Effect of a novel thromboxane A2 receptor antagonist, S-1452, on postischemic brain injury in rats.
OBJECTIVE
Arachidonate metabolites have been implicated in the development of cerebral injury after ischemia. Particular importance has been placed on the balance of thromboxane A2 and prostaglandin I2 because of its regulative activity on platelet functions and arterial tone. The purpose of the present study was to shed light on the role of thromboxane A2 in postischemic brain injury.


METHODS
We evaluated the effects of S-1452, a novel thromboxane A2 receptor antagonist, on brain edema, infarct areas, and survival rate in rats with middle cerebral artery occlusion. A transient middle cerebral artery occlusion model was produced by inserting a piece of silicon-coated nylon thread into the internal carotid artery.


RESULTS
The ratio of plasma thromboxane B2 to 6-keto-prostaglandin F1 alpha significantly rose at 0 hour (P < .05), 1 hour (P < .01), 3 hours (P < .05), and 12 hours (P < .05) and then nearly returned to the normal level at 24 hours after reperfusion following 1-hour occlusion. Pretreatment with S-1452 (5, 10, or 50 mg/kg PO) significantly attenuated the increase in postischemic water content in the cerebral cortex perfused by the anterior cerebral artery and the cerebral cortex perfused by the middle cerebral artery in a dose-dependent manner but slightly attenuated it in the caudate putamen 24 hours after reperfusion following 1-hour occlusion. Pretreatment with S-1452 (10 mg/kg PO) also significantly decreased the areas of infarction in the front parts of the cerebrum. The survival rate of animals after 2 hours of occlusion tended to be improved by treatment with S-1452 (10 mg.kg-1.d-1 PO), although there was no statistical significance.


CONCLUSIONS
Our results suggest that thromboxane A2 is closely related to postischemic brain injury in the early phase of recirculation and that S-1452 may have a protective effect on postischemic brain injury.
Matsuo
Y
Y
Kanzakigawa Laboratory, Shionogi Research Laboratories, Shionogi & Co, Ltd, Osaka, Japan.
Izumiyama
M
M
Onodera
H
H
Kurosawa
A
A
Kogure
K
K
D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000818:Animals; D001834:Body Water / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D002544:Cerebral Infarction / Q000473:pathology; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D002546:Ischemic Attack, Transient / Q000188:drug therapy*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D015427:Reperfusion Injury / Q000517:prevention & control; D016019:Survival Analysis; D013928:Thromboxane A2 / Q000502:physiology*; D013929:Thromboxane B2 / Q000378:metabolism; D013997:Time Factors
D001643:Bridged Bicyclo Compounds; D005229:Fatty Acids, Monounsaturated; D017482:Receptors, Thromboxane; C056566:S 145; D013929:Thromboxane B2; D013928:Thromboxane A2; D015121:6-Ketoprostaglandin F1 alpha