Anti-inflammatory and neuroprotective effects of insulin-like growth factor-1 overexpression in pentylenetetrazole (PTZ)-induced mouse model of chronic epilepsy

Abstract

Epileptogenesis is a dynamic process accompanied by the hippocampal neuroinflammation, aberrant neurogenesis and cognitive decline. Accordingly, anti-neuroinflammation and neuroprotective therapy may be considered in effective prophylaxis and therapeutics for epilepsy. Insulin-like growth factor-1 (IGF-1) is well acknowledged as a neuroprotective factor to promote neurogenesis and neuronal survival and synaptogenesis, wherein there has been controversy as to its implication in epilepsy. In our prior experiments, we established transgenic mice with overexpressed IGF-1 specifically in neural stem cells (NSCs). This experiment sought to investigate the implications of overexpressed IGF-1 in a PTZ-induced mouse model of chronic epilepsy. Herein we demonstrated that increasing hippocampal levels of IGF-1 sufficed to exhibit long-term anti-epileptogenesis effect on epileptic mouse model. The severity of epilepsy was assessed with onset latency, Racine score, percentage of mice with stage IV-V seizures, duration of seizures. Strikingly, IGF-1 transgenic mice showed more lessened severity than the wild-type (W-T) mice. Moreover, IGF-1 transgenic mice exhibited a lesser population of IBA-1-positive cells in CA1 of hippocampus than did W-T mice in the chronic phase, with a significant downregulation of IL-1β, IL-6, and TNF-α in hippocampus, indicating that IGF-1 overexpression significantly mitigated inflammation in the hippocampus. In addition, Nissl staining revealed a greater population of viable neurons in CA1 of IGF-1 transgenic mice versus the W-T mice. TUNEL staining and western blotting indicated fewer apoptotic cells in transgenic mice. Moreover, we identified the evident increase in BrdU-positive and DCX-positive cell populations in dentate gyrus (DG) in IGF-1 transgenic mice, versus the W-T mice, indicative of the role of IGF-1 overexpression in promoting long-term hippocampal neurogenesis in the chronic phase of epilepsy. Collectively, our data authenticated the neuroprotective and antiinflammatory effects of IGF-1 in the chronic phase of epilepsy, which may benefit the long-term anti-epileptogenesis regimens.