Electrophysiological characterization of sodium channel blocking parabens

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

Congreso; 10th Latin American Epilepsy congress; 2018

Purpose: Parabens are widely used as an antimicrobial preservative in drugs, foods and cosmetics. Virtual screening methodologies predicted an anticonvulsant activity of propylparaben (PPB) and methylparaben (MPB) confirmed in MES test (Talevi et al, JComputAidedMolDes 2007;21:527?538). Moreover, in rat brain slices, it was showed that PPB reduced the excitability of CA1 pyramidal neurons and inhibited the current mediated by voltage-dependent Na+ channels (NaV) (Lara-Valderrábano et al, Neurotoxicology 2016;57:183-193). In the present work we fully characterized the effect of PPB on the activity of the human NaV1.2 channel isoform expressed in a heterologous system, and spreading the study to other parabens analogues: MPB, butylparaben (BuPB) and benzylparaben (BnPB).Method: Patch-clamp experiments were performed in HEK293 cell lines stably expressing hNaV1.2 α channel subunit. The effects of parabens were tested on the whole-cell macroscopic NaV current using different voltage clamp protocols that allowed characterize the drug effects on different properties of Na+ channel function. Results: PPB showed a state-dependent inhibition of the hNaV1.2 currents characterized by a left-shift in the steady state inactivation curve (ΔV1/2(100µM)=12.15±1.93) which is consistent with a stabilization of the inactivated state of the channel. The observed effect was concentration-dependent and remarkably, it was higher when the cell membrane was more depolarized. Additionally, PPB promotes a use-dependent inhibition, which was exacerbated at a higher stimulatory frequency.MPB, BuPB and BnPB showed the same pharmacological effects of PPB. Particularly, BuPB (ΔV1/2(100µM)=21.83±5.94) and BnPB (ΔV1/2(100µM)=31.94±3.39) were more efficient in NaV1.2 channel inhibition (p<0.05 and p<0.01 respectively), while MPB (ΔV1/2(100µM)=4.31±1.18) showed lower potency than PPB (p<0.001).Conclusion: This work shows that parabens, in the same way that other anticonvulsant agents, induce a state-dependent inhibition in human NaV1.2 channel being more effective in depolarized cells and presenting a used-dependent effect. Its profile allows propose parabens as beneficial drug in antiepileptic treatment.