The effects of glucocorticoid and inhibitor of glucocorticoid receptor on seizures and cognitive functions in epileptic rats

The relationship between epilepsy, one of the most common neurological diseases in the world, and glucocorticoids released from the adrenal gland at high levels in the event of stress remains unclear. To contribute to the remove of this ambiguity, we aimed to investigate the effects of corticosterone, a natural glucocorticoid found in rats, and the glucocorticoid receptor antagonist mifepristone on epileptic seizures, anxiety-like behaviors, learning and memory processes. In our study, 66 male Wistar albino rats were divided into 6 groups as Control, DMSO, PTZ, CORT+PTZ, MIF+PTZ and MIF+CORT+PTZ. In our experiments, corticosterone (10 mg/kg/s.k.) and mifepristone (5 mg/kg/s.k.) were administered for 26 days. Kindling epilepsy model carried out with 14 doses PTZ (30 mg/kg/i.p.) applications every other day and seizure behaviors were scored according to Racine's scale. After the PTZ kindling process, the elevated plus maze test and open field test were used to detect anxiety-like behaviors, and the Morris water maze test was used to investigate learning and memory functions. Following the behavioral tests, biochemical studies were carried out on hippocampus tissue homogenates and blood plasma samples. In addition, histological examinations were performed on the brain tissues taken from the experimental groups. The longest seizure latency, lowest seizure frequency, and seizure severity results, were seen in the MIF+PTZ group. On the other hand, there was no significant difference in the epileptic seizures between PTZ, CORT+PTZ and MIF+CORT+PTZ groups. In our anxiety tests, the lowest anxiety-like behaviors were detected in the MIF+PTZ and MIF+CORT+PTZ groups. However, more anxiety-like behaviors were observed in the PTZ and CORT+PTZ groups than that of the control group. On the Morris water maze test learning days, learning latency was similar to the control group and significantly lower than the PTZ group in the MIF+PTZ and MIF+CORT+PTZ groups. However, the learning latency of the PTZ group was longer than that of the control group. Among the experimental groups, the highest memory impairment was detected in the PTZ group. Whereas, better memory performance was observed in the MIF+PTZ group than those of the PTZ and CORT+PTZ groups. In our study, the lowest hippocampal BDNF level was detected in the MIF+PTZ group, while plasma BDNF levels were lower in the PTZ, CORT+PTZ and MIF+CORT+PTZ groups than that of the control group. Hippocampal CREB levels of the PTZ group were significantly higher than those of the control and MIF+PTZ groups. Hippocampal TSP-1 levels were found to be significantly lower in the PTZ and CORT+PTZ groups than in the control, MIF+PTZ and MIF+CORT+PTZ groups. While there was no significant difference between the hippocampal serotonin levels of the groups, lower plasma serotonin levels were observed in the PTZ, CORT+PTZ and MIF+CORT+PTZ groups than that of the control. Hippocampal corticosterone level was lower in the MIF+PTZ and MIF+CORT+PTZ groups than that of the control group. However, plasma corticosterone level was higher in the MIF+PTZ group than that of the control. Hippocampal TNF-α levels were higher in the PTZ group than those of the control and MIF+PTZ groups. In addition, plasma TNF-α levels were higher in the PTZ and CORT+PTZ groups than that of the control. As a result of histological examinations of our study, hippocampal neuron loss was observed in all epileptic experimental groups. However, lower hippocampal (DG and CA1) neuronal loss was observed in the MIF+PTZ and MIF+CORT+PTZ groups than those of the PTZ and CORT+PTZ groups. We concluded that mifepristone has positive effects on epileptic seizures, anxiety-like behaviors, memory and learning processes. Mifepristone may inhibit, hyperexcitable neural network formation by reducing hippocampal BDNF levels and getting closer CREB levels to control; by increasing hippocampal TSP-1 and preventing pathological angiogenesis with its antiangiogenic effects; by positively affecting the serotonergic pathway by getting closer 5-HT levels to control; by preventing neuroinflammation via blocking TNF-α levels. As a result, we concluded that it may have shown its effect by preventing hippocampal neuronal loss. In order to clarify the positive effects of mifepristone on epileptogenesis, anxiety and memory processes, it needs to be supported by more experimental and clinical studies.