Sigma-1 as a target for antiseizure and disease-modifying effects? Impact of a positive modulator on kindling acquisition: Impact of a positive modulator on kindling acquisition

Purpose: Sigma-1 is an atypical receptor protein that can affect mitochondrial function and activity of several voltage-gated ion channels and neurotransmitter receptors. Because of its important role in controlling homeostasis, Sigma1 might be an interesting target for disease-modifying and preventive approaches. Building on previous findings, we addressed the hypothesis that E1R, a positive allosteric modulator of Sigma-1, might exert disease-modifying effects with an impact on progression in an amygdala kindling paradigm.

Method: Female NMRI mice were kindled by once daily suprathreshold stimulations via a department electrode in the amygdala. Following pre-kindling threshold analysis, animals were randomly allocated to different treatment groups receiving intraperitoneal injections of vehicle, E1R (50 or 75 mg/kg) or the Sigma-1 antagonist NE100 (35 mg/kg) prior to the stimulations. Kindling progression was evaluated with an analysis of seizure severity as well as seizure and afterdischarge duration.

Results: First data provide evidence that E1R exerts relevant effects on kindling progression with a delay in the generation of generalized seizures. Moreover, the kindling-associated progressive increase of motor and electrographic seizure duration was slowed in E1R-treated mice. In contrast, the progression of seizure severity and duration in animals exposed to NE100 proved to be comparable to that in vehicle-treated mice. Following a washout phase, animals were re-stimulated to evaluate a possible longer lasting effect. Generalized seizures were observed in animals from all groups during the re-stimulation phase.

Conclusion: The findings indicate an impact of positive Sigma1 modulation on the generation of a hyperexcitable kindled network. These data further confirm that Sigma-1 is a target of interest for epilepsy management. Further studies are ongoing to assess a possible disease-modifying and preventive effect in a model with spontaneous recurrent seizures.