Anticonvulsant Compound with Aa Selective Mechanism of Action on Nav1.1 and Nav1.2 Voltage-Gated Sodium Channel Isoform

VALENTINA PASTORE; MARIEL MARDER; NICOLÁS ENRIQUE; PEDRO MARTIN; VERÓNICA MILESI

CABA, Argentina

Congreso; Reunión Conjunta de Sociedades de Biociencias; 2017

Epilepsy is central nervous system (CNS) pathology that affects over 50 million people in the world. Recent studies have demonstrated that in Latin America and Caribbean occurs more than 70% of death in people with epilepsy respect to the entire American continent (been epilepsy the primary cause of death). Antiepileptic drugs (AEDs) are the treatment of choice. AEDs may act via activation of GABAA receptor, inhibition of glutamate receptors or changing voltage-gated ionic channels as sodium (Nav), potassium (Kv) or calcium (Cav). We have studied over these years, a new synthetic compound N-butyl-1,2,3-oxathiazolidine-4-ona-2,2-dioxide (NBOD) as anticonvulsant, antidepressant, anxiolityc and antioxidant effects. As anticonvulsant has a potency over 5000 times higher than valproic acid in MES test. After a series of preliminary studies (in vivo and in vitro) in order to elucidate its mechanism of action; Nav emerged as a promising molecular target. Nav present nine different isoforms, been Nav 1.1, 1.2, 1.4 and 1.6 most prevalent in CNS. Nav have at least three well determined states: open, closed and inactivated. Some AEDs use in clinical, are able to bind to the inactivate state reducing the available fraction of them associated with a significantly reduction of neural hyperexcitability. Using the patch-clamp technique, the molecular mechanism of NBOD effect was explored on Nav 1.1 and 1.2 isoforms stably transfected in HEK293 cell line. Preliminary results demonstrated that NBOD presents an isoform selective effect, while it did not affect the Nav 1.2, it significantly inhibits the Nav 1.1 mediated Na+ current (56%±10, n=4) and the effect was reversible. Moreover, we observed a left shift of h curve (V1/2= -73 mV with NOBD vs. -55 mV (n=4) in control conditions) suggesting that it is able to reduce the available fraction. The results show for the first time an anticonvulsant compound that allow to block selectively the isoform Nav 1.1 respect to Nav 1.2 isoform.