Effect of the craf-1 inhibitor sorafenib on epilepsy and cognitive functions in the pentylenetetrazol-induced kindling model in rats.

Aim: In recent years, neuroinflammation has been recognized as one of the causes of central nervous system diseases, and the role of inflammation is being extensively researched. Additionally, clinical studies support that the pathophysiology of epilepsy is associated with inflammation, and the role of neuroinflammatory mediators in the etiopathogenesis of epileptic seizures is being investigated. cRaf-1 is a protein kinase specifically associated with neurodegenerative diseases due to its capacity to trigger neuroinflammation. Sorafenib, through the inhibition of cRaf-1, may reduce the expression of neuroinflammatory factors, offering a potential preventive approach for neurodegenerative diseases. Methods: In our study, we investigated the effects of different doses of sorafenib (10 mg/kg, 20 mg/kg, and 40 mg/kg) on learning and memory, locomotor activity, and various biochemical parameters in the PTZ-induced epilepsy model. We compared the results with the control group and the group treated with 150 mg/kg sodium valproate. Additionally, we evaluated the morphological changes in the stomach and hippocampal tissues. Results: PTZ significantly increased locomotor activity compared to the control and PTZ+Na-Valp group. Sorafenib-treated groups reduced activity compared to the PTZ group, with a significant effect observed at the dose of 40 mg/kg. In the Morris water maze test, PTZ impair learning, while 20 mg/kg sorafenib positively affected learning. PTZ impaired memory, while Na-Valp and sorafenib attenuated this effect, with the best effect observed at the dose of 10 mg/kg sorafenib. PTZ reduced SOD levels and increased MDA levels in the hippocampus. Sorafenib exhibited antioxidant effects by reducing oxidative damage induced by PTZ. However, the most protective dose was not clearly determined. PTZ increased caspase-3 and TNF-α levels in the hippocampus and serum. Sorafenib suppressed apoptosis and inflammation, with the 40 mg/kg dose showing the most effective results. IL-10 levels increased at the 40 mg/kg dose of sorafenib, while IL-1β and NF-κB levels decreased, indicating a neuroinflammatory preventive effect. Conclusion:Sorafenib was effective in reducing PTZ-induced neuroinflammation and oxidative stress and improving learning-memory functions. However, further research is needed to determine the optimal dose. Key Words: Sorafenib, Kindling epilepsy, Learning and memory, Hippocampus, Rat