The inhibitor of 20-HETE synthesis, TS-011, improves cerebral microcirculatory autoregulation impaired by middle cerebral artery occlusion in mice.
OBJECTIVE
20-Hydroxyeicosatetraenoic acid is a potent vasoconstrictor that contributes to cerebral ischaemia. An inhibitor of 20-Hydroxyeicosatetraenoic acid synthesis, TS-011, reduces infarct volume and improves neurological deficits in animal stroke models. However, little is known about how TS-011 affects the microvessels in ischaemic brain. Here, we investigated the effect of TS-011 on microvessels after cerebral ischaemia.


METHODS
TS-011 (0.3 mg·kg(-1) ) or a vehicle was infused intravenously for 1 h every 6 h in a mouse model of stroke, induced by transient occlusion of the middle cerebral artery occlusion following photothrombosis. The cerebral blood flow velocity and the vascular perfusion area of the peri-infarct microvessels were measured using in vivo two-photon imaging.


RESULTS
The cerebral blood flow velocities in the peri-infarct microvessels decreased at 1 and 7 h after reperfusion, followed by an increase at 24 h after reperfusion in the vehicle-treated mice. We found that TS-011 significantly inhibited both the decrease and the increase in the blood flow velocities in the peri-infarct microvessels seen in the vehicle-treated mice after reperfusion. In addition, TS-011 significantly inhibited the reduction in the microvascular perfusion area after reperfusion, compared with the vehicle-treated group. Moreover, TS-011 significantly reduced the infarct volume by 40% at 72 h after middle cerebral artery occlusion.


CONCLUSIONS
These findings demonstrated that infusion of TS-011 improved defects in the autoregulation of peri-infarct microcirculation and reduced the infarct volume. Our results could be relevant to the treatment of cerebral ischaemia.
Marumo
Toshiyuki
T
Pharmacology Laboratory, Molecular Function and Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd, Saitama, Japan. toshiyuki.marumo@po.rd.taisho.co.jp
Eto
Kei
K
Wake
Hiroaki
H
Omura
Tomohiro
T
Nabekura
Junichi
J
D000818:Animals; D001783:Blood Flow Velocity / Q000187:drug effects / Q000502:physiology; D002545:Brain Ischemia / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D002560:Cerebrovascular Circulation / Q000187:drug effects* / Q000502:physiology; D004195:Disease Models, Animal; D005559:Formamides / Q000008:administration & dosage* / Q000627:therapeutic use*; D006706:Homeostasis / Q000187:drug effects* / Q000502:physiology; D006893:Hydroxyeicosatetraenoic Acids / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D007262:Infusions, Intravenous; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008833:Microcirculation / Q000187:drug effects / Q000502:physiology; D009025:Morpholines / Q000008:administration & dosage* / Q000627:therapeutic use*
D005559:Formamides; D006893:Hydroxyeicosatetraenoic Acids; D009025:Morpholines; C503100:N-(3-chloro-4-morpholin-4-yl) phenyl-N'-hydroxyimido formamide; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid