Effect of ramosetron, a 5-HT3 receptor antagonist on the severity of seizures and memory impairment in electrical amygdala kindled rats

The entorhinal cortex (EC) plays a pivotal role in epileptogenesis and seizures. EC expresses high density of serotonergic receptors, especially 5-HT3 receptors. Cognitive impairment is common among people with epilepsy. The present study investigated the role of 5-HT3 receptor on the severity of seizures and learning and memory impairment by electrical kindling of amygdala in rats. The amygdala kindling was conducted in a chronic kindling manner in male Wistar rats. In fully kindled animals, ramosetron (as a potent and selective 5-HT3 receptor antagonist) was microinjected unilaterally (ad doses of 1, 10 or 100 µg/0.5 µl) into the EC 5 min before the novel object recognition (NOR) and Y-maze tests or kindling stimulations. Applying ramosetron at the concentration of 100 μg/0.5 µl (but not at 1 and 10 µg/0.5 µl) reduced afterdischarge (AD) duration and increased stage 4 latency in the kindled rats. Moreover, the obtained data from the NOR test showed that treatment by ramosetron (10 and 100 µg/0.5 µl) increased the discrimination index in the fully kindled animals. Microinjection of ramosetron (10 and 100 µg/0.5 µl) in fully kindled animals reversed the kindling induced changes in the percentage of spontaneous alternation in Y-maze task. The findings demonstrated an anticonvulsant role for a selective 5-HT3 receptor antagonist microinjected into the EC, therefore, suggesting an excitatory role for the EC 5-HT3 receptors in the amygdala kindling model of epilepsy. This anticonvulsive effect was accompanied with a restoring effect on cognitive behavior in NOR and Y-maze tests.

The Expression of ZnT3 and GFAP Is Potentiated in the Hippocampus of Drug-Resistant Epileptic Rats Induced by Amygdala Kindling

<b><i>Objective:</i></b> The first-line treatment for epilepsy, a chronic neurological disorder characterized by spontaneous seizures, includes the application of anticonvulsant drug therapy. Only one-third of patients are incapable of complete controlling of their seizures after the administration of ≥2 pharmaceuticals. Here, we aimed to observe the ultrastructure changes and the expression of ZnT3 and GFAP in the hippocampus of drug-resistant epileptic rats. <b><i>Methods:</i></b> A total of 50 healthy adult male SD rats were used to generate the model of<i></i>epilepsy by amygdala kindling. After the rats were successfully kindled, pharmacoresistant epileptic (PRE) rats were selected according to their response to phenobarbital and phenytoin. The ultrastructure as well as the expression of zinc transporter 3 (ZnT3, a member of a growing family of mammalian zinc transporters) and glial fibrillary acidic protein (GFAP) were compared among PRE, pharmacosensitive epileptic (PRE), and normal (NRC) rats. <b><i>Results:</i></b> The PRE rats displayed severe synapses, neuronal degeneration, and necrosis. Moreover, the expression of ZnT3 and GFAP was significantly increased in both PRE and PSE rats; compared with NRC rats, the promotion of this expression was more pronounced in the PRE rats. <b><i>Conclusions:</i></b> Taken together, obvious synapses, neuronal degeneration, necrosis, mossy fiber sprouting, and astrogliosis were found in the drug-resistant epileptic rat model induced by amygdala kindling.