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Lovastatin modulates glycogen synthase kinase-3β pathway and inhibits mossy fiber sprouting after pilocarpine-induced status epilepticus.

Lee CY, Jaw T, Tseng HC, Chen IC, Liou HH - PLoS ONE (2012)

Bottom Line: Pilocarpine-induced status epilepticus animal model was taken as our researching material.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 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.

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.

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Related in: MedlinePlus

The experimental design and Timm’s score recorded from different time points.(A) The experimental design of TLE animal model and drug administration. (B) Timm’s score recorded from control and 1 to 3 months after SE induction. 1 month after SE induction, the Timm’s score was significantly increased compared with control group and show an increasing tendency with time. (*compared with control group).
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pone-0038789-g001: The experimental design and Timm’s score recorded from different time points.(A) The experimental design of TLE animal model and drug administration. (B) Timm’s score recorded from control and 1 to 3 months after SE induction. 1 month after SE induction, the Timm’s score was significantly increased compared with control group and show an increasing tendency with time. (*compared with control group).

Mentions: It is known that GSK-3β regulates axonal growth and neuronal polarity through phosphorylating CRMP-2 [18], therefore we examined the expression level and phosphorylation state of GSK-3β and CRMP-2 from control, SE and SE+lovastatin groups, respectively, by western blotting method. We administrated lovastatin (20 mg/kg) to the rats 3 hours after terminating SE by pentobarbital. The experimental regimen is illustrated in Figure 1A. To determine a proper observation time point of MFS, we evaluated the Timm’s score from 1 to 3 months after SE induction. The Timm’s score after SE induction was 0.60±0.15 in control group (n = 16), 2.62±0.25 in 1 month SE group (n = 16, P<0.001), 2.71±0.29 in 2 months SE group (n = 7, P<0.001), and 3.40±0.40 in 3 months SE group (n = 5, P<0.001)(one-way ANOVA and post-hoc Mann-Whitney U test, regression constant, 0.71) (Figure 1B). Therefore, to minimize the animal suffering and consumption and to reduce the experimental duration, we chose 1 month as our observation time point to record Timm’s score.


Lovastatin modulates glycogen synthase kinase-3β pathway and inhibits mossy fiber sprouting after pilocarpine-induced status epilepticus.

Lee CY, Jaw T, Tseng HC, Chen IC, Liou HH - PLoS ONE (2012)

The experimental design and Timm’s score recorded from different time points.(A) The experimental design of TLE animal model and drug administration. (B) Timm’s score recorded from control and 1 to 3 months after SE induction. 1 month after SE induction, the Timm’s score was significantly increased compared with control group and show an increasing tendency with time. (*compared with control group).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3383707&req=5

pone-0038789-g001: The experimental design and Timm’s score recorded from different time points.(A) The experimental design of TLE animal model and drug administration. (B) Timm’s score recorded from control and 1 to 3 months after SE induction. 1 month after SE induction, the Timm’s score was significantly increased compared with control group and show an increasing tendency with time. (*compared with control group).
Mentions: It is known that GSK-3β regulates axonal growth and neuronal polarity through phosphorylating CRMP-2 [18], therefore we examined the expression level and phosphorylation state of GSK-3β and CRMP-2 from control, SE and SE+lovastatin groups, respectively, by western blotting method. We administrated lovastatin (20 mg/kg) to the rats 3 hours after terminating SE by pentobarbital. The experimental regimen is illustrated in Figure 1A. To determine a proper observation time point of MFS, we evaluated the Timm’s score from 1 to 3 months after SE induction. The Timm’s score after SE induction was 0.60±0.15 in control group (n = 16), 2.62±0.25 in 1 month SE group (n = 16, P<0.001), 2.71±0.29 in 2 months SE group (n = 7, P<0.001), and 3.40±0.40 in 3 months SE group (n = 5, P<0.001)(one-way ANOVA and post-hoc Mann-Whitney U test, regression constant, 0.71) (Figure 1B). Therefore, to minimize the animal suffering and consumption and to reduce the experimental duration, we chose 1 month as our observation time point to record Timm’s score.

Bottom Line: Pilocarpine-induced status epilepticus animal model was taken as our researching material.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 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.

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.

Show MeSH
Related in: MedlinePlus