Cyclooxygenase-2-dependent superoxide generation contributes to age-dependent impairment of G protein-mediated cerebrovasodilation

Abstract

Background: Previous studies have observed that activation of cyclooxygenase-2 contributes to generation of superoxide anion after fluid percussion brain injury (FPI). This study was designed to characterize the effects of FPI on the vascular activity of two activators of a pertussis toxin-sensitive G protein, mastoparan and mastoparan-7, and the role of cyclooxygenase2-dependent superoxide anion generation in such effects as a function of age. Methods: Lateral FPI was induced in anesthetized newborn (1-5-day-old) and juvenile (3-4-week-old) pigs equipped with a closed cranial window. Results: Mastoparan (10-8, 10-6 M) elicited pial artery dilation that was blunted more in newborn versus juvenile pigs (9 ± 1 and 16 ± vs. 3 ± 1 and 5 ± 1%, newborn; 9 ± 1 and 15 ± 1 vs. 6 ± 1 and 9 ± 1%, juveniles). Similar results were observed for mastoparan-7 but the inactive analog mastoparan-17 had no effect on pial artery diameter. Indomethacin (a cyclooxygenase-1 and cyclooxygenase-2 inhibitor), NS398 (a cyclooxygenase-2 inhibitor), and polyethylene glycol superoxide dismutase and catalase (free radical scavengers) partially restored impaired mastoparan dilation after FPI in the newborn in a roughly equivalent manner but not in the juvenile (3 ± 1 and 5 ± 1 vs. 8 ± 1 and 13 ± 1% newborn, 6 ± 1 and 9 ± vs. 7 ± 1 and 10 ± 1% juvenile for NS398 pretreatment). Conclusions: These data show that G protein activation elicits cerebrovasodilation that is blunted following FPI in an agedependent manner, and suggest that cyclooxygenase-2-dependent superoxide anion generation contributes to G protein activation-induced dilator impairment after the insult in an age-dependent manner.