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

PASTORE, V; MARTÍN, P; LOPEZ SOTO, J; MUSTAFÁ, R; RAINGO, J; MILESI, V; MARDER, M

Rio de Janeiro

Congreso; 9th International Brain Research Society (IBRO) World Congress.; 2015

International Brain Research Society

ABSTRACT NEW NEUROACTIVES COMPOUNDS AND ITS EFFECTS INVOLTAGE-GATE SODIUM CHANNELValentina Pastorea, Pedro Martinb, E JavierLopez Sotoc, E Roman Mustafac, Jesica Raingoc VeronicaMilesib, Mariel Mardera.a IQUIFIB-CONICET-UBA.Facultad de Farmacia y Bioquímica. Junín 956. Capital Federal. Buenos Aires.Argentina vpastore@qb.ffyb.uba.arb IIFP-CONICET-UNLP, Departamento de CienciasBiológicas . 47 y 115 (B1900BJW), La Plata, Argentina. C Electrophysiology Lab. IMBICE. CONICET CICPBA. 526 yCamino Belgrano, La Plata, Argentina.                Epilepsy is a chronic and progressiveneurological disorder that affects 1?2% of the worldwide population. It ischaracterized by abnormal recurrent synchronization of neural activity.Pharmacotherapy is the treatment of choice for control of epileptic seizuresand the selection of antiepileptic drugs (AEDs) depends on several factors suchas the type of epilepsy and drug tolerability (Browne and Holmes, 2001). AEDsare also beneficial in diverse non-epileptic conditions and are commonly used inthe treatment of migraine headache, neuropathic pain, depression and bipolaraffective disorder.AEDsact at central nervous system on multiple targets including ion channels, neurotransmitterreceptors and transporters; and neurotransmitter metabolic enzymes. It isconvenient to categorize AED actions according to those that involve (1)modulation of voltage-gated ion channels; (2) enhancement of synapticinhibition; and (3) inhibition of synaptic excitation.Inthis work we focus on the action mechanisms of some novel AEDs compounds,bioisosters of classical anticonvulsant as trimethadione and phenytoin. Thisnovel AEDs were synthesized and characterized in our group. We denominate them asN-derivatives-1,2,3-oxathiazolidine-4-one-2,2-dioxide (DIOXIDES), and α-hydroxyamides and their biological profile effect was determined byacute anticonvulsant assays such as maximal electroshock seizure test (MEStest) and subcutaneous pentylenetetrazole seizure test (scPtz test). These newcompounds were 3?4700 times more potent than valproic acid in the MES test andwere no neurotoxic in the RotoRod test (Pastore et al., 2013). Moreover, themost active DIOXIDE (N-butyl-derivative) revealed a significant antidepressant-likeeffect. Preliminary in vivo studies demonstrated that the anticonvulsant effectis not likely related to GABAergic potentiation, while the antidepressant-likeeffect could be due to neuronal voltage-gated sodium channels (Nav) blockage  (Pastore et al., 2014). Nav play afundamental role in the central nervous system since they are responsible forthe initiation and conduction of action potentials. The pharmacologicaldown-modulation of Nav channels in electrical hyperactivityconditions, such as during epileptic seizures, isparticularly beneficial (Sitges et al., 2007). Basedon in vivo previous results, here we test the effect of AEDs on native Navcurrents (rat hippocampal primary neuronal cultures) by voltage clamp patch-clampexperiments. Ourresults show that DIOXIDE inhibits NaV currents in primary neuronalcultures. The peak current was blocked by 60.3 ± 18 % and theeffect was partially washable (% blockage washout: 20.5±7.4) (n=3). Moreover, this drug also slows NaV current activationkinetic. The peak current time was modified from 1.05 ± 0.35 ms in control conditions to 1.77 ± 0.44 ms in presence of DIOXIDEand 1.13 ± 0.32 ms after wash (n=3). Thus, we suggest that NaVcurrent amplitude reduction and the activation time increase could contributeto DIOXIDE antiepileptic and antidepressant action.Inorder to increase our knowledge on its action mechanisms we are currently evaluatingDIOXIDE effect on other ion channels related to epilepsy such as voltage gatedpotassium and calcium channels. ReferenceBrowne, T. R., &Holmes, G. L. Epilepsy. N Engl J Med 344 (2001) 1145?1151.Sitges, M., Chiu, L.M., Guarneros, A., Nekrassov, V. Neuropharm 52 (2007) 598-605.Pastore, V., Wasowski,C., Higgs, J.,Mangialavori, I., Bruno-Blanch, L.E., Marder, M.. EuropeanNeuropsychopharm. 24 (2014) 1405?1414.Pastore, V., Sabatier,L., Enrique, A., Marder, M., Bruno-Blanch, L.E. Bioorg & Med Chem 21 (2013) 841?846.