PMID- 23145776
OWN - NLM
STAT- MEDLINE
DCOM- 20130111
LR  - 20211203
IS  - 1528-1167 (Electronic)
IS  - 0013-9580 (Print)
IS  - 0013-9580 (Linking)
VI  - 53
IP  - 11
DP  - 2012 Nov
TI  - Rapamycin has paradoxical effects on S6 phosphorylation in rats with and without 
      seizures.
PG  - 2026-33
LID - 10.1111/epi.12013 [doi]
AB  - PURPOSE:   Accumulating data have demonstrated that seizures induced by kainate 
      (KA) or pilocarpine activate the mammalian target of rapamycin (mTOR) pathway and 
      that mTOR inhibitor rapamycin can inhibit mTOR activation, which subsequently has 
      potential antiepileptic effects. However, a preliminary study showed a 
      paradoxical exacerbation of increased mTOR pathway activity reflected by S6 
      phosphorylation when rapamycin was administrated within a short period before KA 
      injection. In the present study, we examined this paradoxical effect of rapamycin 
      in more detail, both in normal rats and KA-injected animals. METHODS:   Normal 
      rats or KA-treated rats pretreated with rapamycin at different time intervals 
      were sacrificed at various time points (1, 3, 6, 10, 15, and 24 h) after 
      rapamycin administration or seizure onset for western blotting analysis. 
      Phosphorylation of mTOR signaling target of Akt, mTOR, Rictor, Raptor, S6K, and 
      S6 were analyzed. Seizure activity was monitored behaviorally and graded 
      according to a modified Racine scale (n = 6 for each time point). Neuronal cell 
      death was detected by Fluoro-Jade B staining. KEY FINDINGS:   In normal rats, we 
      found that rapamycin showed the expected dose-dependent inhibition of S6 
      phosphorylation 3-24 h after injection, whereas a paradoxical elevation of S6 
      phosphorylation was observed 1 h after rapamycin. Similarly, pretreatment with 
      rapamycin over 10 h before KA inhibited the KA seizure-induced mTOR activation. 
      In contrast, rapamycin administered 1-6 h before KA caused a paradoxical increase 
      in the KA seizure-induced mTOR activation. Rats pretreated with rapamycin 1 h 
      prior to KA exhibited an increase in severity and duration of seizures and more 
      neuronal cell death as compared to vehicle-treated groups. In contrast, rapamycin 
      pretreated 10 h prior to KA had no effect on the seizures and decreased neuronal 
      cell death. The paradoxical effect of rapamycin on S6 phosphorylation was 
      correlated with upstream mTOR signaling and was reversed by pretreatment of 
      perifosine, an Akt inhibitor. SIGNIFICANCE:   These data indicate the complexity 
      of S6 regulation and its effect on epilepsy. Paradoxical effects of rapamycin 
      need to be considered in clinical applications, such as for potential treatment 
      for epilepsy and other neurologic disorders.
CI  - Wiley Periodicals, Inc. (c) 2012 International League Against Epilepsy.
FAU - Chen, Linglin
AU  - Chen L
AD  - School of Medicine, Zhejiang University City College, Hangzhou, Zhejiang, China
FAU - Hu, Lin
AU  - Hu L
FAU - Dong, Jing-Yin
AU  - Dong JY
FAU - Ye, Qing
AU  - Ye Q
FAU - Hua, Nan
AU  - Hua N
FAU - Wong, Michael
AU  - Wong M
FAU - Zeng, Ling-Hui
AU  - Zeng LH
LA  - eng
GR  - R01 NS056872/NS/NINDS NIH HHS/United States
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Epilepsia
JT  - Epilepsia
JID - 2983306R
RN  - EC 2.7.1.1 (mTOR protein, rat)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Male
MH  - Phosphorylation/drug effects/physiology
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Ribosomal Protein S6 Kinases/antagonists & inhibitors/*metabolism
MH  - Seizures/*drug therapy/*metabolism
MH  - Sirolimus/*pharmacology/therapeutic use
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - Treatment Outcome
PMC - PMC3502022
MID - NIHMS408557
COIS- Disclosure None of the authors has any conflict of interest to disclose. We 
      confirm that we have read the Journal's position on issues involved in ethical 
      publication and affirm that this report is consistent with those guidelines.
EDAT- 2012/11/14 06:00
MHDA- 2013/01/12 06:00
PMCR- 2013/11/01
CRDT- 2012/11/14 06:00
PHST- 2012/11/14 06:00 [entrez]
PHST- 2012/11/14 06:00 [pubmed]
PHST- 2013/01/12 06:00 [medline]
PHST- 2013/11/01 00:00 [pmc-release]
AID - 10.1111/epi.12013 [doi]
PST - ppublish
SO  - Epilepsia. 2012 Nov;53(11):2026-33. doi: 10.1111/epi.12013.