Sigma-1 as a target candidate for antiseizure effects: analysis in the mouse amygdala kindling model of temporal lobe epilepsy

Sigma-1 is an interesting target candidate in neurological disorders because of its regulatory function when homeostasis is compromised by pathophysiological mechanisms in disease states. Here, we assessed the antiseizure effects of methylphenylpiracetam (E1R), a selective positive allosteric Sigma-1 modulator. The antiseizure medication fenfluramine appears to exert its effects via serotonergic signaling. However, evidence exists that interaction with Sigma-1 may also represent a relevant mechanism of action. Thus, we aimed to determine the relative contribution of the interaction of fenfluramine with Sigma-1 by combination with the Sigma-1 antagonist 4-methoxy-3-(2-phenylethoxy)-N,N-dipropylbenzeneethanamine (NE-100).

Method: NMRI female mice (n=12-16) were fully kindled by stimulation via Department-electrode in the amygdala. Effects of E1R and fenfluramine were evaluated at different doses alone and in combination with NE-100. We administered all substances intraperitoneally with pretreatment times of E1R – 60’ and NE-100 - 80’. Fenfluramine was evaluated at different pretreatment times. Tolerability tests focused on Rotarod test and selected Irwin score parameters.

Results: E1R increased generalized seizure thresholds (GST) in a dose-dependent manner (ED50=35.25 mg/kg). All doses up to a maximum of 100 mg/kg were well tolerated. Effects of E1R on GST were partially abolished by NE-100. While we couldn’t demonstrate a clear dose-dependency, fenfluramine increased afterdischarge thresholds (ADT) at 0.1 and 1 mg/kg, and GST at 10 mg/kg at the time of maximum effect (120´). In combination with NE-100, effects on ADT and GST were prevented. Adverse effects of fenfluramine were only observed at a higher dose (30 mg/kg).

Conclusion: Our findings indicate that positive modulation of Sigma-1 by E1R can exert acute antiseizure effects with an impact on seizure generation,

spread and termination. Furthermore, our results confirm that the interaction of fenfluramine with Sigma-1 can be relevant for its antiseizure activity.