Parabens reposition as anticonvulsant drugs

ENRIQUE, A; TALEVI, A; MILESI, V; MARTÍN, P

Mar del Plata

Congreso; Reunión Conjunta de la Sociedad Argentina de Investigación Clínica (SAIC), la Sociedad Argentina de Inmunología (SAI) y la Sociedad Argentina de Fisiología (SAFIS); 2018

SAIC - SAI - SAFIS

Parabens are a homologous series of esters of p-hydroxybenzoic acid, used as antimicrobial preservatives in foods, drugs and cosmetics for over 50 years. It has been shown that propylparaben blocks sodium channels in rat brain slices, reducing the excitability of hippocampal neurons (doi:10.1016/j.neuro.2016.09.019). In addition, it has anticonvulsant activity against Maximal Electroshock Seizure test (doi:10.1007/s10822-007-9136-9) and pilocarpine-induced seizures, and reduces the neuronal damage and excitability induced in this last model(doi:10.1016/j.neuro.2017.01.009).The aim of this study was to fully characterize the mechanism ofaction of propylparaben, other esters of the series (methylparaben,ethylparaben, buthylparaben and benzylparaben) and p-hydroxybenzoic acid, themain metabolite of parabens, on human NaV1.2 sodium channels. We tested theeffect of these compounds on NaV1.2 channel heterologously expressed in HEK293cells by applying thepatch-clamp technique in the whole cell configuration.All parabens, with the exception of methylparaben, inhibited Nav1.2currents in a state- and use-dependent manner. Both effectsincreased as the side of the hydrocarbon chain of the ester group augmented.The state-dependency was observed as a left-shift in V1/2 forsteady-state inactivation curve, which was twice and three times greater,respectively, for buthylparaben and benzylparaben compared with propylparaben(p<0.001). The use-dependent inhibitory effect was observed as a fasterdecay in currents evoked in a train of voltage-steps at 50 Hz (p<0.05). Propylparaben and benzylparabenwere also tested at lower frequencies, where, consistently, they showed a minorand slower inhibitory effect (25 Hz vs. 10 Hz; p<0.01). Finally, p-hydroxybenzoic acidalso inhibited Nav1.2 currents, with a relatively lower potency incomparison with parabens and thus, it may be responsible for a residual blocking effectafter the metabolism of parabens, extending its action.Parabens profile showed that theireffect could be grater in the epileptic focus with respect to normal neuronswhich would be beneficial in antiepileptic treatment.