Oxidative metabolism, apoptosis and perinatal brain injury

Perinatal hypoxic-ischaemic injury (HII) is a significant cause of neurodev elopmental impairment and disability. Studies employing P-31 magnetic reson ance spectroscopy to measure phosphorus metabolites in situ in the brains o f newborn infants and animals have demonstrated that transient hypoxia-isch aemia leads to a delayed disruption in cerebral energy metabolism, the magn itude of which correlates with the subsequent neurodevelopmental impairment , Prominent among the biochemical features of HII is the loss of cellular ATP , resulting in increased intracellular Na+ and Ca2+, and decreased intracel lular K+. These ionic imbalances, together with a breakdown in cellular def ence systems following HII, can contribute to oxidative stress with a net i ncrease in reactive oxygen species, Subsequent damage to lipids, proteins, and DNA and inactivation of key cellular enzymes leads ultimately to cell d eath, Although the precise mechanisms of neuronal loss are unclear, it is now cle ar both apoptosis and necrosis are the significant components of cell death following HII. A number of different factors influence whether a cell will undergo apoptosis or necrosis, including the stage of development, cell ty pe, severity of mitochondrial injury and the availability of ATP for apopto tic execution, This review will focus on some pathological mechanisms of cell death in whi ch there is a disruption to oxidative metabolism, The first sections will d iscuss the process of damage to oxidative metabolism, covering the data col lected both from human infants and from animal models. Following sections w ill deal with the molecular mechanisms that may underlie cerebral energy fa ilure and cell death in this form of brain injury, with a particular emphas is on the role of apoptosis and mitochondria.