Ação anticonvulsivante e neuroprotetora da ivabradina em camundongos

Abstract

Epilepsy is a disease that reaches approximately 1% of the worldwild population and can lead to neurological deficit, intellectual dysfunction, behavioral and social problems. It is defined by the ability to generate recurring seizures crises where currently 30% of all patients do not respond to any kind of therapy. Ivabradine is an agent Antianginal and na Antiarrhythmic that has as the main mechanism of action the blocking of cyclic nucleotide channels activated by Hyperpolarization (HNC). Previous studies have related to the action of this drug with seizures crises. Thus, the objective of this work was to study the possible anticonvulsants and neuroprotective effects of Ivabradine, through chemical models (Pentilenotetrazole-PTZ, Picrotoxine-PICRO and Pilocarpine-PILO) of induction of convulsions in mice, evaluating the neurochemical changes produced in the pre-frontal cortex, hipocampo and cortex striatum body and study of molecular docking in the receptors GABAérgics (gamma-aminobutyric acid-GABAA) and glutamatérgics (N-methyl-D-aspartate-NMDA receptor). Animals were pretreated with Ivabradine-IVA (1, 10 or 20mg/kg) or saline solution intraperitoneal for 3 days. The last day were administered the agents convulsivants and observed by 30 (model of PTZ-85mg/kg, i.p. and PICRO-10mg/kg i.p.) or 60 minutes (PILO-400mg/kg s.c.) and, shortly after, the cerebral areas (pre frontal cortex-P.F.C., Hipocampo-H.C. and cortex, striatum S.E.) were removed for oxidative stress analysis by the following tests: dosage of the Malonaldeído level (MDA), nitrite and reduced glutathione (GSH). The molecular fittings between IVA and receiver GABA, IVA and receiver NMDA receptor and diazepam and GABAA receptor were also carried out. The results showed anticonvulsant action of IVA on the PTZ-induced convulsion model, through increased latency to death (IVA 1mg/kg: 978, 3 ± 193, 0 and 10 mg/kg: 1309, 0 ± 203, 1) when compared to the control group (235, 0 ± 42, 8) and increase of survival percentage (IVA 10 mg/kg: 62, 5%). Similar effect is observed in the seizure induced by PICRO, through the increase in the first latency (IVA 10 mg/kg: 582, 2 ± 42, 0) when compared to the control (426, 0 ± 22, 8). It was also observed an antioxidant effect of IVA by reducing the MDA levels and increased levels of GSH in the three studied areas. In the study of molecular docking Ivabradine showed chemical, spatial and energetic compatibility with the GABAA receptor. In conclusion, our results showed that IVA presented anticonvulsant and neuroprotective action in the PTZ and PICRO models besides displaying interaction with the GABAA receptor.