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1.
ACS Chem Neurosci ; 10(4): 1992-2003, 2019 04 17.
Article in English | MEDLINE | ID: mdl-30351911

ABSTRACT

In view of the clinical need for new antiseizure drugs (ASDs) with novel modes of action, we used a zebrafish seizure model to screen the anticonvulsant activity of medicinal plants used by traditional healers in the Congo for the treatment of epilepsy, and identified a crude plant extract that inhibited pentylenetetrazol (PTZ)-induced seizures in zebrafish larvae. Zebrafish bioassay-guided fractionation of this anticonvulsant Fabaceae species, Indigofera arrecta, identified indirubin, a compound with known inhibitory activity of glycogen synthase kinase (GSK)-3, as the bioactive component. Indirubin, as well as the more potent and selective GSK-3 inhibitor 6-bromoindirubin-3'-oxime (BIO-acetoxime) were tested in zebrafish and rodent seizure assays. Both compounds revealed anticonvulsant activity in PTZ-treated zebrafish larvae, with electroencephalographic recordings revealing reduction of epileptiform discharges. Both indirubin and BIO-acetoxime also showed anticonvulsant activity in the pilocarpine rat model for limbic seizures and in the 6-Hz refractory seizure mouse model. Most interestingly, BIO-acetoxime also exhibited anticonvulsant actions in 6-Hz fully kindled mice. Our findings thus provide the first evidence for anticonvulsant activity of GSK-3 inhibition, thereby implicating GSK-3 as a potential therapeutic entry point for epilepsy. Our results also support the use of zebrafish bioassay-guided fractionation of antiepileptic medicinal plant extracts as an effective strategy for the discovery of new ASDs with novel mechanisms of action.


Subject(s)
Anticonvulsants/therapeutic use , Epilepsy/drug therapy , Epilepsy/enzymology , Glycogen Synthase Kinase 3/antagonists & inhibitors , Glycogen Synthase Kinase 3/metabolism , Protein Kinase Inhibitors/therapeutic use , Animals , Anticonvulsants/pharmacology , Indoles/pharmacology , Indoles/therapeutic use , Male , Mice , Mice, Inbred C57BL , Protein Kinase Inhibitors/pharmacology , Rats , Rats, Wistar , Zebrafish
2.
Epilepsy Behav ; 45: 53-63, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25845493

ABSTRACT

Treatment-resistant seizures affect about a third of patients suffering from epilepsy. To fulfill the need for new medications targeting treatment-resistant seizures, a number of rodent models offer the opportunity to assess a variety of potential treatment approaches. The use of such models, however, has proven to be time-consuming and labor-intensive. In this study, we performed pharmacological characterization of the allylglycine (AG) seizure model, a simple in vivo model for which we demonstrated a high level of treatment resistance. (d,l)-Allylglycine inhibits glutamic acid decarboxylase (GAD) - the key enzyme in γ-aminobutyric acid (GABA) biosynthesis - leading to GABA depletion, seizures, and neuronal damage. We performed a side-by-side comparison of mouse and zebrafish acute AG treatments including biochemical, electrographic, and behavioral assessments. Interestingly, seizure progression rate and GABA depletion kinetics were comparable in both species. Five mechanistically diverse antiepileptic drugs (AEDs) were used. Three out of the five AEDs (levetiracetam, phenytoin, and topiramate) showed only a limited protective effect (mainly mortality delay) at doses close to the TD50 (dose inducing motor impairment in 50% of animals) in mice. The two remaining AEDs (diazepam and sodium valproate) displayed protective activity against AG-induced seizures. Experiments performed in zebrafish larvae revealed behavioral AED activity profiles highly analogous to those obtained in mice. Having demonstrated cross-species similarities and limited efficacy of tested AEDs, we propose the use of AG in zebrafish as a convenient and high-throughput model of treatment-resistant seizures.


Subject(s)
Allylglycine , Anticonvulsants/therapeutic use , Disease Models, Animal , Seizures/drug therapy , Animals , Diazepam/therapeutic use , Fructose/analogs & derivatives , Fructose/therapeutic use , Levetiracetam , Male , Mice , Phenytoin/therapeutic use , Piracetam/analogs & derivatives , Piracetam/therapeutic use , Seizures/chemically induced , Topiramate , Treatment Outcome , Valproic Acid/therapeutic use , Zebrafish
3.
Brain ; 138(Pt 5): 1198-207, 2015 May.
Article in English | MEDLINE | ID: mdl-25783594

ABSTRACT

Photosensitivity is a heritable abnormal cortical response to flickering light, manifesting as particular electroencephalographic changes, with or without seizures. Photosensitivity is prominent in a very rare epileptic encephalopathy due to de novo CHD2 mutations, but is also seen in epileptic encephalopathies due to other gene mutations. We determined whether CHD2 variation underlies photosensitivity in common epilepsies, specific photosensitive epilepsies and individuals with photosensitivity without seizures. We studied 580 individuals with epilepsy and either photosensitive seizures or abnormal photoparoxysmal response on electroencephalography, or both, and 55 individuals with photoparoxysmal response but no seizures. We compared CHD2 sequence data to publicly available data from 34 427 individuals, not enriched for epilepsy. We investigated the role of unique variants seen only once in the entire data set. We sought CHD2 variants in 238 exomes from familial genetic generalized epilepsies, and in other public exome data sets. We identified 11 unique variants in the 580 individuals with photosensitive epilepsies and 128 unique variants in the 34 427 controls: unique CHD2 variation is over-represented in cases overall (P = 2.17 × 10(-5)). Among epilepsy syndromes, there was over-representation of unique CHD2 variants (3/36 cases) in the archetypal photosensitive epilepsy syndrome, eyelid myoclonia with absences (P = 3.50 × 10(-4)). CHD2 variation was not over-represented in photoparoxysmal response without seizures. Zebrafish larvae with chd2 knockdown were tested for photosensitivity. Chd2 knockdown markedly enhanced mild innate zebrafish larval photosensitivity. CHD2 mutation is the first identified cause of the archetypal generalized photosensitive epilepsy syndrome, eyelid myoclonia with absences. Unique CHD2 variants are also associated with photosensitivity in common epilepsies. CHD2 does not encode an ion channel, opening new avenues for research into human cortical excitability.


Subject(s)
DNA-Binding Proteins/genetics , Epilepsy, Reflex/genetics , Genetic Predisposition to Disease , Mutation/genetics , Animals , Electroencephalography , Gene Knockdown Techniques/methods , Humans , Photic Stimulation/methods , Risk Factors , Zebrafish
4.
PLoS One ; 8(12): e81634, 2013.
Article in English | MEDLINE | ID: mdl-24349101

ABSTRACT

In a previous study, we uncovered the anticonvulsant properties of turmeric oil and its sesquiterpenoids (ar-turmerone, α-, ß-turmerone and α-atlantone) in both zebrafish and mouse models of chemically-induced seizures using pentylenetetrazole (PTZ). In this follow-up study, we aimed at evaluating the anticonvulsant activity of ar-turmerone further. A more in-depth anticonvulsant evaluation of ar-turmerone was therefore carried out in the i.v. PTZ and 6-Hz mouse models. The potential toxic effects of ar-turmerone were evaluated using the beam walking test to assess mouse motor function and balance. In addition, determination of the concentration-time profile of ar-turmerone was carried out for a more extended evaluation of its bioavailability in the mouse brain. Ar-turmerone displayed anticonvulsant properties in both acute seizure models in mice and modulated the expression patterns of two seizure-related genes (c-fos and brain-derived neurotrophic factor [bdnf]) in zebrafish. Importantly, no effects on motor function and balance were observed in mice after treatment with ar-turmerone even after administering a dose 500-fold higher than the effective dose in the 6-Hz model. In addition, quantification of its concentration in mouse brains revealed rapid absorption after i.p. administration, capacity to cross the BBB and long-term brain residence. Hence, our results provide additional information on the anticonvulsant properties of ar-turmerone and support further evaluation towards elucidating its mechanism of action, bioavailability, toxicity and potential clinical application.


Subject(s)
Anticonvulsants/pharmacokinetics , Blood-Brain Barrier , Brain/drug effects , Ketones/pharmacokinetics , Seizures/drug therapy , Sesquiterpenes/pharmacokinetics , Animals , Anticonvulsants/pharmacology , Behavior, Animal/drug effects , Brain/metabolism , Brain/physiopathology , Brain-Derived Neurotrophic Factor/genetics , Brain-Derived Neurotrophic Factor/metabolism , Disease Models, Animal , Gene Expression Regulation/drug effects , Injections, Intraperitoneal , Ketones/pharmacology , Male , Mice , Mice, Inbred C57BL , Motor Activity/drug effects , Pentylenetetrazole , Postural Balance/drug effects , Proto-Oncogene Proteins c-fos/genetics , Proto-Oncogene Proteins c-fos/metabolism , Seizures/chemically induced , Seizures/metabolism , Seizures/physiopathology , Sesquiterpenes/pharmacology , Zebrafish
5.
Am J Hum Genet ; 93(5): 967-75, 2013 Nov 07.
Article in English | MEDLINE | ID: mdl-24207121

ABSTRACT

Dravet syndrome is a severe epilepsy syndrome characterized by infantile onset of therapy-resistant, fever-sensitive seizures followed by cognitive decline. Mutations in SCN1A explain about 75% of cases with Dravet syndrome; 90% of these mutations arise de novo. We studied a cohort of nine Dravet-syndrome-affected individuals without an SCN1A mutation (these included some atypical cases with onset at up to 2 years of age) by using whole-exome sequencing in proband-parent trios. In two individuals, we identified a de novo loss-of-function mutation in CHD2 (encoding chromodomain helicase DNA binding protein 2). A third CHD2 mutation was identified in an epileptic proband of a second (stage 2) cohort. All three individuals with a CHD2 mutation had intellectual disability and fever-sensitive generalized seizures, as well as prominent myoclonic seizures starting in the second year of life or later. To explore the functional relevance of CHD2 haploinsufficiency in an in vivo model system, we knocked down chd2 in zebrafish by using targeted morpholino antisense oligomers. chd2-knockdown larvae exhibited altered locomotor activity, and the epileptic nature of this seizure-like behavior was confirmed by field-potential recordings that revealed epileptiform discharges similar to seizures in affected persons. Both altered locomotor activity and epileptiform discharges were absent in appropriate control larvae. Our study provides evidence that de novo loss-of-function mutations in CHD2 are a cause of epileptic encephalopathy with generalized seizures.


Subject(s)
DNA-Binding Proteins/genetics , Epilepsies, Myoclonic/genetics , Animals , Child , Cognition Disorders/genetics , Cognition Disorders/pathology , Cohort Studies , Epilepsies, Myoclonic/pathology , Exome , Female , Gene Knockdown Techniques , Haploinsufficiency , Humans , Intellectual Disability/genetics , Intellectual Disability/pathology , Larva/genetics , Male , NAV1.1 Voltage-Gated Sodium Channel/genetics , Phenotype , Seizures, Febrile/genetics , Seizures, Febrile/pathology , Young Adult , Zebrafish
6.
PLoS One ; 8(1): e54166, 2013.
Article in English | MEDLINE | ID: mdl-23342097

ABSTRACT

Zebrafish have recently emerged as an attractive in vivo model for epilepsy. Seven-day-old zebrafish larvae exposed to the GABA(A) antagonist pentylenetetrazol (PTZ) exhibit increased locomotor activity, seizure-like behavior, and epileptiform electrographic activity. A previous study showed that 12 out of 13 antiepileptic drugs (AEDs) suppressed PTZ-mediated increases in larval movement, indicating the potential utility of zebrafish as a high-throughput in vivo model for AED discovery. However, a question remained as to whether an AED-induced decrease in locomotion is truly indicative of anticonvulsant activity, as some drugs may impair larval movement through other mechanisms such as general toxicity or sedation. We therefore carried out a study in PTZ-treated zebrafish larvae, to directly compare the ability of AEDs to inhibit seizure-like behavioral manifestations with their capacity to suppress epileptiform electrographic activity. We re-tested the 13 AEDs of which 12 were previously reported to inhibit convulsions in the larval movement tracking assay, administering concentrations that did not, on their own, impair locomotion. In parallel, we carried out open-field recordings on larval brains after treatment with each AED. For the majority of AEDs we obtained the same response in both the behavioral and electrographic assays. Overall our data correlate well with those reported in the literature for acute rodent PTZ tests, indicating that the larval zebrafish brain is more discriminatory than previously thought in its response to AEDs with different modes of action. Our results underscore the validity of using the zebrafish larval locomotor assay as a rapid first-pass screening tool in assessing the anticonvulsant and/or proconvulsant activity of compounds, but also highlight the importance of performing adequate validation when using in vivo models.


Subject(s)
Anticonvulsants/therapeutic use , Locomotion/drug effects , Pentylenetetrazole/pharmacology , Seizures/chemically induced , Seizures/drug therapy , Animals , Zebrafish
7.
Epilepsy Behav ; 24(1): 14-22, 2012 May.
Article in English | MEDLINE | ID: mdl-22483646

ABSTRACT

Turmeric, obtained from the rhizomes of Curcuma longa, is used in South Asia as a traditional medicine for the treatment of epilepsy. To date, in vivo studies on the anticonvulsant activity of turmeric have focused on its principal curcuminoid, curcumin. However, poor absorption and rapid metabolism have limited the therapeutic application of curcumin in humans. To explore the therapeutic potential of turmeric for epilepsy further, we analyzed its anticonvulsant activity in a larval zebrafish seizure assay. Initial experiments revealed that the anticonvulsant activity of turmeric in zebrafish larvae cannot be explained solely by the effects of curcumin. Zebrafish bioassay-guided fractionation of turmeric identified bisabolene sesquiterpenoids as additional anticonvulsants that inhibit PTZ-induced seizures in both zebrafish and mice. Here, we present the first report of the anticonvulsant properties of bisabolene sesquiterpenoids and provide evidence which warrants further investigation toward the mechanistic understanding of their neuromodulatory activity.


Subject(s)
Anticonvulsants/therapeutic use , Curcuma/chemistry , Phytotherapy/methods , Plant Extracts/therapeutic use , Seizures/drug therapy , Analysis of Variance , Animals , Animals, Genetically Modified , Chromatography, High Pressure Liquid , Convulsants/toxicity , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Administration Routes , Electroencephalography , Green Fluorescent Proteins/genetics , Magnetic Resonance Spectroscopy , Male , Mass Spectrometry , Mice , Mice, Inbred C57BL , Movement/drug effects , Pentylenetetrazole/toxicity , Plant Extracts/chemistry , Seizures/chemically induced , Valproic Acid/therapeutic use , Zebrafish
8.
Epilepsy Behav ; 22(3): 450-60, 2011 Nov.
Article in English | MEDLINE | ID: mdl-21962757

ABSTRACT

In the past, antidepressants have been thought to possess proconvulsant properties. This assumption remains controversial, however, because anticonvulsant effects have been attributed to certain antidepressants. To date, it remains unclear which antidepressants can be used for the treatment of patients with epilepsy with depression. The present study was designed to determine the anticonvulsant and/or proconvulsant effects of three antidepressants (citalopram, reboxetine, bupropion) against pilocarpine- and pentylenetetrazole-induced acute seizures in larval zebrafish and mice. In zebrafish, all antidepressants were anticonvulsant in the pentylenetetrazole model. In addition, citalopram was anticonvulsant in the zebrafish pilocarpine model, whereas reboxetine and bupropion were without significant effect. In mice all three antidepressants increased some thresholds for pentylenetetrazole-induced convulsive-like behaviors at varying doses, whereas thresholds for pilocarpine-induced convulsive-like behaviors were generally lowered, particularly at the highest doses tested. In general we conclude that the convulsant liability of antidepressants is model and concentration dependent.


Subject(s)
Antidepressive Agents/therapeutic use , Convulsants/toxicity , Seizures/chemically induced , Seizures/drug therapy , Analysis of Variance , Animals , Animals, Genetically Modified , Behavior, Animal/drug effects , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Interactions , Green Fluorescent Proteins/genetics , Male , Mice , Pentylenetetrazole/toxicity , Pilocarpine/toxicity , Seizures/mortality , Seizures/physiopathology , Zebrafish
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