Influence of polyethylene glycol superoxide dismutase/catalase on altered opioid-induced pial artery dilation after brain injury

Abstract

Background: The current study was designed to investigate the influence of pretreatment with the oxygen radical scavengers polyethylene glycol superoxide dismutase and catalase (SODCAT) on altered opioid-induced pial artery dilation after fluid percussion brain injury (FPI) in the newborn pig. It has been observed previously that brain injury produces pial artery vasoconstriction in the piglet associated with elevated cerebrospinal fluid opioid levels. Furthermore, opioid-induced vasodilation and cyclic guanosine monophosphate production are attenuated following brain injury. Finally, oxygen free radicals have been implicated in the pathogenesis of brain injury. Methods: Anesthetized piglets equipped with a closed cranial window were connected to a percussion device consisting of a saline-filled cylindrical reservoir with a metal pendulum. Fluid percussion brain injury of moderate severity (1.9-2.3 atm) was produced by allowing the pendulum to strike a piston on the cylinder. Superoxide dismutase-inhibitable nitroblue tetrazolium reduction was determined as an index of superoxide generation. Results: Superoxide dismutase-inhibitable nitroblue tetrazolium was increased markedly after FPI and these increases were blunted by SODCAT (1,000 U/kg and 10,000 U/kg, respectively) treatment 30 min before FPI (1 ± 1 vs. 14 ± 2 vs. 1 ± 1 pmol/mm 2 for control, FPI, and FPI pretreated with SODCAT, respectively). Methionine enkephalin, an endogenous μ opioid agonist, produced vasodilation that was attenuated by FPI and partially restored by SODCAT pretreatment (17 ± 1, 8 ± 1, and 14 ± 1% for methionine enkephalin 10 -6M during control conditions, after FPI and after FPI pretreated with SODCAT, respectively). Methionine enkephalin-induced dilation was associated with increased cerebrospinal fluid cyclic guanosine monophosphate and these biochemical changes were likewise blunted by FPI and partially restored by SODCAT (342 ± 12 and 640 ± 13 vs. 267 ± 6 and 321 ± 17 vs. 301 ± 9 and 504 ± 43 fmol/ml for resting conditions and 10 -6M methionine enkephalin during control, after FPI, and after FPI pretreated with SODCAT, respectively). Leucine enkephalin, an endogenous δ agonist, induced pial dilation and associated changes in cerebrospinal fluid cyclic guanosine monophosphate, which were similarly altered by FPI and partially restored by SODCAT. Dynorphin, an endogenous κ agonist, which has been shown to revert from a dilator to a constrictor after FPI, was restored to a vasodilator by SODCAT (18 ± 1, -11 ± 4, and 17 ± 5% for dynorphin 10 -6M during control conditions, after FPI, and after FPI pretreated with SODCAT, respectively). Dynorphin-induced vasodilation was associated with a large increase in cerebrospinal fluid cyclic guanosine monophosphate, which was blunted by FPI and partially restored by SODCAT. Conclusions: These data show that superoxide anion is produced after brain injury and that opioid-induced vasodilation and cyclic guanosine monophosphate production are partially restored after brain injury in the presence of SODCAT.