Neurobiology

227

253

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“…X-ray crystallography of human carbonic anhydrase II with zonisamide demonstrates a classical interaction with the protein that is characteristic of sulfonamides, as is zonisamide. Another recent study suggests, however, that although both topiramate and acetazolamide can induce a slow outward K ϩ current in hippocampal neurons (yet another possible mechanism of topiramate 396 ), neither drug exerts this action through effects on carbonic anhydrase. 397 Because of the problem of tolerance, carbonic anhydrase has not been considered a promising target for new AED development.…”

Section: Carbonic Anhydrasementioning

confidence: 98%

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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“…Additional to its ability to antagonize alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors and kainate glutamate receptors [117][118][119], topiramate also facilitates inhibitory GABA A -mediated currents at non-benzodiazepine sites on the GABA A receptor [120,121], inhibits L-type calcium channels and limits calcium-dependent second messenger systems [122], reduces activity-dependent depolarization and excitability of voltage-dependent sodium channels [123], activates potassium conductance [124], and is a weak inhibitor of carbonic anhydrase isoenzymes, CA-II and CA-IV [125], which are found in both neuronal and peripheral tissues. In renal tubules, carbonic anhydrase isoenzyme inhibition reduces hydrogen ion secretion and increases secretion of Na + , K + , , and water, thereby enhancing the likelihood of acidosis and renal stone formation [125,126].…”

Section: Alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic Acid Andmentioning

confidence: 99%

Update on neuropharmacological treatments for alcoholism: Scientific basis and clinical findings

Johnson

2008

Biochemical Pharmacology

247

185

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The past decade has seen an expansion of research and knowledge on pharmacotherapy for the treatment of alcohol dependence. The Food and Drug Administration (FDA)-approved medications naltrexone and acamprosate have shown mixed results in clinical trials. Oral naltrexone and naltrexone depot formulations have generally demonstrated efficacy at treating alcohol dependence, but their treatment effect size is small, and more research is needed to compare the effects of different doses on drinking outcome. Acamprosate has demonstrated efficacy for treating alcohol dependence in European trials, but with a small effect size. In U.S. trials, acamprosate has not proved to be efficacious. Research continues to explore which types of alcohol-dependent individual would benefit the most from treatment with naltrexone or acamprosate. The combination of the two medications demonstrated efficacy for treating alcohol dependence in one European study but not in a multi-site U.S. study. Another FDA-approved medication, disulfiram, is an aversive agent that does not diminish craving for alcohol. Disulfiram is most effective when given to those who are highly compliant or who are receiving their medication under supervision. Of the non-approved medications, topiramate is among the most promising, with a medium effect size in clinical trials. Another promising medication, baclofen, has shown efficacy in small trials. Serotonergic agents such as selective serotonin reuptake inhibitors and the serotonin-3 receptor antagonist, ondansetron, appear to be efficacious only among certain genetic subtypes of alcoholic. As neuroscientific research progresses, other promising medications, as well as medication combinations, for treating alcohol dependence continue to be explored.

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Two new actions of topiramate: inhibition of depolarizing GABAA-mediated responses and activation of a potassium conductance

Cited by 159 publications

References 41 publications

GABAergic synchronization in the limbic system and its role in the generation of epileptiform activity

GABAergic synchronization in the limbic system and its role in the generation of epileptiform activity

Molecular Targets for Antiepileptic Drug Development

Update on neuropharmacological treatments for alcoholism: Scientific basis and clinical findings

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