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FIGURE 2. Simplified Schematic of Brain Damage in Neonatal HI, approximately at the level of primary somatosensory and motor cortex. The two main patterns of injury, partially overlapping in patients, are shown separately for this schematic (adapted from Budday et al., 2014). Two colours have been used to show that many neonatal HI injuries consist of a centre of necrosis (black) and a penumbra of less acutely damaged tissue (gray). The exact location of these sites will vary depending on the nature of the injury. Black/gray areas represent the potential site of lesions, although those shown in this schematic are severe yet unilateral. (A) Primary basal-ganglia and thalamus injury pattern. (B) Primary watershed cortex and underlying white matter injury. Injury can primarily occur either to cortical gray matter or subcortical white matter depending on the nature of the injury. Severity also varies substantially between patients and within the brain of individuals. These have been documented in many human structural imaging studies (Barkovich et al., 1995; Cowan et al., 2003; Kaufman et al., 2003; Rutherford et al., 2004; Miller et al., 2005; Chau et al., 2008, 2012, 2013; Li et al., 2009).
FIGURE 3. Simplified Schematic of Major Molecular Injury Cascades involved in Neonatal HI. A vast number of molecules contribute to neonatal HI injury in the brain and all of these have been investigated in this disorder. These molecular targets can largely be split into the following three cascades. (A) Excitotoxicity (adapted from Vandenberg and Ryan, 2013) Ca2+ = calcium ion, Mg2+ = magnesium ion AMPA-R = α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor, NMDA-R = N-methyl-D-aspartate receptor. (B) Oxidative Stress (adapted from -analysis/oxidative-stress/). For simplicity, only free radicals are shown and physiological pathway substrates have been omitted. NADPH + Nicotinamide Adenine Dinucleotide Phosphate Hydrogen, O2 = oxygen, O2- = negatively-charged oxygen free radiccal, H2O2 = hydrogen peroxide, ROS = ROS1 receptor tyrosine kinase encoded by the ROS1 gene, Blc = B cell leukaemia protein, ER = endoplasmic reticulum, DNA = deoxyribose nucleic acid. (C) Inflammation (adapted from Santiago et al., 2014). BBB = blood brain barrier, IL-6 = interleukin 6, IL-1B = interleukin 1 beta, TNFalpha = tumour necrosis factor alpha, NO = nitric oxide.
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