Kinetic Changes of COX-2 Expression during Reperfusion Period after Ischemic Preconditioning Play a Role in Protection Against Ischemic Damage in Rat Brain

Abstract

A brief ischemic insult induces significant protection against subsequent massive ischemic events. The molecular mechanisms known as preconditioning (PC)-induced ischemic tolerance are not completely understood. W e investigated whether kinetic changes of cyclooxygenase (COX)-2 during reperfusion time-periods after PC were related to ischemic tolerance. Rats were given PC by occlusion of middle cerebral artery (MCAO) for 10 min and sacrificed after the indicated time-periods of reperfusion (1, 2, 4, 8, 12, 18 or 24 h). In PC-treated rats, focal ischemia was induced by occlusion of MCA for 24 h and brain infarct volume was then studied to determine whether different reperfusion time influenced the damage. W e report that the most significant protection against focal ischemia was obtained in rats with 8 h reperfusion after PC. Administration of indomethacin (10 mg/kg, oral) or rofecoxib (5 mg/kg, oral) 48 h prior to PC counteracted the effect of PC. Immunohistochemical analysis showed that COX-2 and HO-1 protein were induced in PC-treated rat brain, which was significantly inhibited by rofecoxib. Taken together, we concluded that the kinetic changes of COX-2 expression during the reperfusion period after PC might be partly responsible for ischemic tolerance.

Role of the Prostaglandin E2 EP1 Receptor in Traumatic Brain Injury

“…The similar relative effect of SC-51089 on behavioral and anatomical outcomes of experimental stroke and excitotoxicity compared to controls [19] , [23] , [31] , [40] was observed in the study with another EP1 receptor antagonist, ONO-8713, in similar experimental conditions [32] , and these outcomes were comparable to the outcomes measured in the EP1 −/− mice with and without drug treatment, suggesting appropriate SC-51089 bioavailability with the treatment regimen used in this study. The effective doses of SC-51089 in published studies focusing on ischemia and excitotoxicity are between 5 and 100 µg/kg [19] , [23] , [31] , [40] and the data suggest a wide therapeutic window for application of this compound (up to 12 h after permanent or transient focal ischemia) [31] , which would be consistent with temporal profiles of COX-2 activation and progression of secondary injuries following ischemia [56] , [57] and TBI [5] , [6] , [8] , [14] , [58] . However, the published data indicate that the therapeutic effect of SC-51089 mouse amygdala kindling model of temporal lobe epilepsy could be obtained at more than three orders of magnitude higher doses [38] .…”