<b>Preclinical efficacy profiles of the Sigma-1 modulator E1R and of fenfluramine in two chronic mouse epilepsy models</b>

<b></b>Given its key homeostatic role affecting mitochondria, ionotropic, and metabotropic receptors as well as voltage-gated ion channels, Sigma-1 receptor (Sig1R) represents an interesting target for epilepsy management. Antiseizure effects of the positive allosteric modulator E1R have already been reported in acute seizure models. While modulation of serotonergic neurotransmission is considered the main mechanism of action of fenfluramine, its interaction with Sig1R may be of additional relevance. To further explore the potential of Sig1R as a target, we assessed the efficacy and tolerability of E1R and fenfluramine in two chronic mouse models, including an amygdala kindling paradigm and the intrahippocampal kainate model. The relative contribution of the interaction with Sig1R was analyzed using combination experiments with the Sig1R antagonist NE-100. While E1R exerted pronounced dose-dependent antiseizure effects at well-tolerated doses in fully kindled mice, only limited effects were observed in response to fenfluramine without a clear dose-dependency. In the intrahippocampal kainate model, E1R failed to influence electrographic seizure activity. In contrast, fenfluramine significantly reduced the frequency of electrographic seizure events and their cumulative duration. Pretreatment with NE-100 reduced the effects of E1R and fenfluramine in the kindling model. Surprisingly, pre-exposure to NE-100 in the intrahippocampal kainate model rather enhanced and prolonged fenfluramine’s antiseizure effects.In conclusion, the kindling data further support Sig1R as an interesting target for novel antiseizure medications. However, it is necessary to further explore the preclinical profile of E1R in chronic epilepsy models with spontaneous seizures. Despite the rather limited effects in the kindling paradigm, the findings from the intrahippocampal kainate model suggest that it is of interest to further assess a possible broad-spectrum potential of fenfluramine.<br><b>Raw datasets</b><code>kdl_data.xlsx</code>This raw dataset contains all the raw used for the figures related to the amygdala Kindling experiments. Each row correspond to a different animal and different parameter and each column to a different compound.The vehicle is recorded to the left of their respective drug experiment (the arrow indicate the association). <i>Abbreviations</i>: adt, afterdisharge threshold; add1, afterdischarge duration 1; add2, total afterdischarge duration; sd, seizure duration; d_adt, delta adt; gst, generalized seizure threshold; d_gst, delta gst; PTT, pretreatment time.<code>s1r-kainate_eeg-sz-frequency_raw-data.csv</code>Contains the count of each type of seizure in the respective time window per animal.<code>s1r-kainate_eeg-sz-cumulative-duration_raw-data.csv</code>Contains the sum of the duration of each type of seizure in the respective time window per animal.<code>s1r-kainate_eeg-sz-mean-duration_raw-data.csv</code>Contains the mean duration of the seizures in the respective time window per animal.