Received for publication January 20, 2005.
Revised March 29, 2005.
Accepted for publication April 1, 2005.

Beneficial Effects of a new 20-HETE Synthesis Inhibitor, TS-011,on Hemorrhagic and Ischemic Stroke

Abstract

The present study characterized the effects of TS-011 (N-(3-Chloro-4-morpholin-4-yl) phenyl- N'-hydroxyimido formamide), a new selective inhibitor of the synthesis of 20-hydroxyeicosatetrenoic acid (20-HETE), on the metabolism of arachidonic acid by human and rat renal microsomes and the inhibitory effects of this compound on hepatic cytochrome P450 (CYP) enzymes involved in drug metabolism. The effects of TS-011 on the fall in cerebral blood flow following subarachnoid hemorrhage (SAH) and in reducing infarct size in ischemic stroke models were also examined since 20-HETE may contribute to the development of cerebral vasospasm. TS-011 inhibited the synthesis of 20-HETE by human renal microsomes and recombinant CYP4A11 and 4F2, 4F3A and 4F3B enzymes with IC₅₀s around 10-50 nM. It had no effect on the activities of CYP1A, 2C9, 2C19, 2D6 or 3A4 enzymes. TS-011 inhibited the synthesis of 20-HETE by rat renal microsomes with an IC₅₀ of 9.19 nM, and it had no effect on epoxygenase activity at a concentration of 100 µM. TS-011 (0.01-1 mg/kg, i.v.) reversed the fall in cerebral blood flow and the increase in 20-HETE levels in the cerebrospinal fluid of rats after SAH. TS-011 also reduced the infarct volume by 35% following transient ischemic stroke and in intracerebral hemorrhage in rats. Injection of 20-HETE (8 or 12 mg/kg) into the carotid artery produced an infarct similar to that seen in the ischemic stroke model. These studies indicate that blockade of the synthesis of 20-HETE with TS-011 opposes cerebral vasospasm following SAH and reduces infarct size in ischemic models of stroke.

Key words: 20-HETE, Cytochrome P450, Enzyme inhibitor, Stroke, Subarachnoid hemorrhage, TS-011

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