Insulin-like Growth Factor-1 Effects on Epilepsy

Abstract According to the Center of Disease Control and Prevention, epilepsy affects 2.2 million Americans, and 65 million people worldwide. Traumatic brain injury is one of the major risk factors causing epileptogenesis, or the development of epilepsy taking place in the latent period between injury and the appearance of spontaneous seizures. In order to prevent epilepsy from developing, therapeutic approaches need to target molecular events that lead from injury to the formation of epileptic circuits. It has been discovered that the mTOR inhibition suppresses abnormal neural circuit reorganization and may reduce spontaneous seizures in some cases, but mTOR inhibition by itself is not enough to completely prevent the onset of spontaneous seizures. This suggests that other signaling pathways and cascades are involved in epileptic activity in the brain. Insulin-like Growth Factor-1 (IGF-1) levels are elevated in brain tissue following head injury.Previous results suggest IGF-1 has pro-epileptogenic effect in an organotypic hippocampal model of posttraumatic epilepsy. It is known that the binding of IGF-1 to IGF-1 receptors (IGF -1 R) leads to activation of MAPK and PI3K signaling cascades, however it is not clear whether IGF-1 activates mTOR, or operates in parallel to PI3K-Akt-mTOR cascade through activation of MAPK. Each of these molecules may be promising targets for anti-epileptogenic drugs, however a more detailed understanding of how these pathways are activated, along with the time sequence of molecular events is necessary. In this study, Western Blot analysis was used in order to measure levels of phosphorylation of Akt, MAPK, and S6 (a marker of mTOR activation), during early post injury period and latent period with and without IGF-1 in the culture medium. Following this study, we plan to determine the timeline of the signaling cascade and will make conclusions on the effects of IGF-1 on the different steps in the cascade with the ultimate goal of developing an effective antiepileptogenic treatment.