The Anticonvulsant Effect of a Novel Indole-Related Compound in the Kainate-Induced Status Epilepticus in Mice: The Role of the Antioxidant and Anti-inflammatory Mechanism.

Abstract

We synthesized a series of novel indole compounds containing aroylhydrazone moieties and evaluated them in mice to check their anticonvulsant activity. In the present study the most potent C3-modified derivative 3e, containing 2-furyl fragment was evaluated in kainate (KA)-induced status epilepticus (SE) and the consequences on oxidative stress and inflammation in the hippocampus in mice were explored. Melatonin was used as positive control while the melatonin receptor antagonist Luzindol was studied alone or in combination with melatonin or 3e, respectively. After intraperitoneal (i.p.) pre-treatment with melatonin 3e, Luzindol + melatonin and Luzindol + 3e for 7 days (melatonin and 3e-30mgkg-1 or 60mgkg-1, Luzindol 10mgkg-1) the animals were i.p. injected with KA (30mgkg-1, i.p.). The 3e decreased the SE-induced seizure intensity while melatonin suppressed seizures at the higher dose of 60mgkg-1. Luzindol blocked the anticonvulsant effect of both Mel and 3e. The dose-dependent antioxidant effect of 3e measured by reduced glutathione (GSH) and total GSH in the hippocampus, was comparable to the effect of melatonin. Luzindol fully blocked the effect of melatonin but affected partially the antioxidant activity of 3e. The KA-induced increased amplifier of neuroinflammation high-mobility group box protein 1 (HMGB1) was neither alleviated by melatonin, nor by 3e. The activation by this DNA-binding protein receptor for advanced glycation end products (RAGE) was not affected by SE, melatonin and 3e pre-treatment. Our results suggest that the novel indole derivate 3e, containing 2-furyl fragment, might be clinically useful as an adjunct therapy against SE and concomitant oxidative stress.