Scientists: Principal Investigator: Eva Kudová (IOCB Prague). Team IOCB Prague: Hana Chodounská, Ewa Szczurowska. Team IPHYS: Hana Kubová, Pavel Mareš
Epilepsy is an umbrella term covering a wide range of syndromes and conditions which manifest with seizures. Pharmacoresistant (refractory) epilepsy is defined as failure to achieve seizure freedom following adequate trials of two tolerated and appropriately chosen antiepileptic drugs. Among epilepsy patients, 30% or more are considered pharmacoresistant. Pharmacoresistant epilepsy can have a devastating effect on the patient’s quality of life and is associated with an increased risk of sudden unexpected death.
Neuroactive steroids are steroidal compounds known to regulate brain excitability through interaction with ligand- and voltage-gated ion channels, as well as GPCRs. We have synthetized novel neurosteroids which show potent anticonvulsant effects in multiple animal models of seizures, including models of pharmacoresistance. The presumed mechanism of action for our lead compound is allosteric modulation of GABAA receptors.
Anticonvulsant efficacy of our lead compound (Compound 1) has been demonstrated in the following animal models:
- Pentylenetetrazole (PTZ)-induced seizures (zebrafish, Fig. 1, panel A), screening model, contracted from ZeClinics, Barcelona, Spain.
- Pentylenetetrazole (PTZ)-induced seizures (rat, Fig. 1, panel B), Institute of Physiology ASCR, Prague, Czech Republic.
- Pentylenetetrazole (PTZ)-induced seizures (mouse), Institute of Physiology ASCR, Prague, Czech Republic. In mice, the anticonvulsant effect in the PTZ-model was sex-dependent (observed in females only).
- 6 Hz Electrical Stimulation Test (rat, Fig. 1, panel C), Institute of Physiology ASCR, Prague, Czech Republic.✤
- Tetramethylenedisulfotetramine (TMDT)-induced seizures (rat). In collaboration with L. Velíšek, M.D., Ph.D., and M.P. Shakarjian, Ph.D., New York Medical College, Valhalla, NY, USA.✤
- Ethyl ketopentoate model (zebrafish, Fig. 1, panel A), contracted from Laboratory for Molecular Biodiscovery KU Leuven, Leuven, Belgium.✤
- Lamotrigine-resistant amygdala kindling model (rat), Epilepsy Therapy Screening program (ETSP), National Institutes of Health/National Institute of Neurological Disorders and Stroke, Rockville, MD, USA (Table 1).✤
[Models marked with ✤ are reported to be pharmacoresistant.]
This project is offered for co-development or licensing.
Preclinical (in-vivo proof of concept, lead optimisation)
neurosteroids epilepsy seizures pharmacoresistance GABAA