Glucocorticoid prevention of neonatal hypoxic-ischemic damage: role of hyperglycemia and antioxidant enzymes.
Recently, we observed that pre-treatment of neonatal rats with dexamethasone prevents brain damage associated with cerebral hypoxia-ischemia (unilateral carotid occlusion + 3 h hypoxia). Presently, we investigate whether hyperglycemia or an induction of endogenous free radical scavengers explains dexamethasone's neuroprotective effect. Pathological damage was examined in rats maintained hyperglycemic during hypoxia-ischemia by the repeated administration of 10% glucose (10 ml/kg, i.p.) at 0, 1, 2 and 3 h of hypoxia (n = 14) and this damage was compared to that in control (n = 15) or dexamethasone (0.1 mg/kg, i.p., n = 15) treated animals. Despite similar elevations in blood glucose at the end of hypoxia, glucose treated animals had greater damage than dexamethasone treated animals and both of these groups had less damage than controls (volumes of damage of approx. 30.9 +/- 10, 3.4 +/- 2.3 and 60.4 +/- 7.1% of the hemisphere, respectively; P < 0.0001). Anti-oxidant enzyme activities were measured within brains of animals treated with dexamethasone or vehicle (n = 44). Activities of the enzymes catalase, glutathione peroxidase and CuZn- or Mn-superoxide dismutase were similar in both treatment groups, with or without exposure to hypoxia-ischemia. Thus, an induction of antioxidant enzymes does not explain dexamethasone's effects whereas the relative hyperglycemia associated with glucocorticoid treatment may contribute partially. Neither account fully for dexamethasone's protective effect suggesting an additional glucocorticoid mediated mechanism must be involved.
Tuor
U I
UI
Division of Neonatology, Hospital for Sick Children Research Institute, Toronto, Ont., Canada.
Simone
C S
CS
Arellano
R
R
Tanswell
K
K
Post
M
M
D000818:Animals; D000831:Animals, Newborn; D001786:Blood Glucose / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D002545:Brain Ischemia / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D002374:Catalase / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology*; D005260:Female; D016166:Free Radical Scavengers; D005947:Glucose / Q000494:pharmacology; D005979:Glutathione Peroxidase / Q000378:metabolism*; D006943:Hyperglycemia / Q000503:physiopathology*; D000860:Hypoxia / Q000473:pathology / Q000503:physiopathology*; D007527:Isoenzymes / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013482:Superoxide Dismutase / Q000378:metabolism*
D001786:Blood Glucose; D016166:Free Radical Scavengers; D007527:Isoenzymes; D003907:Dexamethasone; D002374:Catalase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D005947:Glucose