The Sigma1 protein as a target for therapeutic management of epilepsy: preclinical validation in chronic mouse models

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Chronic administration of antiseizure drugs represents one of the mainstays for therapeutic management of epilepsy in veterinary and human medicine. Unfortunately, a satisfactory therapeutic success and seizure control is not achieved in a relevant number of patients. Moreover, the majority of available drugs have been developed to suppress seizures, but have not been designed to target pathophysiological mechanisms and to exert disease-modifying effects. The development of disease-modifying approaches holds the promise to result in more efficacious strategies helping to reduce the intrinsic severity of the disease and to overcome drug resistance. Sigma1 is an atypical receptor protein that is located in the endoplasmic reticulum membrane and serves a chaperone function. In response to cell stress Sigma1 affects calcium signaling at the ER-mitochondrial interface and, upon translocation to the cell membrane, interacts with different ion channels and receptors. While Sigma1 does not seem to play a major role in normal and basal cell function, it seems to serve an important protective and regulatory function, when homeostasis is threatened by pathophysiological mechanisms in disease states. Therefore, Sigma1 is considered as a promising target with the potential to mediate disease-modifying effects. In our project, we will study the preservation and disease-associated regulation of Sigma1 expression in tissue from two different mouse epilepsy models. We will then address the hypothesis that genetic and pharmacological targeting of Sigma1 affects seizure thresholds, seizure parameters, and development of a hyperexcitable network. In addition, the impact on behavioral alterations will be assessed. Respective effects will be studied in two chronic mouse epilepsy models, the amygdala kindling paradigm with repeated seizure induction and the intrahippocampal kainate model with development of spontaneous recurrent seizures. The consequences of Sigma1 genetic deficiency will be explored by comparison between Sigma1 knockout and wildtype mice. For pharmacological targeting the following Sigma1 ligands will be tested: E1R as a selective positive allosteric modulator; NE-100 as a selective antagonist; fenfluramine with combined mechanism of action with effects on serotonergic signaling and Sigma1. In addition, we will test drug combinations with NE-100 to confirm the relevance of the compound’s interaction with Sigma1 for E1R and to determine the relative contribution of the compound’s interaction with Sigma1 for fenfluramine. It is expected that the experimental findings provide a basis for future translational development of novel disease-modifying approaches that help to overcome drug resistance.