Brain Advance Access published online on July 14, 2008
Brain, doi:10.1093/brain/awn150
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Supra- and sub-baseline phosphocreatine recovery in developing brain after transient hypoxia-ischaemia: relation to baseline energetics, insult severity and outcome
1Centre for Perinatal Brain Research, Institute for Women's Health, 86-96 Chenies Mews, WC1E 6HX, London, UK, 2Center for Developmental & Cognitive Neuroscience, Department of Pediatrics & Child Health, Kurume University School of Medicine, 67 Asahimachi, Kurume, Fukuoka, 830-0011 Japan and 3Department of Medical Physics & Bio-engineering, University College London Hospitals NHS Foundation Trust, Ground Floor Rosenheim Building, 25 Grafton Way, London, WC1E 6DB, UK
Correspondence to:
Dr Osuke Iwata, Center for Developmental & Cognitive Neuroscience, Department of Pediatrics & Child Health, Kurume University School of Medicine, 67 Asahimachi, Kurume, Fukuoka 830-0011, Japan. E-mail: o.iwata{at}orbix.uk.net
Following hypoxia-ischaemia (HI), an early biomarker of insult severity is desirable to target neuroprotective therapies to patients most likely to benefit; currently there are no biomarkers within the ‘latent phase’ period before the establishment of secondary energy failure. Brief transient phosphocreatine (PCr) recovery overshoot (measured absolutely or relative to nucleotide triphosphate, NTP) following HI has been observed in cardiac and skeletal muscle; its significance however is unclear. To investigate cerebral PCr recovery levels after HI in relation to (i) baseline metabolism, (ii) insult severity, (iii) energy metabolism at recovery and (iv) subsequent metabolic derangement, cerebral NTP, PCr and inorganic phosphate (relative to the exchangeable high-energy phosphate pool) were measured serially in an in vivo model of perinatal asphyxial encephalopathy using phosphorus-31 magnetic resonance spectroscopy. Measures were compared either in all piglets or between 3 subgroups with no (n = 5, favourable outcome), moderate (n = 8, intermediate outcome) or severe (n = 5, unfavourable outcome) secondary energy failure at 24 h after HI. Maximum NTP, PCr and inorganic phosphate recoveries were observed 2–8 h after HI. Following resuscitation, in subjects with favourable outcome PCr recovered to higher than its baseline level (overshoot); in subjects with unfavourable outcome maximum PCr recovery was lower than baseline and lower than in subjects with favourable and intermediate outcomes. Recovery PCr correlated linearly and negatively with both acute insult severity and baseline PCr/NTP. These results suggest that recovery metabolism 2–8 h after HI may provide an early biomarker of injury severity. PCr recovery overshoot in the developing brain may indicate a protective response to HI leading to cell recovery, survival and protection against subsequent stress. In addition, baseline cerebral metabolism (PCr/NTP) may identify vulnerable infants prior to invasive surgery.
Key Words: hypoxia-ischaemia; MRS; brain protection; energy substrates
Abbreviations: 31P, phosphorus-31; MRS, magnetic resonance spectroscopy; HI, hypoxia-ischaemia; PCr, phosphocreatine; NTP, nucleotide triphosphate; SE, standard error; Pi, inorganic phosphate; EPP, exchangeable high-energy phosphate pool
Received January 22, 2008. Revised June 11, 2008. Accepted June 16, 2008.
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