An Emerging Role for Sigma-1 Receptors in the Treatment of Developmental and Epileptic Encephalopathies

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 recepto...

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Bibliographic Details
Published in:International journal of molecular sciences 2021-08, Vol.22 (16), p.8416
Main Authors: Martin, Parthena, Reeder, Thadd, Sourbron, Jo, de Witte, Peter A M, Gammaitoni, Arnold R, Galer, Bradley S
Format: Article
Language:English
Subjects:
Alzheimer's disease
Animals
Anticonvulsants - pharmacology
Brain Diseases - drug therapy
Brain Diseases - metabolism
Clinical trials
Cognition
Convulsions & seizures
developmental and epileptic encephalopathy
Epilepsy
Epileptic Syndromes - drug therapy
Epileptic Syndromes - metabolism
Fenfluramine
Fenfluramine - pharmacology
Homeostasis
Humans
Ligands
Mitochondria
Mutation
Neuromodulation
Neuroprotection
Pathophysiology
Physiology
Plasma
Proteins
Receptors, sigma - metabolism
Review
Seizures
Seizures - drug therapy
Seizures - metabolism
Serotonin
serotonin receptor
Sigma-1 Receptor
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Summary: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.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms22168416