Activation of sphingosine 1-phosphate receptor-1 by FTY720 is neuroprotective after ischemic stroke in rats.
OBJECTIVE
FTY720 is a known sphingosine 1-phosphate receptor agonist. In the present study, we investigated the neuroprotective effect of postischemic administration of FTY720 in rats with 2 hours transient middle cerebral artery occlusion (MCAO).


METHODS
One hundred eleven male rats were randomly assigned to sham-operated and MCAO treated with vehicle, 0.25 mg/kg and 1 mg/kg of FTY720, another selective sphingosine 1-phosphate receptor-1 agonist SEW2871 (5 mg/kg), or 0.25 mg/kg of FTY720 plus a sphingosine 1-phosphate antagonist, VPC23019 (0.5 mg/kg). Drugs were injected intraperitoneally immediately after reperfusion. Neurological score and infarct volume were assessed at 24 and 72 hours after MCAO. Western blotting, immunohistochemistry, and terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate-biotin nick end-labeling were conducted at 24 hours after MCAO.


RESULTS
FTY720 significantly reduced infarct volume and improved neurological score at 24 and 72 hours after MCAO compared with the vehicle group. SEW2871 showed similar neuroprotective effects to FTY720, whereas VPC 20319 abolished the neuroprotective effects of FTY720. FTY720 significantly retained Akt and extracellular signal-regulated kinase phosphorylation and Bcl-2 expression and decreased cleaved caspase-3 expression and terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate-biotin nick end-labeling-positive neurons at 24 hours after MCAO. VPC23019 blocked the antiapoptotic effects of FTY720.


CONCLUSIONS
These data suggest that activation of sphingosine 1-phosphate-1 by FTY720 reduces neuronal death after transient MCAO.
Hasegawa
Yu
Y
Department of Physiology, Loma Linda University School of Medicine, Loma Linda, Calif 92354, USA.
Suzuki
Hidenori
H
Sozen
Takumi
T
Rolland
William
W
Zhang
John H
JH
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000503:physiopathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D000068876:Fingolimod Hydrochloride; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D020287:In Situ Nick-End Labeling; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D009410:Nerve Degeneration / Q000188:drug therapy / Q000209:etiology / Q000517:prevention & control; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D010069:Oxadiazoles / Q000494:pharmacology / Q000627:therapeutic use; D011409:Propylene Glycols / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D049349:Receptors, Lysosphingolipid / Q000819:agonists* / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D020521:Stroke / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D013876:Thiophenes / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome
D051017:Apoptosis Regulatory Proteins; D007166:Immunosuppressive Agents; D018696:Neuroprotective Agents; D010069:Oxadiazoles; D011409:Propylene Glycols; D049349:Receptors, Lysosphingolipid; C503964:SEW2871; D013876:Thiophenes; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine