Blockade of T-type calcium channels prevents tonic-clonic seizures in a maximal electroshock seizure model

Sakkaki, Sophie; Gangarossa, Giuseppe; Lerat, Benoit; Françon, Dominique; Forichon, Luc; Chemin, Jean; Valjent, Emmanuel; Lerner‐Natoli, Mireille; Lory, Philippe

doi:10.1016/j.neuropharm.2015.09.032

Cited by 26 publications

(18 citation statements)

References 52 publications

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“…Two novel T-type channel blockers, TTA-A2 and Z944, reduced tonic seizure frequency in the maximal electroshock (MES) model or delayed kindling, respectively. 12,13 This pharmacologic inhibition of rodent T-type channels effectively reduced seizures, mimicking the phenotype of homozygous null Cacna1g KO/KO mice, which are resistant to induction of tonic seizures by MES and display reduced epileptogenicity in response to kainate. 12,14 Similarly, the results of our study showed Cacna1g-mediated modulation of focal motor seizures in a genetic model.…”

Section: Resultsmentioning

confidence: 85%

“…Recent evidence from other studies suggests that T‐type calcium channels can contribute to epilepsies in addition to absence. Two novel T‐type channel blockers, TTA‐A2 and Z944, reduced tonic seizure frequency in the maximal electroshock (MES) model or delayed kindling, respectively . This pharmacologic inhibition of rodent T‐type channels effectively reduced seizures, mimicking the phenotype of homozygous null Cacna1g KO/KO mice, which are resistant to induction of tonic seizures by MES and display reduced epileptogenicity in response to kainate .…”

Section: Resultsmentioning

confidence: 94%

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Cacna1g is a genetic modifier of epilepsy caused by mutation of voltage‐gated sodium channel Scn2a

et al. 2016

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Summary More than 1200 mutations in neuronal voltage-gated sodium channel genes have been identified in patients with several epilepsy syndromes. A common feature of genetic epilepsies is variable expressivity among individuals with the same mutation. The Scn2aQ54 transgenic mouse model has a mutation in Scn2a that results in spontaneous epilepsy. Scn2aQ54 phenotype severity varies depending on the genetic strain background, making it a useful model for identifying and characterizing epilepsy modifier genes. Scn2aQ54 mice on the [C57BL/6JxSJL/J]F1 background exhibit earlier seizure onset, elevated spontaneous seizure frequency, and decreased survival compared to Scn2aQ54 mice congenic on the C57BL/6J strain. Genetic mapping and RNA-Seq analysis identified Cacna1g as a candidate modifier gene at the Moe1 locus, which influences Scn2aQ54 phenotype severity. In this study, we evaluated the modifier potential of Cacna1g, encoding the Cav3.1 voltage-gated calcium channel, by testing whether transgenic alteration of Cacna1g expression modifies severity of the Scn2aQ54 seizure phenotype. Scn2aQ54 mice exhibited increased spontaneous seizure frequency with elevated Cacna1g expression and decreased seizure frequency with decreased Cacna1g expression. These results provide support for Cacna1g as an epilepsy modifier gene and suggest that modulation of Cav3.1 may be an effective therapeutic strategy.

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Section: Resultsmentioning

confidence: 85%

Section: Resultsmentioning

confidence: 94%

Cacna1g is a genetic modifier of epilepsy caused by mutation of voltage‐gated sodium channel Scn2a

et al. 2016

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“…The loss of thalamocortical oscillations was also observed in central medial nucleus, which reflects the overall importance of Cav3.1 channels in thalamic neurons [146]. Cav3.1 −/− mice were less prone to develop tonic seizures in the maximal electroshock seizure test, compared with wt littermates and Cav3.2 −/− mice, suggesting a prominent role of the Cav3.1 isoform in mediating tonic seizure [127]. Interestingly, overexpression of the Cav3.1 channel in a Cacna1g transgenic mouse line results in a pure absence epilepsy phenotype with no ataxia or other neurological disturbances [57], suggesting that an increase in Cav3.1 current is sufficient to the pathogenesis of spike-wave seizures.…”

Section: Cav3 Physiologymentioning

confidence: 80%

Neuronal Cav3 channelopathies: recent progress and perspectives

Lory

Nicole

Monteil

2020

Pflugers Arch - Eur J Physiol

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T-type, low-voltage activated, calcium channels, now designated Cav3 channels, are involved in a wide variety of physiological functions, especially in nervous systems. Their unique electrophysiological properties allow them to finely regulate neuronal excitability and to contribute to sensory processing, sleep, and hormone and neurotransmitter release. In the last two decades, genetic studies, including exploration of knockout mouse models, have greatly contributed to elucidate the role of Cav3 channels in normal physiology, their regulation, and their implication in diseases. Mutations in genes encoding Cav3 channels (CACNA1G, CACNA1H, and CACNA1I) have been linked to a variety of neurodevelopmental, neurological, and psychiatric diseases designated here as neuronal Cav3 channelopathies. In this review, we describe and discuss the clinical findings and supporting in vitro and in vivo studies of the mutant channels, with a focus on de novo, gain-of-function missense mutations recently discovered in CACNA1G and CACNA1H. Overall, the studies of the Cav3 channelopathies help deciphering the pathogenic mechanisms of corresponding diseases and better delineate the properties and physiological roles Cav3 channels.

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“…Cav3.2 channel overexpression was also found associated to neuroendocrine differentiation of prostate cancer cells [ 60 ]. Importantly, TTCCs represent novel interesting molecular targets for pain and epilepsy [ 31 , 33 , 43 , 61 – 63 ]. Inhibition of TTCCs has been reported to play an important role in the therapeutic action of many drugs [ 64 ].…”

Section: Discussionmentioning

confidence: 99%

Modulation of T-type Ca2+ channels by Lavender and Rosemary extracts

Alaoui

Chemin

Fechtali³

et al. 2017

PLoS ONE

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Medicinal plants represent a significant reservoir of unexplored substances for early-stage drug discovery. Of interest, two flowering Mediterranean plants have been used for thousands of years for their beneficial effects on nervous disorders, including anxiety and mood. However, the therapeutic potential of these plants regarding their ability to target ion channels and neuronal excitability remains largely unknown. Towards this goal, we have investigated the ability of Lavender and Rosemary to modulate T-type calcium channels (TTCCs). TTCCs play important roles in neuronal excitability, neuroprotection, sensory processes and sleep. These channels are also involved in epilepsy and pain. Using the whole-cell patch-clamp technique, we have characterized how Lavender and Rosemary extracts, as well as their major active compounds Linalool and Rosmarinic acid, modulate the electrophysiological properties of recombinant TTCCs (CaV3.2) expressed in HEK-293T cells. Both the methanolic and essential oil extracts as well as the active compounds of these plants inhibit Cav3.2 current in a concentration-dependent manner. In addition, these products also induce a negative shift of the steady-state inactivation of CaV3.2 current with no change in the activation properties. Taken together, our findings reveal that TTCCs are a molecular target of the Lavender and Rosemary compounds, suggesting that inhibition of TTCCs could contribute to the anxiolytic and the neuroprotective effects of these plants.

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Blockade of T-type calcium channels prevents tonic-clonic seizures in a maximal electroshock seizure model

Cited by 26 publications

References 52 publications

Cacna1g is a genetic modifier of epilepsy caused by mutation of voltage‐gated sodium channel Scn2a

Cacna1g is a genetic modifier of epilepsy caused by mutation of voltage‐gated sodium channel Scn2a

Neuronal Cav3 channelopathies: recent progress and perspectives

Modulation of T-type Ca2+ channels by Lavender and Rosemary extracts

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