IQUIFIB   02644
INSTITUTO DE QUIMICA Y FISICOQUIMICA BIOLOGICAS "PROF. ALEJANDRO C. PALADINI"
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
A novel anticonvulsant/antidepressant alpha-hydroxyamide exerts its mechanism of action through voltage gated sodium channels
Autor/es:
JOSEFINA HIGGS; MARIEL MARDER; VALENTINA PASTORE; PEDRO MARTIN; CRISTINA WASOWSKI; VERONICA MILESI
Lugar:
Mar del Plata
Reunión:
Congreso; Reunión Conjunta 2016 - SAIC, SAI, SAFE; 2016
Institución organizadora:
SAIC, SAI, SAFE
Resumen:
In patients with epilepsy, anxiety and depression are frequent psychiatric comorbidities but they often remain unrecognized and untreated. We have synthesized a novel α-hydroxyamide, N-propyl-2,2-diphenyl-2-hydroxyacetamide (1), which is effective as anticonvulsant in the maximal electroshock test (ED50: 2.5mg/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 novel compound also has antidepressant activity in two experimental models: forced swimming (FST) and tail suspension (TST) tests. It is known that antidepressant drugs modify, in different ways, the activity of neurons, by increasing monoamine levels and by modulating ion channels. Sodium channels are molecular targets for antiepileptic drugs, which can also be mood stabilizers. So, in order to elucidate its mechanism of action, we made different in vivo/in vitro assays. Compound 1 demonstrated antidepressant activity (FST and TST) in Swiss male mice at 0.3-30 mg/kg i.p. (CICUAL EXP-FYB N° 0031682/2014). Its capacity to act via GABAA receptor ([3H]flunitrazepam binding assay); serotonin 5-HT1A receptor ([3H] 8-OH-DPAT binding assay) and voltage gated sodium channels using veratrine, a voltage gated sodium channel agonist (in vivo) and in a HEK 293 cell line that expressed Nav 1.1 (electrophysiology) was also evaluated. As a result, we found that its effects are not likely related to 5-HT1A or GABAergic pathways; but its anticonvulsant/antidepressant-like effects could be due to its voltage gated sodium channel blocking properties. We observed that the antidepressant-like effect induced by 1, at 1 mg/kg and 10 mg/kg, was reversed by the presence of veratrine and a 30% inhibition of the sodium current using patch clamp technique in HEK 293 cell line that expressed Nav 1.1. This combined anticonvulsant/antidepressant-like profile may represent a valuable tool for the treatment of these disorders.