NEW NEUROACTIVES COMPOUNDS AND ITS EFFECTS IN VOLTAGE-GATE SODIUM CHANNEL

PASTORE VALENTINA; MARTIN PEDRO; LOPEZ SOTO JAVIER; MUSTAFA ROMAN; RAINGO JESICA; MILESI VERONICA; MARDER MARIEL

Congreso; IBRO; 2015

IBRO

Epilepsy is a chronic and progressive neurological disorder that affects 1?2% of the worldwide population. It is characterized by abnormal recurrent synchronization of neural activity. Pharmacotherapy is the treatment of choice for control of epileptic seizures and the selection of antiepileptic drugs (AEDs) depends on several factors such as the type of epilepsy and drug tolerability (Browne and Holmes, 2001). AEDs are also beneficial in diverse non-epileptic conditions and are commonly used in the treatment of migraine headache, neuropathic pain, depression and bipolar affective disorder.AEDs act at central nervous system on multiple targets including ion channels, neurotransmitter receptors and transporters; and neurotransmitter metabolic enzymes. It is convenient to categorize AED actions according to those that involve (1) modulation of voltage-gated ion channels; (2) enhancement of synaptic inhibition; and (3) inhibition of synaptic excitation.In this work we focus on the action mechanisms of some novel AEDs compounds, bioisosters of classical anticonvulsant as trimethadione and phenytoin. This novel AEDs were synthesized and characterized in our group. We denominate them as N-derivatives-1,2,3-oxathiazolidine-4-one-2,2-dioxide (DIOXIDES), and α-hydroxyamides and their biological profile effect was determined by acute anticonvulsant assays such as maximal electroshock seizure test (MES test) and subcutaneous pentylenetetrazole seizure test (scPtz test). These new compounds were 3?4700 times more potent than valproic acid in the MES test and were no neurotoxic in the RotoRod test (Pastore et al., 2013). Moreover, the most active DIOXIDE (N-butyl-derivative) revealed a significant antidepressant-like effect. Preliminary in vivo studies demonstrated that the anticonvulsant effect is not likely related to GABAergic potentiation, while the antidepressant-like effect could be due to neuronal voltage-gated sodium channels (Nav) blockage (Pastore et al., 2014). Nav play a fundamental role in the central nervous system since they are responsible for the initiation and conduction of action potentials. The pharmacological down-modulation of Nav channels in electrical hyperactivity conditions, such as during epileptic seizures, is particularly beneficial (Sitges et al., 2007). Based on in vivo previous results, here we test the effect of AEDs on native Nav currents (rat hippocampal primary neuronal cultures) by voltage clamp patch-clamp experiments. Our results show that DIOXIDE inhibits NaV currents in primary neuronal cultures. The peak current was blocked by 60.3 ± 18 % and the effect was partially washable (% blockage washout: 20.5±7.4) (n=3). Moreover, this drug also slows NaV current activation kinetic. The peak current time was modified from 1.05 ± 0.35 ms in control conditions to 1.77 ± 0.44 ms in presence of DIOXIDE and 1.13 ± 0.32 ms after wash (n=3). Thus, we suggest that NaV current amplitude reduction and the activation time increase could contribute to DIOXIDE antiepileptic and antidepressant action.In order to increase our knowledge on its action mechanisms we are currently evaluating DIOXIDE effect on other ion channels related to epilepsy such as voltage gated potassium and calcium channels.