Validation of the 6 Hz refractory seizure mouse model for intracerebroventricularly administered compounds

- Validation of 6 Hz model for blood-brain barrier impermeable compounds.
- Seizure evocation in NMRI mice at 49 mA with ECT Unit 57800 Ugo Basile stimulator.
- Seizure duration as novel, accurate parameter to express results in the 6 Hz model.
- Levetiracetam decreases seizure duration after i.p. and i.c.v. administration.
- I.p. and i.c.v. administered sodium phenytoin does not alter seizure duration.

The six hertz (6 Hz) refractory seizure model is considered an indispensable chain of the Anticonvulsant Screening Project. We here describe an adapted protocol using the intracerebroventricular (i.c.v.) delivery route, which will allow researchers to perform targetvalidation or proof-of-principle studies using promising compounds with unknown or limited blood-brain barrier permeability (e.g. neuropeptides and peptidomimetics) in this model. Seizures were induced by single application of a current intensity of 49 mA to i.c.v.-implanted NMRI mice using an ECT Unit 57800 Ugo Basile stimulator. By applying these key parameters, c-Fos immunohistochemistry revealed the recruitment of the dentate gyrus, ratifying this model as a valuable tool for testing i.c.v. administered compounds against therapy-resistant seizures. This finding was further strengthened, since i.c.v. administration of levetiracetam suppressed 6 Hz-evoked seizure severity but sodium phenytoin did not. We also propose to use “seizure duration” as an alternative, accurate parameter to express the results within this model.