Cyclooxygenase-2 inhibitor NS398 preserves neuronal function after hypoxia/ischemia in piglets

Abstract

Anoxic stress attenuates NMDA-induced pial arteriolar dilation via a mechanism involving actions of cyclooxygenase (COX)-derived reactive oxygen species (ROS). We examined whether the selective COX-2 inhibitor NS398 would protect neuronal function after global hypoxia/ischemia (H/I) in piglets. Pial arteriolar responses to NMDA (10-100 micromol/l) were determined using intravital microscopy in anesthetized piglets before and 1 h after H/I. Study groups received vehicle, 0.3, 1, or 5 mg/kg NS398, or 0.3 mg/kg indomethacin (n = 7, 6, 6, 5 and 8, respectively) i.v. 20 min prior to H/I. H/I reduced NMDA- induced dilation to 44 +/- 6% (100 micromol/l NMDA, mean +/- s.e.m.) of the pre-ischemic response in vehicle animals (p < 0.05). However, NS398 dose-dependently protected arteriolar dilation to NMDA (77 +/- 8, 81 +/- 16, and 102 +/- 10% preservation at 0.3, 1 and 5 mg/kg, respectively). Indomethacin caused similar preservation. However, indomethacin but not NS398 reduced serum thromboxane B(2) levels to undetectable values. In conclusion, COX-2 appears to be a major source of ROS in the piglet cerebral cortex after H/I.

Effects of hypothermia on neuronal-vascular function after cerebral ischemia in piglets

“…It seems likely that NMDA receptors are a primary target of ROS derived from COX metabolism of arachidonic acid as well as from damaged mitochondria after ischemia (22,24,30). Our studies showing that administration of structurally different inhibitors of COX (indomethacin and NS398) (4,12,18), as well as superoxide dismutase (4), is able to preserve NMDAinduced dilation following a variety of hypoxic/ischemic conditions provide support for the concept that superoxide formation via the COX pathway is a pivotal event in neuronal dysfunction under these conditions.…”

“…Indomethacin, which decreases ROS production in newborn piglet brain after ischemia (2) and asphyxia (26), has been shown to preserve the NMDA response after asphyxia (12), ischemia (18), and hypoxia (4). Similar protective effects have been obtained following administration of superoxide dismutase (4) or the selective blockade of COX-2.…”

“…To extend our previous finding that indomethacin preserved NMDA-induced vasodilation during less severe insults, piglets in this group were pretreated with 5 mg/kg iv of indomethacin 20 min before ischemia. This dose of indomethacin is sufficient to inhibit COX and to prevent anoxia-induced increases in superoxide anion production (18,26). Measurements of NMDA responses were made before the indomethacin infusion and were compared with the response to NMDA after 1 h of reperfusion.…”

Hydrogen is neuroprotective and preserves neurovascular reactivity following asphyxia in newborn pigs

“…In our laboratory, the newborn piglet model has long been used to study the morphology and functional responses of cerebrovascular system in physiologic and pathologic conditions [61][62][63][64][65][66][67]. We and others have repeatedly shown that hypoxic-ischemic stress in newborn piglets severely attenuated CR to various so called "hypoxia-ischemia sensitive" stimuli determined in pial arterioles 1 hour after the insult [61,64,[68][69][70].…”

“…We and others have repeatedly shown that hypoxic-ischemic stress in newborn piglets severely attenuated CR to various so called "hypoxia-ischemia sensitive" stimuli determined in pial arterioles 1 hour after the insult [61,64,[68][69][70]. The attenuated CR showed spontaneous recovery, and it appeared intact as early as 4 hours after the ischemic insult [61,62,68,70].…”