A novel anticonvulsant/antidepressant α-hydroxyamide exerts its mechanism of action through voltage gated sodium channels

VALENTINA PASTORE; PEDRO MARTIN; CRISTINA WASOWSKI; VERONICA MILESI; JOSEFINA HIGGS; MARIEL MARDER

Mar del Plata

Congreso; LXI Reunión Anual de la Sociedad Argentina de Investigación Clínica (SAIC), LXIV Reunión Anual de la Sociedad Argentina de Inmunología (SAI), XLVIII Reunión Anual de la Sociedad Argentina de Farmacología Experimental (SAFE); 2016

Sociedad Argentina de Investigación Clínica (SAIC), la Sociedad Argentina de Inmunología (SAI) y la Sociedad Argentina de Farmacología Experimental (SAFE)

In patients with epilepsy, anxiety anddepression are frequent  psychiatric comorbidities but they oftenremain unrecognized and  untreated. We have synthesized a novel α-hydroxyamide, N-propyl,2,2-diphenyl-2-hydroxyacetamide (C1), which is effective as anticonvulsant in the maximal electroshocktest (ED50:2.5 mg/kg). Taking into account that there are clinical anticonvulsants that are also used as mood stabilizers, i.e. lamotrigine, topiramate, phenytoin; we evaluated if this novelcompound also has antidepressant  activityin two experimental models: forced swimming (FST) and tail suspension (TST) tests. It isknown that antidepressant drugs modify, in different ways, theactivity of neurons, by increasing monoamine levels and bymodulating ion channels. Sodium channels are molecular targets forantiepileptic drugs, which can also be mood stabilizers. So, inorder to elucidate its mechanism of action, we made different in vivo/in vitro assays. Compound C1 demonstratedantidepressant activity (FST and TST) in Swiss male mice at 0.3-30  mg/kg i.p. (CICUAL EXP-FFYB N° 0031682/2014).Its capacity to act via GABAA receptor ( [3H] flunitrazepam binding assay); serotonin 5HT1Areceptor ( [3H] 8-OH-DPAT binding assay) and voltage gated sodiumchannels using veratrine, a voltage gated sodium channel agonist (in vivo) and in a HEK 293 cell line that expressed Nav1.1 (electrophysiology) was also evaluated. As a result, wefound that its effects are not likely related to 5HT1A or GABAergic pathways;but its  anticonvulsant/antidepressant-like effectscould be due to its voltage gated sodium channel blocking properties. We observed that the antidepressant-like effect inducedby C1, at 1mg/kg and 10mg/kg, was reversed by the presence ofveratrine and a 30 % inhibition of the sodium current using patchclamp technique in HEK 293 cell line that expressed Nav 1.1.This combined anticonvulsant/ antidepressant- like profile may represent avaluable tool for the treatment of these disorders.