The inhibitor of 20-HETE synthesis, TS-011, improves cerebral microcirculatory autoregulation impaired by middle cerebral artery occlusion in mice |
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Authors: | Toshiyuki Marumo Kei Eto Hiroaki Wake Tomohiro Omura Junichi Nabekura |
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Institution: | 1Pharmacology Laboratory, Molecular Function and Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd, Saitama, Japan;2Division of Homeostatic Development, National Institute of Physiological Sciences, Okazaki, Japan;3Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Saitama, Japan;4Department of Physiological Sciences, The Graduate School for Advanced Study, Hayama, Japan |
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Abstract: | BACKGROUND AND PURPOSE20-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.EXPERIMENTAL APPROACHTS-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.KEY RESULTSThe 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 AND IMPLICATIONSThese 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. |
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Keywords: | 20-HETE ischaemia microcirculation peri-infarct two-photon microscopy |
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