ts-011 and Brain-Ischemia

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.. 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.. 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.. 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.

Topics: Animals; Blood Flow Velocity; Brain Ischemia; Cerebrovascular Circulation; Disease Models, Animal; Formamides; Homeostasis; Hydroxyeicosatetraenoic Acids; Infarction, Middle Cerebral Artery; Infusions, Intravenous; Male; Mice; Mice, Inbred C57BL; Microcirculation; Morpholines

TS-011, a potent and selective inhibitor of 20-HETE synthesis, has been described as providing significant benefits in animal stroke models. However, no studies have investigated changes in brain 20-HETE levels after cerebral ischemia. Also lacking are studies of TS-011 pharmacodynamics with respect to brain 20-HETE levels that may explain the benefits of TS-011 in animal models of ischemic stroke. The present study sought to explore changes in 20-HETE levels in brain tissue, as well as in plasma, after a 90-min episode of transient focal cerebral ischemia. Pharmacodynamics of TS-011 were also examined. Then, we evaluated the long-term effects of TS-011 when administered as in this pharmacodynamics study. The major findings of the present study are as follows: (1) brain 20-HETE levels increased significantly within 7.5h after MCAO; (2) TS-011 at doses of 0.1 and 0.3mg/kg administered at regular 6-h intervals appeared to reduce brain 20-HETE levels continuously; (3) TS-011 when administered as in this pharmacodynamics study improved long-term neurological and functional outcomes. These findings strongly suggest that 20-HETE plays an important role in the development of neurological and functional deficits after focal cerebral ischemia and that TS-011 may provide benefits in patients suffering ischemic stroke.

Topics: Animals; Brain; Brain Ischemia; Cerebral Arteries; Cerebrovascular Circulation; Dose-Response Relationship, Drug; Drug Administration Schedule; Formamides; Hydroxyeicosatetraenoic Acids; Ischemic Attack, Transient; Morpholines; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Treatment Outcome; Up-Regulation; Vasodilation

Arachidonic acid that is released following cerebral ischemia can be metabolized to 20-hydroxyeicosatetraenoic acid (20-HETE). 20-HETE is a potent vasoconstrictor that may contribute to ischemic injury. This study examined the effects of blockading the synthesis of 20-HETE with TS-011 on infarct size after transient occlusion of the middle cerebral artery (MCAO) of rats and after thromboembolic stroke in monkeys.. Rats were treated with TS-011 or vehicle at various times after MCAO. Infarct size was measured by 2,3,5-triphenyltetrazolium chloride (TTC) staining and plasma levels of 20-HETE were determined by liquid chromatography mass spectrometry (LC/MS). The effect of TS-011 on infarct size was also studied in monkeys after introduction of a clot into the internal carotid artery.. Plasma levels of 20-HETE increased after MCAO in rats. TS-011 (0.01 to 1.0 mg/kg per hour) reduced infarct volume by 40%. Chronic administration of TS-011 for 7 days reduced neurological deficits after MCAO in rats. TS-011 given in combination with tissue plasminogen activator also improved neurological outcome in the stroke model in monkeys.. These results suggest that blockade of the formation of 20-HETE with TS-011 may be useful for the treatment of ischemic stroke.

Topics: Animals; Brain Ischemia; Dose-Response Relationship, Drug; Formamides; Gas Chromatography-Mass Spectrometry; Haplorhini; Hydroxyeicosatetraenoic Acids; Male; Morpholines; Rats; Rats, Wistar; Reperfusion Injury