Effects of agomelatine on electrocorticogram activity on penicillin-induced seizure model of rats.

Agomelatine is a new antidepressant drug acting as an antagonist of 5-hydroxytryptamine receptor 2C (5-HTR2C) and agonist of melatonergic receptors 1 and 2 (MT1 and MT2). Because of this dual action, it is an atypical antidepressant. The aim of this study was to investigate chronic anticonvulsant effects of agomelatine on penicillin-induced epilepsy model. Adult male Sprague-Dawley rats divided into four groups and were administered with tap water (vehicle), and agomelatine doses of 10 mg/kg, 50 mg/kg and 100 mg/kg for 14 days via oral gavage. After the last doses were given, epileptic seizures were induced by intracortical penicillin (500 IU/2.5 µl) application in rats under urethane (1.25 g/kg intraperitoneal) anesthesia. Electrocorticogram (ECoG) recordings were obtained from the somatomotor cortex through 90 min, and spike frequencies and amplitudes were analyzed. The spike frequency analyses revealed that only 50 mg/kg agomelatine administration decreased the spike frequencies of hypersynchronous discharge of neurons caused by penicillin (p < 0.05). No significant differences in amplitudes between experimental groups were observed. In addition, mRNA expressions of vesicular glutamate transporter 1 (VGLUT1) and vesicular gamma-aminobutyric acid transporter (VGAT) in response to the agomelatine active dose, 50 mg/kg, showed no significant effect of agomelatine on the mRNA expression. Our results indicate that chronic treatment with agomelatine may have potential anticonvulsant effects. Agomelatine may be a promising drug for epilepsy patients having depression due to its antiepileptic and antidepressant effects.

Anticonvulsant activity of resveratrol-loaded liposomes in vivo.

Resveratrol (3,5,4'-stilbenetriol), a natural polyphenol produced by various plants, has attracted attention over the past decade because of its multiple beneficial properties, including anti-inflammatory, anti-oxidant and chemopreventive, yet, there is limited information about its antiepileptic effects. Moreover, its poor solubility in water and low bioavailability are the challenging issues. In the present study, we aimed to investigate effects of free resveratrol and resveratrol delivered in amphipathic liposomal delivery system, which has a high blood-brain barrier crossing potential, on penicillin-induced epileptic seizure model. For this purpose, adult male Sprague-Dawley rats were divided into four groups as saline (Control), liposome (LIP), free resveratrol (RES) and resveratrol+liposome (RES+LIP). Penicillin-induced epileptic activity was recorded for 120 min by electrocorticography. Glutathione S-transferase (GST), Glutathione (GSH), Superoxide dismutase (SOD) and Malondialdehyde (MDA) assays were performed in brain tissues collected. Our results showed that RES+LIP was the most effective anticonvulsant treatment on penicillin-induced epileptic seizures when compared to control, as RES+LIP immediately decreased the number of spikes per minute. GST and SOD activity, as well as the GSH levels, were significantly increased in the RES+LIP group as compared with the control group. Also, the MDA levels were significantly higher in the RES+LIP compared to RES and control groups. In conclusion, RES+LIP treatment was more effective on the decrease in spike frequency and spike amplitudes than other treatments. Our results suggest that the RES+LIP is more effective than RES on penicillin-induced epileptiform activity.

HMG-CoA reductase inhibitor rosuvastatin improves abnormal brain electrical activity via mechanisms involving eNOS.

Apart from its repressing effect on plasma lipid levels, 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors exert neuroprotective functions in animal models of neurodegenerative disorders. In view of these promising observations, we were interested in whether HMG-CoA reductase inhibition would affect epileptiform activity in the brain. To elucidate this issue, atorvastatin, simvastatin and rosuvastatin were administered orally at a dose of 20 mg/kg each for 3 days and their anti-epileptic activities were tested and compared in rats. Epileptiform activity in the brain was induced by an intracortical penicillin G injection. Among HMG-CoA reductase inhibitors, simvastatin-treatment was less effective in terms of spike frequency as compared with atorvastatin- and rosuvastatin-treated animals. Atorvastatin treatment reduced spike frequencies and amplitudes significantly throughout the experiment. However, the most pronounced anti-epileptic effect was observed in rosuvastatin-treated animals, which was associated with improved blood-brain barrier (BBB) integrity, increased expression of endothelial nitric oxide synthase (eNOS) mRNA and decreased expressions of pro-apoptotic p53, Bax and caspase-3 mRNAs. Inhibition of eNOS activity with L-NG-Nitroarginine Methyl Ester (L-NAME) reversed the anti-epileptic effect of rosuvastatin significantly. However, L-NAME did not alter the effect of rosuvastatin on the levels of p53, Bax and caspase-3 mRNA expression. Here, we provide evidence that among HMG-CoA reductase inhibitors, rosuvastatin was the most effective statin on the reduction of epileptiform activity, which was associated with improved BBB permeability, increased expression of eNOS and decreased expressions of pro-apoptotic p53, Bax and caspase-3. Our observation also revealed that the anti-epileptic effect of rosuvastatin was dependent on the increased expression level of eNOS. The robust anti-epileptic effect encourages proof-of-concept studies with rosuvastatin in human epilepsy patients with hypercholesterolemia.