PMID- 28343295
OWN - NLM
STAT- MEDLINE
DCOM- 20181231
LR  - 20210222
IS  - 1559-1182 (Electronic)
IS  - 0893-7648 (Linking)
VI  - 55
IP  - 3
DP  - 2018 Mar
TI  - Identification of Sphingosine 1-Phosphate Receptor Subtype 1 (S1P(1)) as a 
      Pathogenic Factor in Transient Focal Cerebral Ischemia.
PG  - 2320-2332
LID - 10.1007/s12035-017-0468-8 [doi]
AB  - Medically relevant roles of receptor-mediated sphingosine 1-phosphate (S1P) 
      signaling have become a successful or promising target for multiple sclerosis or 
      cerebral ischemia. Animal-based proof-of-concept validation for the latter is 
      particularly through the neuroprotective efficacy of FTY720, a non-selective S1P 
      receptor modulator, presumably via activation of S1P(1). In spite of a clear link 
      between S1P signaling and cerebral ischemia, it remains unknown whether the role 
      of S1P(1) is pathogenic or neuroprotective. Here, we investigated the involvement 
      of S1P(1) along with its role in cerebral ischemia using a transient middle 
      cerebral artery occlusion ("tMCAO") model. Brain damage following tMCAO, as 
      assessed by brain infarction, neurological deficit score, and neural cell death, 
      was reduced by oral administration of AUY954, a selective S1P(1) modulator as a 
      functional antagonist, in a therapeutic paradigm, indicating that S1P(1) is a 
      pathogenic mediator rather than a neuroprotective mediator. This pathogenic role 
      of S1P(1) in cerebral ischemia was reaffirmed because tMCAO-induced brain damage 
      was reduced by genetic knockdown with an intracerebroventricular microinjection 
      of S1P(1) shRNA lentivirus into the brain. Genetic knockdown of S1P(1) or AUY954 
      exposure reduced microglial activation, as assessed by reduction in the number of 
      activated microglia and reversed morphology from amoeboid to ramified, and 
      microglial proliferation in ischemic brain. Its role in microglial activation was 
      recapitulated in lipopolysaccharide-stimulated primary mouse microglia, in which 
      the mRNA expression level of TNF-alpha and IL-1beta, well-known markers for microglial 
      activation, was reduced in microglia transfected with S1P(1) siRNA. These data 
      suggest that the pathogenic role of S1P(1) is associated with microglial 
      activation in ischemic brain. Additionally, the pathogenic role of S1P(1) in 
      cerebral ischemia appears to be associated with the blood-brain barrier 
      disruption and brain-derived neurotrophic factor (BDNF) downregulation. Overall, 
      findings from the current study clearly identify S1P(1) signaling as a pathogenic 
      factor in transient focal cerebral ischemia, further implicating S1P(1) 
      antagonists including functional antagonists as plausible therapeutic agents for 
      human stroke.
FAU - Gaire, Bhakta Prasad
AU  - Gaire BP
AD  - Gachon University, Incheon, 406-799, Republic of Korea.
FAU - Lee, Chi-Ho
AU  - Lee CH
AD  - Gachon University, Incheon, 406-799, Republic of Korea.
FAU - Sapkota, Arjun
AU  - Sapkota A
AD  - Gachon University, Incheon, 406-799, Republic of Korea.
FAU - Lee, Sang Yeul
AU  - Lee SY
AD  - Department of Pharmacy and Institute of Pharmaceutical Science and Technology, 
      Hanyang University, Ansan, 55 Hanynagdaehak-ro, Sangnok-gu, Ansan, Gyeonggi-do, 
      15588, Republic of Korea.
FAU - Chun, Jerold
AU  - Chun J
AD  - Department of Molecular Biology, Dorris Neuroscience Center, The Scripps Research 
      Institute, La Jolla, CA, 92037, USA.
FAU - Cho, Hee Jun
AU  - Cho HJ
AD  - TherlifEx, Namdong-gu, Incheon, 21653, Republic of Korea.
FAU - Nam, Tae-Gyu
AU  - Nam TG
AD  - Department of Pharmacy and Institute of Pharmaceutical Science and Technology, 
      Hanyang University, Ansan, 55 Hanynagdaehak-ro, Sangnok-gu, Ansan, Gyeonggi-do, 
      15588, Republic of Korea. tnam@hanyang.ac.kr.
FAU - Choi, Ji Woong
AU  - Choi JW
AD  - Gachon University, Incheon, 406-799, Republic of Korea. pharmchoi@gachon.ac.kr.
LA  - eng
GR  - NRF-2014M3A9B6069339/National Research Foundation of Korea/International
GR  - HI13C18200000/Ministry of Health and Welfare/International
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20170325
PL  - United States
TA  - Mol Neurobiol
JT  - Molecular neurobiology
JID - 8900963
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Receptors, Lysosphingolipid)
SB  - IM
MH  - Animals
MH  - Cells, Cultured
MH  - Ischemic Attack, Transient/genetics/*metabolism/pathology
MH  - Male
MH  - Mice
MH  - Mice, Inbred ICR
MH  - Microglia/metabolism/pathology
MH  - RNA, Small Interfering/pharmacology
MH  - Receptors, Lysosphingolipid/*antagonists & inhibitors/genetics/*metabolism
OTO - NOTNLM
OT  - AUY954
OT  - Microglia
OT  - S1P1
OT  - S1P1 shRNA
OT  - Transient middle cerebral artery occlusion (tMCAO)
EDAT- 2017/03/28 06:00
MHDA- 2019/01/01 06:00
CRDT- 2017/03/27 06:00
PHST- 2016/11/27 00:00 [received]
PHST- 2017/02/23 00:00 [accepted]
PHST- 2017/03/28 06:00 [pubmed]
PHST- 2019/01/01 06:00 [medline]
PHST- 2017/03/27 06:00 [entrez]
AID - 10.1007/s12035-017-0468-8 [pii]
AID - 10.1007/s12035-017-0468-8 [doi]
PST - ppublish
SO  - Mol Neurobiol. 2018 Mar;55(3):2320-2332. doi: 10.1007/s12035-017-0468-8. Epub 
      2017 Mar 25.