PMID- 28109197
OWN - NLM
STAT- MEDLINE
DCOM- 20180102
LR  - 20211204
IS  - 1742-2094 (Electronic)
IS  - 1742-2094 (Linking)
VI  - 14
IP  - 1
DP  - 2017 Jan 21
TI  - Everolimus is better than rapamycin in attenuating neuroinflammation in kainic 
      acid-induced seizures.
PG  - 15
LID - 10.1186/s12974-017-0797-6 [doi]
LID - 15
AB  - BACKGROUND: Microglia is responsible for neuroinflammation, which may aggravate 
      brain injury in diseases like epilepsy. Mammalian target of rapamycin (mTOR) 
      kinase is related to microglial activation with subsequent neuroinflammation. In 
      the present study, rapamycin and everolimus, both as mTOR inhibitors, were 
      investigated in models of kainic acid (KA)-induced seizure and lipopolysaccharide 
      (LPS)-induced neuroinflammation. METHODS: In vitro, we treated BV2 cells with KA 
      and LPS. In vivo, KA was used to induce seizures on postnatal day 25 in 
      B6.129P-Cx3cr1(tm1Litt)/J mice. Rapamycin and everolimus were evaluated in their 
      modulation of neuroinflammation detected by real-time PCR, Western blotting, and 
      immunostaining. RESULTS: Everolimus was significantly more effective than 
      rapamycin in inhibiting iNOS and mTOR signaling pathways in both models of 
      neuroinflammation (LPS) and seizure (KA). Everolimus significantly attenuated the 
      mRNA expression of iNOS by LPS and nitrite production by KA and LPS than that by 
      rapamycin. Only everolimus attenuated the mRNA expression of mTOR by LPS and KA 
      treatment. In the present study, we also found that the modulation of mTOR under 
      LPS and KA treatment was not mediated by Akt pathway but was primarily mediated 
      by ERK phosphorylation, which was more significantly attenuated by everolimus. 
      This inhibition of ERK phosphorylation and microglial activation in the 
      hippocampus by everolimus was also confirmed in KA-treated mice. CONCLUSIONS: 
      Rapamycin and everolimus can block the activation of inflammation-related 
      molecules and attenuated the microglial activation. Everolimus had better 
      efficacy than rapamycin, possibly mediated by the inhibition of ERK 
      phosphorylation. Taken together, mTOR inhibitor can be a potential 
      pharmacological target of anti-inflammation and seizure treatment.
FAU - Yang, Ming-Tao
AU  - Yang MT
AD  - Department of Pediatrics, Far Eastern Memorial Hospital, New Taipei City, Taiwan.
AD  - Department of Chemical Engineering and Materials Science, Yuan Ze University, 
      Taoyuan, Taiwan.
FAU - Lin, Yi-Chin
AU  - Lin YC
AD  - Department of Pediatric Neurology, National Taiwan University Children's 
      Hospital, No. 7 Chung-Shan South Road, Taipei, 100, Taiwan.
AD  - Graduate Institute of Brain and Mind Science, National Taiwan University, Taipei, 
      Taiwan.
FAU - Ho, Whae-Hong
AU  - Ho WH
AD  - Department of Pediatric Neurology, National Taiwan University Children's 
      Hospital, No. 7 Chung-Shan South Road, Taipei, 100, Taiwan.
FAU - Liu, Chao-Lin
AU  - Liu CL
AD  - Department of Chemical Engineering, Ming Chi University of Technology, New Taipei 
      City, Taiwan.
AD  - College of Engineering, Chang Gung University, Taoyuan, Taiwan.
FAU - Lee, Wang-Tso
AU  - Lee WT
AD  - Department of Pediatric Neurology, National Taiwan University Children's 
      Hospital, No. 7 Chung-Shan South Road, Taipei, 100, Taiwan. leeped@hotmail.com.
AD  - Graduate Institute of Brain and Mind Science, National Taiwan University, Taipei, 
      Taiwan. leeped@hotmail.com.
LA  - eng
PT  - Journal Article
DEP - 20170121
PL  - England
TA  - J Neuroinflammation
JT  - Journal of neuroinflammation
JID - 101222974
RN  - 0 (Convulsants)
RN  - 0 (Immunosuppressive Agents)
RN  - 9HW64Q8G6G (Everolimus)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - SIV03811UC (Kainic Acid)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Convulsants/toxicity
MH  - Everolimus/*pharmacology
MH  - Immunosuppressive Agents/*pharmacology
MH  - Inflammation/*pathology
MH  - Kainic Acid/toxicity
MH  - Mice
MH  - Microglia/drug effects
MH  - Seizures/chemically induced/*pathology
MH  - Sirolimus/*pharmacology
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors
PMC - PMC5251325
OTO - NOTNLM
OT  - ERK
OT  - Epilepsy
OT  - Everolimus
OT  - Kainic acid
OT  - Neuroinflammation
OT  - Rapamycin
OT  - mTOR
EDAT- 2017/01/22 06:00
MHDA- 2018/01/03 06:00
PMCR- 2017/01/21
CRDT- 2017/01/22 06:00
PHST- 2016/08/18 00:00 [received]
PHST- 2017/01/12 00:00 [accepted]
PHST- 2017/01/22 06:00 [entrez]
PHST- 2017/01/22 06:00 [pubmed]
PHST- 2018/01/03 06:00 [medline]
PHST- 2017/01/21 00:00 [pmc-release]
AID - 10.1186/s12974-017-0797-6 [pii]
AID - 797 [pii]
AID - 10.1186/s12974-017-0797-6 [doi]
PST - epublish
SO  - J Neuroinflammation. 2017 Jan 21;14(1):15. doi: 10.1186/s12974-017-0797-6.