Lovastatin Modulates Glycogen Synthase Kinase-3β Pathway and Inhibits Mossy Fiber Sprouting after Pilocarpine-Induced Status Epilepticus

Chun-Yao Lee,Horng-Huei Liou,I-Chun Chen,Huan-Chin Tseng,Thomas Jaw,Ken Arai

doi:10.1371/journal.pone.0038789

Chun-Yao Lee, Horng-Huei Liou + Show 4 more

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https://doi.org/10.1371/journal.pone.0038789

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Abstract

This study was undertaken to assay the effect of lovastatin on the glycogen synthase kinase-3 beta (GSK-3β) and collapsin responsive mediator protein-2 (CRMP-2) signaling pathway and mossy fiber sprouting (MFS) in epileptic rats. MFS in the dentate gyrus (DG) is an important feature of temporal lobe epilepsy (TLE) and is highly related to the severity and the frequency of spontaneous recurrent seizures. However, the molecular mechanism of MFS is mostly unknown. GSK-3β and CRMP-2 are the genes responsible for axonal growth and neuronal polarity in the hippocampus, therefore this pathway is a potential target to investigate MFS. Pilocarpine-induced status epilepticus animal model was taken as our researching material. Western blot, histological and electrophysiological techniques were used as the studying tools. The results showed that the expression level of GSK-3β and CRMP-2 were elevated after seizure induction, and the administration of lovastatin reversed this effect and significantly reduced the extent of MFS in both DG and CA3 region in the hippocampus. The alteration of expression level of GSK-3β and CRMP-2 after seizure induction proposes that GSK-3β and CRMP-2 are crucial for MFS and epiletogenesis. The fact that lovastatin reversed the expression level of GSK-3β and CRMP-2 indicated that GSK-3β and CRMP-2 are possible to be a novel mechanism of lovatstain to suppress MFS and revealed a new therapeutic target and researching direction for studying the mechanism of MFS and epileptogenesis.

Highlights

Temporal lobe epilepsy (TLE) is the most prevalent symptom in patients who are diagnosed with epilepsy
It is known that glycogen synthase kinase-3 beta (GSK-3b) regulates axonal growth and neuronal polarity through phosphorylating collapsin responsive mediator protein-2 (CRMP-2) [18], we examined the expression level and phosphorylation state of glycogen synthase kinase-3b (GSK3b) and CRMP-2 from control, status epilepticus (SE) and SE+lovastatin groups, respectively, by western blotting method
We found an increased expression of GSK3b, pGSK-3b and CRMP-2 after SE induction

Summary

Introduction

Temporal lobe epilepsy (TLE) is the most prevalent symptom in patients who are diagnosed with epilepsy. Several pathological features have been found in the hippocampal formation under epileptic condition, including hippocampal sclerosis, massive amount of neuronal loss caused by either necrosis or apoptosis, neurogenesis, neuro-inflammation, granule cell dispersion (GCD) and mossy fiber sprouting (MFS) [1]. Among all these features caused by epileptic injury, MFS in the dentate gyrus (DG) is the most important index that is highly correlated with the frequency of SRS and the severity of TLE [2,3]. The underlying mechanism of MFS is still not well-understood

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