31P NMR spectroscopy of perinatal hypoxic-ischemic brain damage: a model to evaluate neuroprotective drugs in immature rats.
Cerebral energy metabolism can be measured non-invasively in unanesthetized neonatal rats with 31P NMR spectroscopy. Using this technique, serial changes in high energy phosphates were determined from the right cerebral hemispheres of 7 day postnatal rat pups during a hypoxic-ischemic insult known to produce focal brain injury. During 3 h of hypoxia-ischemia the concentration of ATP dropped to 33 +/- 8% of prehypoxic (baseline) levels, phosphocreatine (PCr)/Pi decreased from 1.5 +/- 0.51 to 0.16 +/- 0.06, while pH decreased nominally by 0.2 units. After 2.5 h of recovery in air, ATP returned to 75 +/- 10% of baseline levels, PCr/Pi rose to 1.1 +/- 0.28, and pH returned to its normal value of 7.16 +/- 0.06. This model was used to test the efficacy of the adenosine deaminase inhibitor, 2-deoxycoformycin (DCF) as a potential neuroprotective drug. The data for the drug- and saline-treated populations were analyzed by integrating ATP and Pi/PCr levels over specific time intervals, expressing it relative to baseline levels, and modeling it with cubic splines. Pretreatment with 500 micrograms/kg DCF shows a small, but statistically significant, preservation of both ATP and phosphorylation potential during hypoxia and initial recovery. Brain water content (edema) at 42 h recovery was apparently associated with both mean ATP and mean Pi/PCr in the last 2 h of hypoxia-ischemia. When ATP fell below 70% of baseline, brain edema was evident at 42 h of recovery. This methodology is suitable for extension to human infants.
Williams
G D
GD
Department of Radiology (Center for NMR Research), Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, Hershey 17033.
Palmer
C
C
Roberts
R L
RL
Heitjan
D F
DF
Smith
M B
MB
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D000833:Animals, Suckling / Q000378:metabolism*; D001238:Asphyxia Neonatorum; D001921:Brain / Q000378:metabolism*; D002545:Brain Ischemia / Q000188:drug therapy / Q000378:metabolism*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004734:Energy Metabolism / Q000187:drug effects; D006801:Humans; D000860:Hypoxia / Q000188:drug therapy / Q000378:metabolism*; D007231:Infant, Newborn; D009682:Magnetic Resonance Spectroscopy; D015649:Pentostatin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D010725:Phosphocreatine / Q000378:metabolism*; D010759:Phosphorus Isotopes; D051381:Rats; D011919:Rats, Inbred Strains / Q000378:metabolism
D010759:Phosphorus Isotopes; D010725:Phosphocreatine; D015649:Pentostatin; D000255:Adenosine Triphosphate