Topiramate as an Inhibitor of Carbonic Anhydrase Isoenzymes

Dodgson, Susanna J.; Shank, Richard P.; Maryanoff, Bruce E.

doi:10.1111/j.1528-1157.2000.tb02169.x

Cited by 182 publications

(167 citation statements)

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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: 92%

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

Avoli¹,

Curtis²

2011

Progress in Neurobiology

224

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: 92%

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

Avoli¹,

Curtis²

2011

Progress in Neurobiology

224

253

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“…32 Topiramate's enhancement of gamma-aminobutyric acid (GABA)-mediated chloride fluxes, 34 blockade of kainateinduced fluxes, 35 and state-dependent blockade of Na þ channels 36 appear relevant to its antiseizure activity, but bear no obvious relationship to appetite or weight loss. Topiramate is also a weak inhibitor of carbonic anhydrase, especially isoenzymes II and IV, 37 which presumably accounts for its frequent induction of paraesthesia.…”

Section: Discussionmentioning

confidence: 99%

A randomized double-blind placebo-controlled study of the long-term efficacy and safety of topiramate in the treatment of obese subjects

et al. 2004

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BACKGROUND: Treatment of obese subjects with topiramate has recently been associated with significant weight loss in a 6-month dose-ranging study. OBJECTIVE: To investigate the long-term efficacy and safety of topiramate in obese subjects. DESIGN: Randomised, double-blind, placebo-controlled study investigating three doses of topiramate: 96, 192, and 256 mg/ day. All subjects also participated in a nonpharmacological weight-loss programme. SUBJECTS: The study included 1289 subjects 18-75 y with a body mass index Z30 kg/m 2 and o50 kg/m 2 in the absence of comorbidities, or Z27 kg/m 2 and o50 kg/m 2 in the presence of controlled hypertension and/or dyslipidaemia. DURATION: The original study design was for a 6-week, single-blind, placebo run-in phase followed by an 8-week titration phase and 2 y of maintenance at the assigned dose. Sponsor ended study early in order to develop a new controlled-release formulation with the potential to enhance tolerability and simplify dosing in this patient population. Therefore, none of the subjects completed the full 2 y of treatment. Efficacy results are based on subjects who were enrolled early enough to have had an opportunity to complete 1 y at their assigned dose (modified intent-to-treat population, MITT) before learning of the decision to terminate the study. Safety results are based on all subjects who took at least one dose of study medication. RESULTS: The safety population consisted of 1282 subjects, and the MITT efficacy population was 854 subjects. At 60 weeks, subjects in the placebo group lost 1.7% of their baseline body weight, while subjects in the topiramate 96, 192, and 256 mg/day treatment groups lost 7.0, 9.1, and 9.7%, respectively (Po0.001, MITT, last observation carried forward). Weight loss Z5% of baseline weight was achieved by 18% of subjects in the placebo arm vs 54, 61, and 67% of subjects receiving topiramate 96, 192, and 256 mg/day, respectively; weight loss Z10% was achieved by 6 vs 29, 40, and 44%, respectively (Po0.001). Weight loss was accompanied by significant improvements in blood pressure (systolic/diastolic changes of þ 0.4/ þ 1.0, À3.1/À1.3, À5.7/À3.4, and À4.6/À2.4 mmHg were observed for placebo, topiramate 96 mg/day, 192 mg/day, and 256 mg/day, respectively, Po0.001) and glucose and insulin. The most common adverse events more frequently observed in topiramatetreated subjects occurred mostly during the titration phase and were related to the central or peripheral nervous system and included paresthesia, difficulty with concentration/attention, depression, difficulty with memory, language problems, nervousness, and psychomotor slowing. CONCLUSION: Topiramate treatment of obese subjects over the course of 1 y resulted in clinically significant weight loss. Improvements were also observed in blood pressure and glucose tolerance.

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“…Two more recently introduced AEDs, zonisamide and topiramate, also inhibit carbonic anhydrase, which may contribute to their side effects, including kidney stones and perhaps also oligohydrosis and hyperthermia. 392,393 The action of topiramate on carbonic anhydrase has been assumed not to contribute to its clinical efficacy, because cross-tolerance to the anticonvulsant activity of topiramate does not occur with acetazolamide in mice. 394 However, a recent study finds closely comparable potency for acetazolamide and the two AEDs against cytosolic carbonic anydrase isozyme II and mitochondrial carbonic anhydrase isozyme V. 395 Carbonic anhydrase is a zinc-containing enzyme that is inhibited by interaction of sulfonamide or sulfamate compounds with the Zn(II) ion and specific residues of the protein.…”

Section: Carbonic Anhydrasementioning

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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Topiramate as an Inhibitor of Carbonic Anhydrase Isoenzymes

Cited by 182 publications

References 18 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

A randomized double-blind placebo-controlled study of the long-term efficacy and safety of topiramate in the treatment of obese subjects

Molecular Targets for Antiepileptic Drug Development

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