Abstract
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.
Highlights
Dravet syndrome (DS) is a rare, but severe developmental epileptic encephalopathy that begins in infancy [1, 2]
To validate the zebrafish scn1Lab−/− mutant model and the experimental conditions used in this study, we first tested a series of antiepileptic drugs (AEDs) proposed by different treatment algorithms for DS [8,9,10, 22, 23], including valproate (VPA), racemic fenfluramine [( ±)-FFA], topiramate (TPM), stiripentol (STP), cannabidiol (CBD), clobazam (CLB) and levetiracetam (LEV)
AEDs that should be avoided by DS patients, like carbamazepine (CBZ), phenytoin (PHT) and lamotrigine (LGT) were examined as they target the sodium channel resulting in seizure aggravation [6, 24]
Summary
Dravet syndrome (DS) is a rare, but severe developmental epileptic encephalopathy that begins in infancy [1, 2]. The first seizures are typically triggered by fever, and are characterized by long-lasting hemiclonic or generalized clonic or tonic–clonic convulsions. The seizures evolve with age, and multiple seizure types may occur, such as focal, atypical absences, and myoclonic seizures. Motor dysfunction, behavioural disorder, and cognitive impairment appear [3, 4]. Increased incidence of mortality is reported in DS patients, especially due to a higher risk of sudden unexpected death [5, 6]. Regarding the genetic architecture of DS, a de novo mutation in the gene SCN1A which encodes for an α (pore-forming) subunit of the
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