The effect of antioxidative combination therapy on post hypoxic-ischemic perfusion, metabolism, and electrical activity of the newborn brain.
Reoxygenation and reperfusion after severe hypoxia and ischemia (HI) contribute substantially to birth asphyxia-related brain injury. Excess production of free radicals via metabolization of arachidonic acid, xanthine oxidase, and non-protein-bound iron play an important role. Cerebral reperfusion injury is characterized by a decrease in perfusion, oxygen consumption, and electrical activity of the brain. Reduction of free radical production may attenuate these features. We therefore induced severe HI in 35 newborn lambs, and upon reperfusion the lambs received a placebo [control (CONT), n = 7], the cyclooxygenase inhibitor indomethacin (INDO, 0.3 mg/kg/i.v., n = 7), the xanthine oxidase inhibitor allopurinol (ALLO, 20 mg/kg/i.v., n = 7), the iron chelator deferoxamine (DFO, 2.5 mg/kg/i.v., n = 7), or a combination of these drugs (COMB, n = 7). In each group changes (%) from pre-HI values were investigated for brain perfusion [measured by carotid artery flow (Qcar, mL/min)], (relative) cerebral O2 metabolism (CMR(O2)), and electrocortical brain activity (ECBA, microV) at 15, 60, 120, and 180 min post-HI. Qcar decreased significantly at 120 and 180 min post-HI in CONT (p < 0.05), but not in INDO, ALLO, DFO, and COMB groups. CMR(O2) decreased significantly in CONT at 60 min post-HI (p < 0.05), remained stable in DFO and INDO, and was significantly higher in ALLO and COMB (p < 0.05) at 120 and 180 min post-HI. ECBA was significantly lower in CONT during the whole post-HI period (p < 0.05), ECBA in INDO and COMB were significantly decreased at 60 and 120 min post-HI (p < 0.05), but recovered afterward, whereas DFO and ALLO remained stable during the post-HI period. In conclusion preservation of Qcar and CMR(O2), and recovery of ECBA occurred after treatment with INDO, ALLO, and DFO; combination of these drugs did not have an additional positive effect.
Department of Pediatrics, Leiden University Hospital, The Netherlands.
M
M
Shadid
R
R
Moison
P
P
Steendijk
L
L
Hiltermann
H M
HM
Berger
F
F
van Bel
D000493:Allopurinol / Q000627:therapeutic use*; D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000627:therapeutic use*; D001238:Asphyxia Neonatorum / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology*; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism*; D002545:Brain Ischemia / Q000378:metabolism / Q000503:physiopathology*; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use; D003676:Deferoxamine / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D004562:Electrocardiography / Q000187:drug effects; D006801:Humans; D007213:Indomethacin / Q000627:therapeutic use*; D007231:Infant, Newborn; D007502:Iron Chelating Agents / Q000627:therapeutic use; D010101:Oxygen Consumption / Q000187:drug effects; D012016:Reference Values; D015424:Reperfusion; D012756:Sheep; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors
D000975:Antioxidants; D016861:Cyclooxygenase Inhibitors; D007502:Iron Chelating Agents; D000493:Allopurinol; D014969:Xanthine Oxidase; D003676:Deferoxamine; D007213:Indomethacin