Abstract:Epilepsy is a chronic brain disorder characterized by recurrent seizures due to abnormal, excessive and synchronous neuronal activities in the brain. It affects approximately 65 million people worldwide, one third of which are still estimated to suffer from refractory seizures. Glutamic acid decarboxylase (GAD) that converts glutamate into GABA is a key enzyme in the dynamic regulation of neural network excitability. Importantly, clinical evidence shows that lowered GAD activity is associated with several form… Show more
“…Clinical evidence shows that lowered GAD activity is associated with several forms of treatment-resistant epilepsy, and the model is considered to be relevant as a platform for novel antiepileptic drug discovery. 13 Conversely, the PTZ model, which conceptually builds on GABA A inhibition, is most sensitive to GABAergic AEDs (eg, barbiturates or benzodiazepines). 12 In general, the data showed good concordance between the three measurements.…”
Section: Discussionmentioning
confidence: 99%
“…Wild‐type zebrafish (AB strain) were used for experiments with PTZ and EKP. The Tg(elavl3:eGFP‐apoAequorin ) zebrafish line was used for the bioluminescence experiments …”
Section: Methodsmentioning
confidence: 99%
“…Similarly, Tg(elavl3:eGFP‐apoAequorin ) zebrafish larvae were preexposed to coelenterazine‐h (NanoLight Technology) and pretreated at 6 dpf with VHC or compound. Emitted photons were counted in a light‐tight thermostatted perfusion chamber at 7 dpf as described previously . For chemical induction of seizures, larvae were acutely exposed after compound pretreatment to 20 mmol·L –1 PTZ or 400 μmol·L –1 EKP …”
Section: Methodsmentioning
confidence: 99%
“…Emitted photons were counted in a light-tight thermostatted perfusion chamber at 7 dpf as described previously. 13 For chemical induction of seizures, larvae were acutely exposed after compound pretreatment to 20 mmol·L -1 PTZ 12 or 400 μmol·L -1 EKP. 13…”
Section: Pharmacological Evaluation In Zebrafishmentioning
confidence: 99%
“…Using the zebrafish DS model, our aim was to examine the possibility to repurpose these marketed medicines as AEDs, in particular in difficult to treat epilepsies such as DS. To examine further their potential broader antiseizure profile, we also tested the compounds in a pentylenetetrazol (PTZ) and a treatment‐resistant ethyl ketopentenoate (EKP) model in zebrafish. Our results show that LIS selectively decreased seizure activity in the DS zebrafish model, whereas EFA exhibited a broader antiseizure activity.…”
SummaryDravet syndrome (DS) is a severe genetic epileptic encephalopathy with onset during the first year of life. Zebrafish models recapitulating human diseases are often used as drug discovery platforms, but also for drug repurposing testing. It was recently shown that pharmacological modulation of three serotonergic (5‐HT) receptors (5‐HT
1D, 5‐HT
2C, 5‐HT
2A) exerts antiseizure effects in a zebrafish scn1Lab
−/− mutant model of DS. Using the zebrafish DS model, our aim was to examine the possibility of repurposing efavirenz (EFA), lisuride (LIS), and rizatriptan (RIZA), marketed medicines with a 5‐HT on‐ or off‐target profile, as antiepileptic drugs for DS. To examine whether these compounds have a broader antiseizure profile, they were tested in pentylenetetrazol and ethyl ketopentenoate (EKP) zebrafish models. Pharmacological effects were assessed by locomotor behavior, local field potential brain recordings, and bioluminescence. EFA was active in all models, whereas LIS was selectively active in the zebrafish DS model. Mainly, a poor response was observed to RIZA. Taken together, our preclinical results show that LIS could be a potential candidate for DS treatment. EFA was also active in the EKP model, characterized by a high level of treatment resistance, and hence these data are potentially important for future treatment of drug‐resistant epilepsy.
“…Clinical evidence shows that lowered GAD activity is associated with several forms of treatment-resistant epilepsy, and the model is considered to be relevant as a platform for novel antiepileptic drug discovery. 13 Conversely, the PTZ model, which conceptually builds on GABA A inhibition, is most sensitive to GABAergic AEDs (eg, barbiturates or benzodiazepines). 12 In general, the data showed good concordance between the three measurements.…”
Section: Discussionmentioning
confidence: 99%
“…Wild‐type zebrafish (AB strain) were used for experiments with PTZ and EKP. The Tg(elavl3:eGFP‐apoAequorin ) zebrafish line was used for the bioluminescence experiments …”
Section: Methodsmentioning
confidence: 99%
“…Similarly, Tg(elavl3:eGFP‐apoAequorin ) zebrafish larvae were preexposed to coelenterazine‐h (NanoLight Technology) and pretreated at 6 dpf with VHC or compound. Emitted photons were counted in a light‐tight thermostatted perfusion chamber at 7 dpf as described previously . For chemical induction of seizures, larvae were acutely exposed after compound pretreatment to 20 mmol·L –1 PTZ or 400 μmol·L –1 EKP …”
Section: Methodsmentioning
confidence: 99%
“…Emitted photons were counted in a light-tight thermostatted perfusion chamber at 7 dpf as described previously. 13 For chemical induction of seizures, larvae were acutely exposed after compound pretreatment to 20 mmol·L -1 PTZ 12 or 400 μmol·L -1 EKP. 13…”
Section: Pharmacological Evaluation In Zebrafishmentioning
confidence: 99%
“…Using the zebrafish DS model, our aim was to examine the possibility to repurpose these marketed medicines as AEDs, in particular in difficult to treat epilepsies such as DS. To examine further their potential broader antiseizure profile, we also tested the compounds in a pentylenetetrazol (PTZ) and a treatment‐resistant ethyl ketopentenoate (EKP) model in zebrafish. Our results show that LIS selectively decreased seizure activity in the DS zebrafish model, whereas EFA exhibited a broader antiseizure activity.…”
SummaryDravet syndrome (DS) is a severe genetic epileptic encephalopathy with onset during the first year of life. Zebrafish models recapitulating human diseases are often used as drug discovery platforms, but also for drug repurposing testing. It was recently shown that pharmacological modulation of three serotonergic (5‐HT) receptors (5‐HT
1D, 5‐HT
2C, 5‐HT
2A) exerts antiseizure effects in a zebrafish scn1Lab
−/− mutant model of DS. Using the zebrafish DS model, our aim was to examine the possibility of repurposing efavirenz (EFA), lisuride (LIS), and rizatriptan (RIZA), marketed medicines with a 5‐HT on‐ or off‐target profile, as antiepileptic drugs for DS. To examine whether these compounds have a broader antiseizure profile, they were tested in pentylenetetrazol and ethyl ketopentenoate (EKP) zebrafish models. Pharmacological effects were assessed by locomotor behavior, local field potential brain recordings, and bioluminescence. EFA was active in all models, whereas LIS was selectively active in the zebrafish DS model. Mainly, a poor response was observed to RIZA. Taken together, our preclinical results show that LIS could be a potential candidate for DS treatment. EFA was also active in the EKP model, characterized by a high level of treatment resistance, and hence these data are potentially important for future treatment of drug‐resistant epilepsy.
Dravet syndrome (DS) is a rare genetic encephalopathy that is characterized by severe seizures and highly resistant to commonly used antiepileptic drugs (AEDs). In 2020, FDA has approved fenfluramine (FFA) for treatment of seizures associated with DS. However, the clinically used FFA is a racemic mixture (i.e. (±)-FFA), that is substantially metabolized to norfenfluramine (norFFA), and it is presently not known whether the efficacy of FFA is due to a single enantiomer of FFA, or to both, and whether the norFFA enantiomers also contribute significantly. In this study, the antiepileptic activity of enantiomers of FFA (i.e. (+)-FFA and (−)-FFA) and norFFA (i.e. (+)-norFFA and (−)-norFFA) was explored using the zebrafish scn1Lab−/− mutant model of DS. To validate the experimental conditions used, we assessed the activity of various AEDs typically used in the fight against DS, including combination therapy. Overall, our results are highly consistent with the treatment algorithm proposed by the updated current practice in the clinical management of DS. Our results show that (+)-FFA, (−)-FFA and (+)-norFFA displayed significant antiepileptic effects in the preclinical model, and thus can be considered as compounds actively contributing to the clinical efficacy of FFA. In case of (−)-norFFA, the results were less conclusive. We also investigated the uptake kinetics of the enantiomers of FFA and norFFA in larval zebrafish heads. The data show that the total uptake of each compound increased in a time-dependent fashion. A somewhat similar uptake was observed for the (+)-norFFA and (−)-norFFA, implying that the levo/dextrotation of the structure did not dramatically affect the uptake. Significantly, when comparing (+)-FFA with the less lipophilic (+)-norFFA, the data clearly show that the nor-metabolite of FFA is taken up less than the parent compound.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.