NYMC Student Theses and Dissertations

Date of Award

4-2-2024

Document Type

Doctoral Dissertation - Restricted (NYMC/Touro only) Access

Degree Name

Doctor of Philosophy

Department

Cell Biology

First Advisor

Dr. Libor Velisek

Abstract

Infantile epileptic spasm syndrome (IESS) is a severe developmental epilepsy of infancy characterized by myoclonic-tonic seizures, hypsarrhythmia on electroencephalography, and limited responsiveness to current therapies. Beyond early seizures, IESS is associated with persistent cognitive, behavioral, and developmental impairments and progression to more severe epilepsy syndromes. Despite its devastating impact, the underlying mechanisms remain incompletely understood, underscoring the need for new therapeutic strategies.

The goal of this thesis was to investigate the therapeutic potential and mechanism of action of the Sigma-1 receptor (S1R) in IESS. Using a preclinical rat model, we evaluated the efficacy of the selective S1R agonist, alazocine (SKF-10047), through behavioral and electroencephalographic measures. We also examined its interaction with the NMDA receptor, with a specific focus on the GluN2B subunit.

SKF-10047 produced a dose-dependent reduction in spasm frequency and normalized EEG patterns toward baseline with chronic administration. Long-term EEG monitoring revealed spontaneous seizures in untreated animals, whereas no spontaneous seizures were observed in SKF-10047-treated rats.

Mechanistic studies confirmed S1R dependence, as co-administration of the antagonist NE100 abolished both spasm suppression and survival benefits. Selective GluN2B blockade prevented spasm reduction but did not eliminate mortality protection. Western blot analysis demonstrated that SKF-10047 did not alter GluN1 or GluN2B expression, further supporting a functional rather than expression-based mechanism of action.

Together, these findings identify S1R agonism as a promising therapeutic strategy for IESS and support its role in modulating NMDA receptor signaling to produce sustained behavioral and electroclinical improvements.

Keywords

Infantile Epileptic Spasm Syndrome, Sigma-1 Receptor, SKF-10047

Disciplines

Medicine and Health Sciences

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