Neuropharmacologic Considerations in Psychic Seizures

Toman, James E. P.

doi:10.1212/wnl.1.11-12.444

Cited by 50 publications

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“…Next, we assessed the susceptibility of male Scn3a +/Hyp mutants to focal seizures using the 6 Hz “psychomotor” seizure induction paradigm (Brown et al, 1953; Toman, 1951). Male Scn3a +/Hyp mutants and WT littermates were tested at current intensities of 16 mA, 24 mA, and 30 mA.…”

Section: Resultsmentioning

confidence: 99%

SCN3A deficiency associated with increased seizure susceptibility

Lamar

Vanoye

Calhoun

et al. 2017

Neurobiology of Disease

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Mutations in voltage-gated sodium channels expressed highly in the brain (SCN1A, SCN2A, SCN3A, and SCN8A) are responsible for an increasing number of epilepsy syndromes. In particular, mutations in the SCN3A gene, encoding the pore-forming Nav1.3 α subunit, have been identified in patients with focal epilepsy. Biophysical characterization of epilepsy-associated SCN3A variants suggests that both gain- and loss-of-function SCN3A mutations may lead to increased seizure susceptibility. In this report, we identified a novel SCN3A variant (L247P) by whole exome sequencing of a child with focal epilepsy, developmental delay, and autonomic nervous system dysfunction. Voltage clamp analysis showed no detectable sodium current in a heterologous expression system expressing the SCN3A-L247P variant. Furthermore, cell surface biotinylation demonstrated a reduction in the amount of SCN3A-L247P at the cell surface, suggesting the SCN3A-L247P variant is a trafficking-deficient mutant. To further explore the possible clinical consequences of reduced SCN3A activity, we investigated the effect of a hypomorphic Scn3a allele (Scn3aHyp) on seizure susceptibility and behavior using a gene trap mouse line. Heterozygous Scn3a mutant mice (Scn3a+/Hyp) did not exhibit spontaneous seizures nor were they susceptible to hyperthermia-induced seizures. However, they displayed increased susceptibility to electroconvulsive (6 Hz) and chemiconvulsive (flurothyl and kainic acid) induced seizures. Scn3a+/Hyp mice also exhibited deficits in locomotor activity and motor learning. Taken together, these results provide evidence that loss-of-function of SCN3A caused by reduced protein expression or deficient trafficking to the plasma membrane may contribute to increased seizure susceptibility.

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Section: Resultsmentioning

confidence: 99%

SCN3A deficiency associated with increased seizure susceptibility

Lamar

Vanoye

Calhoun

et al. 2017

Neurobiology of Disease

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“…Minimal clonic seizures are characterized by rhythmic face and forelimb clonus, rearing and falling, and ventral neck flexion. Minimal THE seizures are characterized by a tonic-clonic flexion-extension sequence that starts with tonic forelimb extension, followed by hindlimb flexion, and terminates in full THE (180 degrees to the torso) (24)(25)(26).…”

Section: Baseline Seizure Thresholdsmentioning

confidence: 99%

Mice Carrying the Szt1 Mutation Exhibit Increased Seizure Susceptibility and Altered Sensitivity to Compounds Acting at the M‐Channel

et al. 2004

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Summary:Purpose: Mutations in the genes that encode subunits of the M-type K + channel (KCNQ2/KCNQ3) and nicotinic acetylcholine receptor (CHRNA4) cause epilepsy in humans. The purpose of this study was to examine the effects of the Szt1 mutation, which not only deletes most of the C-terminus of mouse Kcnq2, but also renders the Chnra4 and Arfgap-1 genes hemizygous, on seizure susceptibility and sensitivity to drugs that target the M-type K + channel. Methods: The proconvulsant effects of the M-channel blocker linopirdine (LPD) and anticonvulsant effects of the M-channel enhancer retigabine (RGB) were assessed by electroconvulsive threshold (ECT) testing in C57BL/6J-Szt1/+ (Szt1) and littermate control C57BL/6J+/+ (B6) mice. The effects of the Szt1 mutation on minimal clonic, minimal tonic hindlimb extension, and partial psychomotor seizures were evaluated by varying stimulation intensity and frequency.Results: Szt1 mouse seizure thresholds were significantly reduced relative to B6 littermates in the minimal clonic, minimal tonic hindlimb extension, and partial psychomotor seizure models. Mice were injected with LPD and RGB and subjected to ECT testing. In the minimal clonic seizure model, Szt1 mice were significantly more sensitive to LPD than were B6 mice [median effective dose (ED 50 ) = 3.4 ± 1.1 mg/kg and 7.6 ± 1.0 mg/kg, respectively]; in the partial psychomotor seizure model, Szt1 mice were significantly less sensitive to RGB than were B6 mice (ED 50 = 11.6 ± 1.4 mg/kg and 3.4 ± 1.3 mg/kg, respectively).Conclusions: These results suggest that the Szt1 mutation alters baseline seizure susceptibility and pharmacosensitivity in a naturally occurring mouse model.

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“…The mouse 6 Hz model of psychomotor seizures was originally developed in the 1950s 1,2 and has been used to characterize established antiseizure drugs (ASDs) as well as novel compounds for their potential utility in the treatment of epilepsy. [3][4][5][6][7][8][9][10][11][12] Efficacy in the mouse 6 Hz model has been observed for compounds comprising several distinct mechanisms of action, including sodium channel blockers, benzodiazepines and barbiturates, the SV2A ligands, d2d ligands, potassium channel modifiers, and others, with varying degrees of efficacy.…”

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confidence: 99%

Development and pharmacologic characterization of the rat 6 Hz model of partial seizures

et al. 2017

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SUMMARY Objective The mouse 6 Hz model of psychomotor seizures is a well-established and commonly used pre-clinical model for antiseizure drug (ASD) discovery. Despite its widespread use both in the identification and differentiation of novel ASDs in mice, a corresponding assay in rats has not been developed. We established a method for 6 Hz seizure induction in rats, with similar seizure behaviors as those observed in mice including head nod, jaw clonus, and forelimb clonus. Methods A convulsive current that elicits these seizure behaviors in 97% of rats (CC97) was determined using a Probit analysis. Numerous prototype ASDs were evaluated in this model using stimulus intensities of 1.5× and 2× the CC97, which is comparable to the approach used in the mouse 6 Hz seizure model (e.g., 32 and 44 mA stimulus intensities). The ASDs evaluated include carbamazepine, clobazam, clonazepam, eslicarbazepine, ethosuximide, ezogabine, gabapentin, lacosamide, lamotrigine, levetiracetam, phenobarbital, phenytoin, rufinamide, tiagabine, topiramate, and sodium valproate. Median effective dose (ED50) and median toxic (motor impairment) dose (TD50) values were obtained for each compound. Results Compounds that were effective at the 1.5×CC97 stimulus intensity at PI values > 1 included clobazam, ethosuximide, ezogabine, levetiracetam, phenobarbital, and sodium valproate. Compounds that were effective at the 2×CC97 stimulus intensity at PI values > 1 included ezogabine, phenobarbital, and sodium valproate. Significance In a similar manner to use of the mouse 6 Hz model, development of a rat 6 Hz test will aid in the differentiation of antiseizure drugs, as well as in study design and dose selection for chronic rat models of pharmacoresistant epilepsy. The limited number of established ASDs with demonstrable efficacy at the higher stimulus intensity suggests that, like the mouse 6 Hz 44 mA model, the rat 6 Hz seizure model may be a useful screening tool for pharmacoresistant seizures.

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Neuropharmacologic Considerations in Psychic Seizures

Cited by 50 publications

References 0 publications

SCN3A deficiency associated with increased seizure susceptibility

SCN3A deficiency associated with increased seizure susceptibility

Mice Carrying the Szt1 Mutation Exhibit Increased Seizure Susceptibility and Altered Sensitivity to Compounds Acting at the M‐Channel

Development and pharmacologic characterization of the rat 6 Hz model of partial seizures

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