PMID- 29186197
OWN - NLM
STAT- MEDLINE
DCOM- 20180101
LR  - 20211204
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 12
IP  - 11
DP  - 2017
TI  - Fingolimod suppresses neuronal autophagy through the mTOR/p70S6K pathway and 
      alleviates ischemic brain damage in mice.
PG  - e0188748
LID - 10.1371/journal.pone.0188748 [doi]
LID - e0188748
AB  - The bioactive, signaling lipid, sphingosine-1-phosphate (S1P), and its analog, 
      fingolimod (FTY720), have previously shown neuroprotective effects against 
      ischemic brain injury. However, the underlying mechanisms have not yet been fully 
      clarified. The roles of autophagy in ischemic stroke are being increasingly 
      recognized. In the present study, we sought to determine whether the S1P pathway 
      is involved in neuronal autophagy and investigate its possible mechanisms 
      following stroke. Interestingly, we found that FTY720 significantly attenuates 
      infarct volumes and reduces neuronal apoptosis on days 1 and 3 post stroke, 
      accompanied by amelioration of functional deficits. Additionally, FTY720 was 
      found to decrease the induction of autophagosome proteins, microtubule-associated 
      protein 1 light chain 3(LC3-II) and Beclin1, following ischemic stroke in a 
      dose-dependent manner. Meanwhile, protein levels of the mammalian target of 
      rapamycin (mTOR) and the 70-kDa ribosomal protein, S6 kinase1 (p70S6K), were also 
      up-regulated in FTY720-treated animals, and the nonspecific SphK inhibitor, 
      N,N-dimethylsphingosine (DMS), was found to cause a reverse effect. Our results 
      indicate that modulation of the S1P signaling pathway by FTY720 could effectively 
      decrease neuronal autophagy through the mTOR/p70S6K pathway and attenuate 
      ischemic brain injury in mice.
FAU - Li, Xiao
AU  - Li X
AD  - Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong 
      University of Science and Technology, Wuhan, China.
AD  - Department of geriatrics, Wuhan General Hospital of PLA, Wuhan, China.
FAU - Wang, Ming-Huan
AU  - Wang MH
AD  - Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong 
      University of Science and Technology, Wuhan, China.
FAU - Qin, Chuan
AU  - Qin C
AD  - Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong 
      University of Science and Technology, Wuhan, China.
FAU - Fan, Wen-Hui
AU  - Fan WH
AD  - Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong 
      University of Science and Technology, Wuhan, China.
FAU - Tian, Dai-Shi
AU  - Tian DS
AD  - Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong 
      University of Science and Technology, Wuhan, China.
FAU - Liu, Jun-Li
AU  - Liu JL
AUID- ORCID: 0000-0001-9082-692X
AD  - Cancer center, Union Hospital, Tongji Medical College, Huazhong University of 
      Science and Technology, Wuhan, China.
LA  - eng
PT  - Journal Article
DEP - 20171129
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Neuroprotective Agents)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - G926EC510T (Fingolimod Hydrochloride)
SB  - IM
MH  - Animals
MH  - Apoptosis/drug effects
MH  - Autophagy/*drug effects
MH  - Behavior, Animal
MH  - Brain Ischemia/enzymology/etiology/metabolism/*pathology
MH  - Dose-Response Relationship, Drug
MH  - Fingolimod Hydrochloride/*pharmacology
MH  - Magnetic Resonance Imaging
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Neurons/*drug effects
MH  - Neuroprotective Agents/*pharmacology
MH  - Ribosomal Protein S6 Kinases, 70-kDa/*metabolism
MH  - Signal Transduction/drug effects
MH  - TOR Serine-Threonine Kinases/*metabolism
MH  - Thrombosis/complications
PMC - PMC5706683
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2017/12/01 06:00
MHDA- 2018/01/02 06:00
PMCR- 2017/11/29
CRDT- 2017/11/30 06:00
PHST- 2017/04/26 00:00 [received]
PHST- 2017/11/13 00:00 [accepted]
PHST- 2017/11/30 06:00 [entrez]
PHST- 2017/12/01 06:00 [pubmed]
PHST- 2018/01/02 06:00 [medline]
PHST- 2017/11/29 00:00 [pmc-release]
AID - PONE-D-17-16091 [pii]
AID - 10.1371/journal.pone.0188748 [doi]
PST - epublish
SO  - PLoS One. 2017 Nov 29;12(11):e0188748. doi: 10.1371/journal.pone.0188748. 
      eCollection 2017.