Current strategies in designing new neuroprotective drugs against epilepsy combine two or more pharmacophores that are aimed at different targets in the complex cascade of mechanisms that cause neurodegenerative diseases. Our group has designed new molecules that combine a benzodiazepine and a dihydropyridine moiety. Lead compound JM-20 (3-ethoxycarbonyl-2-methyl-4-(2-nitrophenyl)-4,11-dihydro-1H-pyrido[2,3-b][1,5]benzodiazepine) is a member of this family currently under investigation. The combination endows this new chemical entity with actions in more than one neuroprotective mechanism: the capacity to counteract the glutamate and calcium mediated excitotoxicity and the neuronal death via mitochondrial intrinsic pathway. Excitotoxicity and calcium mediated mitochondrial dysfunction are accepted to be of major importance in the etiology of epilepsy, supporting our hypothesis that the novel molecule JM-20 can be neuroprotective.

In Cuba is very difficult to carry out projects to study mechanisms associated with antiepileptic drugs. Therefore it would be very important for our group has collaborative projects in order to develop these studies.

Please, if anyone has experimental models associated with this disease and want to have a joint project with our group, we would be very grateful

We have collected 5 sets of experimental data that support our claim that CNS in general, and epilepsy disease in particular, is a potential interesting target for JM-20:

1) ability to pass blood brain barrier after oral administration, evidenced by GABA-ergic effects in vivo;

2) lack of acute toxicity of JM-20 at 2000 mg/kg vs in vivo neuroprotective effects at 8 mg/kg;

3) neuroprotective effects in different neuronal cells exposed to toxic doses of H2O2 and glutamate;

4) mitochondrial protection in vitro and in vivo;

5) neuroprotection in different in vivo models of brain ischemic damage, evidenced clinically (neurological score) and histologically (TTC staining, infarct area, hematoxylin-eosin staining of hippocampus, cortex and striatum, and the morphometric analysis).

Thanking in advance

MD. Yanier Nuñez Figueredo

Head of Neuropharmacology Lab

Drug Research and Development Center

Havana, Cuba