Lamotrigine inhibits Ca2+ currents in cortical neurons: functional implications

Stefani, Alessandro; Spadoni, Francesca; Siniscalchi, Antonio; Bernardi, Giorgio

doi:10.1016/0014-2999(96)00265-8

Cited by 180 publications

(92 citation statements)

References 11 publications

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“…Antiepileptics of the gabapentinoid family bind to a2d subunits and may exert their actions by inhibiting their trafficking functions, resulting in a reduction of calcium current density at the cell membrane with a consequent loss of synaptic transmission (Gee et al 1996;Marais et al 2001;Sills 2006;Hendrich et al 2008). Other AEDs, such as sodium valproate, topiramate, lamotrigine, and phenytoin, have also been shown to block calcium channels (Twombly et al 1988;Kelly et al 1990;Stefani et al 1996;Hainsworth et al 2003;Kuzmiski et al 2005). However, two points need to be borne in mind.…”

Section: Calcium Channels and Epilepsymentioning

confidence: 99%

The Role of Calcium Channels in Epilepsy

Rajakulendran

Hanna

2016

Cold Spring Harb Perspect Med

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A central theme in the quest to unravel the genetic basis of epilepsy has been the effort to elucidate the roles played by inherited defects in ion channels. The ubiquitous expression of voltage-gated calcium channels (VGCCs) throughout the central nervous system (CNS), along with their involvement in fundamental processes, such as neuronal excitability and synaptic transmission, has made them attractive candidates. Recent insights provided by the identification of mutations in the P/Q-type calcium channel in humans and rodents with epilepsy and the finding of thalamic T-type calcium channel dysfunction in the absence of seizures have raised expectations of a causal role of calcium channels in the polygenic inheritance of idiopathic epilepsy. In this review, we consider how genetic variation in neuronal VGCCs may influence the development of epilepsy.

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Section: Calcium Channels and Epilepsymentioning

confidence: 99%

The Role of Calcium Channels in Epilepsy

Rajakulendran

Hanna

2016

Cold Spring Harb Perspect Med

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“…91 Similarly, although the anticonvulsant activity of lamotrigine is believed to be mediated primarily by effects on voltage-gated Na ϩ channels, lamotrigine also inhibits high voltage-activated (N-and P/Q-type) Ca 2ϩ channels (but inhibits R-type minimally, and T-or L-type Ca 2ϩ channels not at all). [92][93][94][95] Whereas effects on Na ϩ channels are believed to be responsible for the inhibitory action of Na ϩ channel-blocking AEDs on synaptic glutamate release, inhibitory actions on voltage-gated Ca 2ϩ channels may also contribute, especially for lamotrigine (through its blocking action on N-type channels). 96,97 Recently, it has become apparent that the molecular targets for gabapentin and pregabalin are ␣2-␦ proteins, specifically ␣2-␦-1 and ␣2-␦-2.…”

Section: Voltage-gated Calcium Channelsmentioning

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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“…For example, lamotrigine and topiramate were identified largely by activity in the MES test, yet their pharmacodynamic actions must be different from the prototypical sodium channel blocking AEDs phenytoin and carbamazepine since they have distinct clinical activities. In fact, while all four drugs do interact with fast transient and persistent sodium channels, lamotrigine at clinically relevant concentrations also has substantial effects on high voltage-activated calcium channels (Stefani et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Molecular targets versus models for new antiepileptic drug discovery

Rogawski¹

2006

Epilepsy Research

142

101

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Animal models have played a key role in the discovery and characterization of all marketed antiepileptic drugs (AED). The conventional wisdom is that the standard animal screening models are becoming obsolete because they fail to identify compounds that act in mechanistically new ways and as a result do not offer therapeutic advantages over presently available agents. In fact, far from only detecting me-too drugs, the models often uncover compounds with distinctive profiles of activity in various types of epilepsy and in addition have unexpected efficacy in non-epilepsy conditions, such as neuropathic pain, bipolar disorder, and migraine. Moreover, the animal models-because they are unbiased with respect to mechanism-provide an opportunity to uncover drugs that act in new ways and through new targets, such as α2δ and SV2A. In vitro testing is not likely to replace screening in animal models because in vitro systems cannot model the specific pharmacodynamic actions required for seizure protection, and do not assess bioavailability and brain accessibility.

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Lamotrigine inhibits Ca2+ currents in cortical neurons: functional implications

Cited by 180 publications

References 11 publications

The Role of Calcium Channels in Epilepsy

The Role of Calcium Channels in Epilepsy

Molecular Targets for Antiepileptic Drug Development

Molecular targets versus models for new antiepileptic drug discovery

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