Stiripentol inhibits spike‐and‐wave discharges in animal models of absence seizures: A new mechanism of action involving T‐type calcium channels

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Summary

Objective

Stiripentol (STP; Diacomit®) is an antiepileptic drug indicated for Dravet syndrome that has been identified as a γ‐aminobutyric acid (GABAergic) positive allosteric modulator. Dravet syndrome is characterized by multiple seizure types: generalized tonic–clonic, focal, myoclonic, and absence seizures. In addition to its antiepileptic effects on tonic–clonic seizures, STP has also been reported to reduce the frequency of atypical absence seizures in patients. Our study focused on STP potential effects on absence seizures, to better characterize its full spectrum of mechanisms of action.

Methods

STP effects on absence seizures were quantified by electroencephalographic recording in two animal models: rats treated with a low dose of pentylenetetrazol (20 mg/kg ip) and rats from the WAG/Rij strain. In addition, we characterized STP effects on T‐type calcium channel activity. Peak currents were recorded with manual patch clamp on cells transfected with cDNA encoding for the human isoform for Ca _v3.1, Ca _v3.2, and Ca _v3.3.

Results

STP administered before pentylenetetrazol almost completely abolished the generation of spike‐and‐wave discharges (SWDs) at the dose of 300 mg/kg. At this dose, STP also statistically significantly decreased SWD cumulated duration and number in WAG/Rij rats. Its antiepileptic effect was maintained in WAG/Rij rats, whose seizures were aggravated by the GABA agonist THIP (gaboxadol hydrochloride). Furthermore, electrophysiological recordings showed that STP inhibits T‐type calcium channel peak activity, with a higher specificity for the Ca _v3.3 subtype.

Significance

In addition to its previously characterized anticonvulsive properties, these data highlight a new mechanism of action of STP on abnormal thalamocortical activity. This strong antiabsence effect on seizures is correlated with an inhibition of T‐type calcium channels. This new mechanism of action could be implicated in the specificity of STP therapeutic effects in Dravet syndrome.

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Most cited references 53

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GABA(A) receptors: immunocytochemical distribution of 13 subunits in the adult rat brain.

S Pirker, A Wieselthaler, W. Sieghart … (2000)

GABA(A) receptors are ligand-operated chloride channels assembled from five subunits in a heteropentameric manner. Using immunocytochemistry, we investigated the distribution of GABA(A) receptor subunits deriving from 13 different genes (alpha1-alpha6, beta1-beta3, gamma1-gamma3 and delta) in the adult rat brain. Subunit alpha1-, beta1-, beta2-, beta3- and gamma2-immunoreactivities were found throughout the brain, although differences in their distribution were observed. Subunit alpha2-, alpha3-, alpha4-, alpha5-, alpha6-, gamma1- and delta-immunoreactivities were more confined to certain brain areas. Thus, alpha2-subunit-immunoreactivity was preferentially located in forebrain areas and the cerebellum. Subunit alpha6-immunoreactivity was only present in granule cells of the cerebellum and the cochlear nucleus, and subunit gamma1-immunoreactivity was preferentially located in the central and medial amygdaloid nuclei, in pallidal areas, the substantia nigra pars reticulata and the inferior olive. The alpha5-subunit-immunoreactivity was strongest in Ammon's horn, the olfactory bulb and hypothalamus. In contrast, alpha4-subunit-immunoreactivity was detected in the thalamus, dentate gyrus, olfactory tubercle and basal ganglia. Subunit alpha3-immunoreactivity was observed in the glomerular and external plexiform layers of the olfactory bulb, in the inner layers of the cerebral cortex, the reticular thalamic nucleus, the zonal and superficial layers of the superior colliculus, the amygdala and cranial nerve nuclei. Only faint subunit gamma3-immunoreactivity was detected in most areas; it was darkest in midbrain and pontine nuclei. Subunit delta-immunoreactivity was frequently co-distributed with alpha4 subunit-immunoreactivity, e.g. in the thalamus, striatum, outer layers of the cortex and dentate molecular layer. Striking examples of complementary distribution of certain subunit-immunoreactivities were observed. Thus, subunit alpha2-, alpha4-, beta1-, beta3- and delta-immunoreactivities were considerably more concentrated in the neostriatum than in the pallidum and entopeduncular nucleus. In contrast, labeling for the alpha1-, beta2-, gamma1- and gamma2-subunits prevailed in the pallidum compared to the striatum. With the exception of the reticular thalamic nucleus, which was prominently stained for subunits alpha3, beta1, beta3 and gamma2, most thalamic nuclei were rich in alpha1-, alpha4-, beta2- and delta-immunoreactivities. Whereas the dorsal lateral geniculate nucleus was strongly immunoreactive for subunits alpha4, beta2 and delta, the ventral lateral geniculate nucleus was predominantly labeled for subunits alpha2, alpha3, beta1, beta3 and gamma2; subunit alpha1- and alpha5-immunoreactivities were about equally distributed in both areas. In most hypothalamic areas, immunoreactivities for subunits alpha1, alpha2, beta1, beta2 and beta3 were observed. In the supraoptic nucleus, staining of conspicuous dendritic networks with subunit alpha1, alpha2, beta2, and gamma2 antibodies was contrasted by perykarya labeled for alpha5-, beta1- and delta-immunoreactivities. Among all brain regions, the median emminence was most heavily labeled for subunit beta2-immunoreactivity. In most pontine and cranial nerve nuclei and in the medulla, only subunit alpha1-, beta2- and gamma2-immunoreactivities were strong, whereas the inferior olive was significantly labeled only for subunits beta1, gamma1 and gamma2. In this study, a highly heterogeneous distribution of 13 different GABA(A) receptor subunit-immunoreactivities was observed. This distribution and the apparently typical patterns of co-distribution of these GABA(A) receptor subunits support the assumption of multiple, differently assembled GABA(A) receptor subtypes and their heterogeneous distribution within the adult rat brain.

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The distribution of thirteen GABAA receptor subunit mRNAs in the rat brain. III. Embryonic and postnatal development.

DJ Laurie, W Wisden, PH Seeburg (1992)

The embryonic and postnatal expression of 13 GABAA receptor subunit genes in the rat CNS was studied by in situ hybridization. Each transcript exhibited a unique regional and temporal developmental expression profile. For example, in both embryonic and early postnatal cortex and thalamus, expression of the alpha 2, alpha 3, alpha 5, and beta 3 mRNAs was pronounced. In particular, the alpha 5 gene expression underwent a prominent peak in early brain. Subsequently, the thalamocortical expression of these four genes substantially diminished and was superseded in the adult by the alpha 1, alpha 4, beta 2, and delta subunit mRNAs. Similarly, gamma 1 and gamma 3 gene expression also dropped markedly during development, their initial stronger expression being restricted to relatively few structures. In contrast, gamma 2 gene expression was widespread and mostly remained constant with increasing age. The medial septum and globus pallidus were regions expressing few subunits in both early postnatal and adult stages, allowing clear developmental combinatorial changes to be inferred (alpha 2/alpha 3 beta 2 gamma 2 to alpha 1 beta 2 gamma 2, alpha 2/alpha 3 beta 2 gamma 1 to alpha 1 beta 2 gamma 1/gamma 2, respectively). In contrast, cerebellar Purkinje cells exhibited no developmental switch, expressing only the alpha 1, beta 2, beta 3, and gamma 2 mRNAs from birth to adult. Certain GABAA transcripts were also detected in germinal zones (e.g., beta 1, beta 3, gamma 1) and in embryonic peripheral tissues such as dorsal root ganglia (e.g., alpha 2, alpha 3, beta 3, gamma 2) and intestine (gamma 3). Some parallels in regional and temporal CNS expression were noted (e.g., alpha 1 beta 2, alpha 2 beta 3, alpha 4/alpha 6 delta), whereas the alpha 5 and beta 1 regional mRNA expressions converted over time. The changes of GABAA receptor subunit gene expression suggest a molecular explanation for earlier observations on changing ligand binding affinities. Thus, the composition, and presumably properties, of embryonic/early postnatal rat GABAA receptors differs markedly from those expressed in the adult brain.

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Prognostic, clinical and demographic features in SCN1A mutation-positive Dravet syndrome.

R. Ellis, A Brunklaus, Catherine Reavey … (2012)

Dravet syndrome is a severe infantile onset epileptic encephalopathy associated with mutations in the sodium channel alpha 1 subunit gene SCN1A. To date no large studies have systematically examined the prognostic, clinical and demographic features of the disease. We prospectively collected data on a UK cohort of individuals with Dravet syndrome during a 5-year study period and analysed demographic information based on UK population and birth figures. From structured referral data we examined a range of clinical characteristics including epilepsy phenotype, seizure precipitants, electroencephalography data, imaging studies, mutation class and response to medication. Predictors of developmental outcome were determined by logistic regression. We identified 241 cases with SCN1A mutation-positive Dravet syndrome, 207 of which were UK-based. The incidence of mutation-positive Dravet syndrome is at least 1:40 900 UK births. Clinical features predicting a worse developmental outcome included status epilepticus (odds ratio = 3.1; confidence interval = 1.5-6.3; P = 0.003), interictal electroencephalography abnormalities in the first year of life (odds ratio = 5.7; confidence interval = 1.9-16.8; P = 0.002) and motor disorder (odds ratio = 3.3; confidence interval = 1.7-6.4; P < 0.001). No significant effect was seen for seizure precipitants, magnetic resonance imaging abnormalities or mutation class (truncating versus missense). Abnormal magnetic resonance imaging was documented in 11% of cases, principally with findings of non-specific brain atrophy or hippocampal changes. Sodium valproate, benzodiazepines and topiramate were reported as being the most helpful medications at the time of referral. Aggravation of seizures was reported for carbamazepine and lamotrigine. The identification of factors influencing prognosis both aids counselling and encourages early, syndrome-specific therapy. Prevention of status epilepticus with regular medication and emergency protocols is important and may influence developmental outcome.

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Author and article information

Contributors

Veronique Riban:

ORCID: https://orcid.org/0000-0003-4757-4995

vriban@yahoo.fr

Journal

Journal ID (nlm-ta): Epilepsia

Journal ID (iso-abbrev): Epilepsia

Journal ID (doi): 10.1111/(ISSN)1528-1167

Journal ID (publisher-id): EPI

Title: Epilepsia

Publisher: John Wiley and Sons Inc. (Hoboken )

ISSN (Print): 0013-9580

ISSN (Electronic): 1528-1167

Publication date (Electronic): 09 March 2022

Publication date (Print): May 2022

Volume: 63

Issue: 5 ( doiID: 10.1111/epi.v63.5 )

Pages: 1200-1210

Affiliations

[ ¹ ] Pharmacology Department Biocodex Compiègne France

[ ² ] B’SYS Witterswil Switzerland

Author notes

[*] [* ] Correspondence

Veronique Riban, Biocodex, 3 Chemin d’Armancourt, 60200 Compiègne, France.

Email: vriban@ 123456yahoo.fr

Author information

Veronique Riban https://orcid.org/0000-0003-4757-4995

Article

Publisher ID: EPI17201

DOI: 10.1111/epi.17201

PMC ID: 9314114

PubMed ID: 35184274

SO-VID: 89205876-3c1e-4dcd-b500-b8cb4901c4b0

License:

This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

History

Date revision received : 13 February 2022

Date received : 11 October 2021

Date accepted : 15 February 2022

Page count

Figures: 4, Tables: 0, Pages: 11, Words: 6478

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source-schema-version-number 2.0

cover-date May 2022

details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_JATSPMC version:6.1.7 mode:remove_FC converted:25.07.2022

ScienceOpen disciplines: Neurology

Keywords: absence seizures,dravet syndrome,epilepsy,spike‐and‐wave discharges,stiripentol,thalamocortical oscillations

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ScienceOpen disciplines: Neurology

Keywords: absence seizures, dravet syndrome, epilepsy, spike‐and‐wave discharges, stiripentol, thalamocortical oscillations

Stiripentol inhibits spike‐and‐wave discharges in animal models of absence seizures: A new mechanism of action involving T‐type calcium channels

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Karger: Neurology and Neuroscience

Most cited references 53

GABA(A) receptors: immunocytochemical distribution of 13 subunits in the adult rat brain.

The distribution of thirteen GABAA receptor subunit mRNAs in the rat brain. III. Embryonic and postnatal development.

Prognostic, clinical and demographic features in SCN1A mutation-positive Dravet syndrome.

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