A new anticonvulsant compound prevents the oxidative damage induced by pentylenetetrazole and exerts antidepressant-like effects in mice

PASTORE, V.; WASOWSKI, C; BRUNO-BLANCH, L.; MARDER, M

La Habana

Congreso; 20th Latinoamerican Congress on Pharmacology and Therapeutic, 5th Iberoamerican Congress on Pharmacology, 5th International and 10th National Congresses of the Cuban Society of Pharmacology; 2013

ASOCIACIÓN LATINOAMERICANA DE FARMACOLOGÍA SOCIEDAD CUBANA DE FARMACOLOGÍA

Epilepsy is recognized as one of the most common and serious neurological disorder affecting 1-2% of the world?s population. Among various factors supposed to play role in epilepsy, oxidative stress and reactive species (ROS) in seizure disorders have recently emerged. The most important effect of free radicals is lipid peroxidation (LP), which causes disruption of cell membrane thereby leading to their destruction. An increased of free radicals also decreased glutathione (GSH) concentration in the epileptic focus. We have synthesized N-butyl-1,2,3-oxathiazolidine-4-one-2,2-dioxide (NBOD), a bioisoster of trimethadione (a classical anticonvulsant), which showed anticonvulsant properties in maximal electroshock seizure (MES) and pentylenetetrazole (scPTZ) tests in mice, with ED50 of 0.06 mg/kg and 18 mg/kg, respectively. Many reports have suggested that ROS generation may underlie the convulsant and neurotoxic effects of PTZ. NBOD countered the effects of PTZ and protected brain from oxidative damage by decreasing LP and restoring GSH content. Additionally, major depression is common in patients with epilepsy and correlates with a poor quality of life so a treatment with antidepressants is required. The continuous search for new, safer, and more effective drugs with both anticonvulsant and antidepressant activity are therefore imperative and is a challenge in medicinal chemistry. The antidepressant activity of NBOD was also evaluated. A significant effect in the forced swimming and tail suspension tests (FST and TST), the most widely used models for assessing antidepressant activity in rodents, was observed. According to their molecular targets antiepileptic drugs have been categorized in three groups: those that block voltage gated ion channels (Na and Ca), those that enhance GABAergic inhibition or reduce glutamatergic excitation. Preliminary studies on the mechanism of action of NBOD suggested that its anticonvulsant effect is not mediated via the GABAA receptor and that Na channels would be involved in its antidepressant activity.