Linsitinib (OSI-906) modulates brain energy metabolism and seizure activity in the lithium-pilocarpine rat model

Abstract

Abstract Background Epileptic seizure is a process of energy accumulation, bursting, and depletion accompanied by the production, spread, and termination of epileptic discharges. The energy required for a seizure is mainly provided through mitochondrial production of ATP. Mitochondrial diseases often lead to epileptic seizures, and energy depletion caused by seizures can lead to mitochondrial dysfunction. The energy metabolism has become a key target for treatment of epileptic diseases. Method The effect of OSI-906, an insulin receptor (IR)/ insulin-like growth factor 1 receptor (IGF-1R) inhibitor, on behaviors and electroencephalographic activity in the lithium-pilocarpine rats were tested. 18F-FDG positron emission tomography (PET)/ computed tomography (CT) was performed to detect the relative whole-brain glucose uptake values. Electron microscopy was performed to observe the ultrastructure of neuronal and mitochondrial damage. The changes in blood glucose at different time points before and after the intervention were tested and the effects of OSI-906 on IR/IGF-1R and downstream Akt signaling in the context of seizures were evaluated. Results The OSI-906 treatment applied 3 days before the pilocarpine-induced seizures significantly reduced the seizure severity, prolonged the seizure latency and decreased the EEG energy density. MicroPET/CT revealed that 50 mg/kg of OSI-906 inhibited the 18F-FDG glucose uptake after epileptic seizures, suggesting that OSI-906, through inhibiting IR/IGF-1R and the downstream AKT signaling, may regulate the excessive energy consumption of the epileptic brain. The OSI-906 treatment also reduced the mitochondrial damage caused by epileptic seizures. Conclusion The IR/IGF-1R inhibitor OSI-906 can significantly reduce the sensitivity and severity of pilocarpine-induced seizures by inhibiting the IR/IGF-1R and the downstream Akt signaling pathway.

Keywords

• Epilepsy
• Mitochondria
• Energy metabolism
• Insulin receptor
• IGF-1 receptor
• Akt signaling