Effects of fenfluramine and sigma‐1‐dependent pharmacological and genetic modulation in a mouse kindling model

OBJECTIVE: Sigma-1 is a chaperone protein that serves as a key homeostatic regulator, implicated in neuronal excitability and seizure control. Positive allosteric modulators offer a use-dependent means to enhance Sigma-1 activity, potentially with favorable tolerability compared to direct agonists. This study examined the role of sigma-1 in ictogenesis, seizure spread, and termination, and evaluated whether sigma-1 targeting could modify progression in the amygdala kindling model. METHODS: Using the mouse amygdala kindling paradigm, we assessed the effects of subchronic administration of the sigma-1 positive allosteric modulator E1R and of the antiseizure medication fenfluramine on seizure thresholds, severity, duration, and progression of kindling. Tolerability, behavioral outcomes, and potential disease-modifying effects were evaluated. Additional experiments investigated the influence of sigma-1 antagonism (NE-100) and genetic sigma-1 deficiency on E1R efficacy and seizure development. RESULTS: E1R delayed kindling acquisition, increased seizure thresholds in both naïve and kindled animals, and reduced seizure duration without evidence of tolerance or significant adverse effects. Subchronic E1R exposure slowed or prevented progression to generalized seizures, although effects did not persist after drug withdrawal. Sigma-1 deficiency prolonged seizure duration, supporting a role in the termination of endogenous seizures. High-dose NE-100 partially antagonized E1R effects, whereas genetic deficiency did not, possibly due to compensatory mechanisms. Fenfluramine did not affect kindling progression in this model. SIGNIFICANCE: Positive allosteric modulation of sigma-1 attenuates ictogenesis and seizure severity and appears to contribute to endogenous seizure-termination mechanisms. Although E1R influences seizure generation in response to repeated stimulation, it does not produce sustained disease-modifying effects after discontinuation. These findings support a functional role of sigma-1 positive allosteric modulators as promising candidates for seizure management in the model used. The absence of persistent effects after withdrawal argues against disease modification under the current conditions and warrants further investigation in chronic epilepsy models evaluating long-term therapeutic, disease-modifying, or preventive potential.