Abstract
Developmental and epileptic encephalopathies (DEEs) are complex conditions characterized primarily by seizures associated with neurodevelopmental and motor deficits. Recent evidence supports sigma-1 receptor modulation in both neuroprotection and antiseizure activity, suggesting that sigma-1 receptors may play a role in the pathogenesis of DEEs, and that targeting this receptor has the potential to positively impact both seizures and non-seizure outcomes in these disorders. Recent studies have demonstrated that the antiseizure medication fenfluramine, a serotonin-releasing drug that also acts as a positive modulator of sigma-1 receptors, reduces seizures and improves everyday executive functions (behavior, emotions, cognition) in patients with Dravet syndrome and Lennox-Gastaut syndrome. Here, we review the evidence for sigma-1 activity in reducing seizure frequency and promoting neuroprotection in the context of DEE pathophysiology and clinical presentation, using fenfluramine as a case example. Challenges and opportunities for future research include developing appropriate models for evaluating sigma-1 receptors in these syndromic epileptic conditions with multisystem involvement and complex clinical presentation.
Highlights
It is notable that fenfluramine—with profound antiseizure activities in two Developmental and epileptic encephalopathies (DEEs) (Dravet and Lennox-Gastaut syndromes)—was recently discovered to be a positive modulator of
The empirical evidence reviewed in this report suggests a model whereby fenfluramine restores the homeostatic balance between inhibitory GABAergic and excitatory glutamatergic activity to dampen seizure activity in Dravet syndrome and other DEEs (Figure 1)
Data from zebrafish models suggest that fenfluramine restores dendritic arborization of GABAergic neurons
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. ANAVEX 2-73 (blarcamesine), which has agonist activity both at the Sigma1R and at muscarinic receptors, is currently in clinical trials for neurodegenerative diseases (NCT03774459, NCT03790709; Alzheimer’s disease, Parkinson’s disease dementia, and Rett syndrome (which manifests with seizures in most patients)) and was granted FDA’s Orphan Drug Designation for infantile spasms in 2016 [41,42,54,55,56,57] These recent studies (Supplemental Table S2) have clarified that fenfluramine possesses dual activities: as a serotonergic agent, acting as a potent 5-HT releaser with agonist activity at 5-HT1D , 2A , and 2C receptors, and as a positive modulator of Sigma1R. 5-HT, serotonin; ASM, antiseizure medication; ED50 , effective dose in 50% of the study population; FFA, fenfluramine; HINT1, histidine triad nucleotide binding protein 1; i.p., intraperitoneal injection; NMDA, N-methyl-D-aspartic acid; PRE-084, Sigma1R agonist; PTZ, pentylenetetrazol; SCZ, semicarbazide; Sigma1R, sigma-1 receptor; SOMCL-668, highly selective potent Sigma1R allosteric modulator
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