The inhibitor of 20-HETE synthesis, TS-011, improves cerebral microcirculatory autoregulation impaired by middle cerebral artery occlusion in mice.

Abstract

BACKGROUND AND PURPOSE:

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.

EXPERIMENTAL APPROACH:

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.

KEY 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 AND IMPLICATIONS:

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.

• Authors: Toshiyuki Marumo, Kei Eto, Hiroaki Wake, Tomohiro Omura, Junichi Nabekura
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 161 Issue 6 Pg. 1391-402 (Nov 2010) ISSN: 1476-5381 [Electronic] England
• PMID: 20735406 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2010 The Authors. British Journal of Pharmacology © 2010 The British Pharmacological Society.

Chemical References

• Formamides
• Hydroxyeicosatetraenoic Acids
• Morpholines
• N-(3-chloro-4-morpholin-4-yl) phenyl-N'-hydroxyimido formamide
• 20-hydroxy-5,8,11,14-eicosatetraenoic acid

Topics

• Animals
• Blood Flow Velocity (drug effects, physiology)
• Brain Ischemia (drug therapy, etiology, physiopathology)
• Cerebrovascular Circulation (drug effects, physiology)
• Disease Models, Animal
• Formamides (administration & dosage, therapeutic use)
• Homeostasis (drug effects, physiology)
• Hydroxyeicosatetraenoic Acids (antagonists & inhibitors, biosynthesis)
• Infarction, Middle Cerebral Artery (drug therapy, etiology, physiopathology)
• Infusions, Intravenous
• Male
• Mice
• Mice, Inbred C57BL
• Microcirculation (drug effects, physiology)
• Morpholines (administration & dosage, therapeutic use)