Spectrum of Mechanisms of Action of Fenfluramine in the Treatment of Rare Epilepsies
Fenfluramine (FFA) is an anticonvulsant used in the treatment of rare epilepsies such as Dravet syndrome and Lennox-Gastaut syndrome. In addition to effectively reducing seizure frequency, it also mitigates non-seizure comorbidities in patients with these conditions. Last year, Belgian authors published a detailed review of all its described mechanisms of action. They also explain how these mechanisms might contribute to the clinical benefits of FFA beyond seizure suppression, such as reducing the risk of sudden unexpected death in epilepsy (SUDEP) or improving executive functions.
Introduction
Developmental and epileptic encephalopathies (DEE) are rare, therapeutically resistant epilepsies with high seizure frequency accompanied by many non-seizure comorbidities. According to the current therapeutic approach, it is appropriate to target multiple mechanisms in severe DEE to achieve greater clinical benefits. Therefore, combinations of anticonvulsants or drugs with multimodal effects are used. Among anticonvulsants, Fenfluramine has a unique dual mechanism of action (affecting the σ1 receptor and serotonergic activity), which helps maintain a balance between excitatory and inhibitory neurotransmitters, but its efficacy is likely mediated through additional pathways.
Primary Mechanisms of Anticonvulsant Efficacy of FFA
Fenfluramine is a racemate of levo- and dextro-fenfluramine. Both enantiomers are quickly metabolized to norfenfluramine, which also shows pharmacological activity.
Increase in Serotonergic Neurotransmission
Dextro-FFA (dexfenfluramine) promotes serotonergic neurotransmission by inhibiting serotonin reuptake and stimulating its release. This can activate various serotonin receptors, several of which are involved in its anticonvulsant effects.
Activation of Serotonin Receptors
Out of the 14 known serotonin receptors, 6 have been shown to be affected by fenfluramine. Its agonistic effects have been observed on 5-HT1D, 5-HT2A, 5-HT2B, 5-HT2C, and 5-HT4 receptors, and antagonistic effects on the 5-HT1A receptor. The agonistic activity of FFA is likely responsible for its anticonvulsant efficacy, with stimulation of 5-HT4 possibly linked to the reduced risk of SUDEP.
Modulation of σ Receptors
FFA has a high affinity for σ1 receptors and acts as a positive modulator. This contributes to its anticonvulsant efficacy and likely helps reduce the risk of SUDEP.
Increase in GABAergic Neurotransmission
FFA promotes GABAergic neurotransmission by releasing serotonin at GABAergic synapses and stimulating 5-HT2A and 5-HT2C receptors. It has also been shown to restore dendritic arborization of GABAergic neurons in Dravet syndrome.
Secondary Mechanisms of FFA Action
Modulation of Dopaminergic Neurotransmission
Levo-fenfluramine, unlike dexfenfluramine, does not have serotonergic effects but can modulate dopaminergic transmission. It likely does not bind directly to dopamine receptors but may reduce dopamine-mediated neurotransmission. This effect is more relevant in reducing appetite (a known effect of FFA previously used in treating obesity) than in seizure control.
Modulation of Noradrenergic Neurotransmission
According to current knowledge, the influence of FFA on noradrenergic neurotransmission could contribute to its clinical benefits by alleviating issues with concentration, learning, and attention in cases of attention deficit hyperactivity disorder (ADHD).
Influence on the Endocrine System
Fenfluramine affects several hormones. FFA's effects on prolactin, corticotropin (ACTH), oxytocin, and vasopressin lead to reduced appetite. However, there is minimal evidence that this mechanism of action contributes to its anticonvulsant effects. Further research is warranted on FFA's impact on neuroactive steroids, such as progesterone derivatives.
Effects of FFA Beyond Seizure Suppression
Clinical and preclinical data suggest that fenfluramine has positive effects on non-seizure comorbidities in patients with DEE, besides controlling seizures. It has been found to reduce mortality due to SUDEP (1.7 deaths per patient per year after its introduction vs. 11.7 deaths per patient per year before its introduction vs. 9.3 deaths per patient per year in historical cohorts). The mechanisms underpinning these effects are still under investigation. Evidence suggests a crucial role for 5-HT4 and σ1 receptors. In some patients with Dravet syndrome, FFA also improves everyday executive functions, including emotion and behavior regulation. These effects are at least partially independent of its impact on seizure frequency reduction. The precise mechanisms, however, need to be further elucidated.
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Source: Sourbron J., Lagae L. Fenfluramine: a plethora of mechanisms? Front Pharmacol 2023 May 12; 14: 1192022, doi: 10.3389/fphar.2023.1192022.
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