Pharmacological interventions in the newborn piglet in the first 24 h after hypoxia-ischemia. A hemodynamic and electrophysiological perspective.
The purpose of this study was to investigate whether combined inhibition of neuronal and inducible nitric oxide synthase (NOS) by 2-iminobiotin, free radical scavenging by allopurinol, and non-protein-bound iron chelation with deferoxamine improved cerebral oxygenation, electrocortical brain activity, and brain energy status during the first 24 h after hypoxia-ischemia (HI) in the newborn piglet. Forty-three newborn piglets were subjected to 1 h of severe HI by occluding both carotid arteries and phosphorous magnetic resonance spectroscopy ((31)P-MRS)-guided hypoxia, whereas five served as sham-operated controls. Upon reperfusion, piglets received vehicle (n=12), 2-iminobiotin (n=11), allopurinol (n=10), or deferoxamine (n=10). Cerebral oxygenation was recorded with near-infrared spectrophotometry (NIRS), electrocortical brain activity was assessed with amplitude-integrated EEG (aEEG), and cerebral energy status with (31)P-MRS. The oxygenated hemoglobin (HbO(2)) and total hemoglobin (tHb) were significantly increased in vehicle-treated piglets compared with 2-iminobiotin-treated and deferoxamine-treated piglets. No change in deoxygenated Hb (HHb) was demonstrated over time. The aEEG was significantly preserved in 2-iminobiotin- and deferoxamine-treated piglets compared with vehicle-treated piglets. Allopurinol treatment was not as effective as 2-iminobiotin treatment after HI. Phosphocreatine/inorganic phosphate ratios (PCr/P(i)) were significantly decreased for vehicle-treated piglets at 24 h post-HI, whereas 2-iminobiotin, allopurinol, and deferoxamine prevented the development of secondary energy failure. We speculate that the beneficial effects, especially of 2-iminobiotin, but also of deferoxamine, are due to reduced peroxynitrite-mediated oxidation.
Peeters-Scholte
Cacha
C
Department of Neonatology, Wilhelmina Children's Hospital, PO Box 85090, 3508 AB Utrecht, The Netherlands.
van den Tweel
Evelyn
E
Ioroi
Tomoaki
T
Post
Ilka
I
Braun
Kees
K
Veldhuis
Wouter
W
Nicolay
Klaas
K
Groenendaal
Floris
F
van Bel
Frank
F
D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001710:Biotin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects* / Q000503:physiopathology*; D003676:Deferoxamine / Q000494:pharmacology; D004569:Electroencephalography; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D006454:Hemoglobins / Q000378:metabolism*; D020925:Hypoxia-Ischemia, Brain / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology*; D007502:Iron Chelating Agents / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D010761:Phosphorus Radioisotopes; D013053:Spectrophotometry; D013552:Swine; D013997:Time Factors
D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D006454:Hemoglobins; D007502:Iron Chelating Agents; D010761:Phosphorus Radioisotopes; D000493:Allopurinol; D001710:Biotin; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; C028072:2-iminobiotin; D003676:Deferoxamine