Abstract
BackgroundEpileptic 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.MethodThe 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.ResultsThe 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.ConclusionThe 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.
Highlights
Epileptic seizure is a process of energy accumulation, bursting, and depletion accompanied by the production, spread, and termination of epileptic discharges
MicroPET/computed tomography (CT) revealed that 50 mg/ kg of OSI-906 inhibited the 18F-FDG glucose uptake after epileptic seizures, suggesting that OSI-906, through inhibiting insulin receptor (IR)/IGF-1 receptor (IGF-1R) and the downstream AKT signaling, may regulate the excessive energy consumption of the epileptic brain
In this study we evaluated the effects of OSI-906 on the IR/IGF-1R and the downstream phosphatidylinositol 3-kinase (PI3K)/AKT signaling, the energy metabolism level, and the mitochondrial morphology in the brain of a rat model with lithium-pilocarpine-induced epileptic seizures, as well as the effect on lithium-pilocarpine-induced epileptic seizures in the rat model
Summary
Epileptic seizure is a process of energy accumulation, bursting, and depletion accompanied by the production, spread, and termination of epileptic discharges. An epileptic seizure represents a process of energy accumulation, bursting and depletion, accompanied by the production, spread and termination of epileptic discharges that lead to neuronal injury [3, 4]. Insulin and insulin-like growth factor-1 (IGF-1) are multipotent bioactive substances found in almost all tissues In the brain they are involved in energy and glucose homeostasis and affect neuronal survival, learning, memory, and injury repair [9, 10]. Intracerebroventricular injection of neuroprotective doses of IGF-1 in other neurological diseases may promote epileptic seizures and the development of epilepsy by activating IGF-1R and the downstream signaling [15]
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