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Principal Supervisor: Mariya Hristova
Subsidiary Supervisor: Francesca Cordeiro
Project Summary:
Hypoxic-ischemic encephalopathy (HIE) results in cerebral tissue loss leading to lifelong disabilities like cerebral palsy, mental retardation and retinopathy, which present substantial socio-economic burden to the individual, family and healthcare system. Development of therapeutic strategies to ameliorate the severity or even prevent hypoxic-ischemic (HI) brain injury and retinopathy is of great importance. Current clinical care (controlled re-oxygenation and hypothermia) is only partially effective with >50% of treated children still developing neuro-disabilities. Our long term goal is to identify key factors mediating HI-induced brain damage and retinopathy, and to allow clinical intervention through their pharmacological inhibition alone or in combination with other agents such as stem cells or hypothermia, so to reduce the incidence of HI-induced brain injury and retinopathy.
Birth asphyxia causes severe oxidative stress (OS) due to excess calcium influx [1, 2] and hydrogen peroxide accumulation [3]. Oxygen deprivation around the time of birth down-regulates antioxidant enzymes and activates nitric oxide synthase and oxidases, thus promoting generation of reactive oxygen species (ROS) upon re-oxygenation. OS contributes to post-ischemic mitochondrial respiration impairment [4]. When the amount of ROS surpasses the scavenging capacity of the mitochondria, mitochondrial permeability transition may occur thus potentiating OS and initiating apoptosis [2, 5].
Several antioxidant strategies (melatonin, lutein, and erythropoietin) are now tested to reduce the OS and its damaging effects in neonatal HI. The aim of this project is to test different natural antioxidants in neonatal HI model in isolation or combined with hypothermia, and to assess their neuroprotective effects on brain and retinal damage following neonatal HI.
References:
- Forder JP, Tymianski M: Postsynaptic mechanisms of excitotoxicity: Involvement of postsynaptic density proteins, radicals, and oxidant molecules. Neuroscience 2009, 158:293–300
- Rocha-Ferreira E, Hristova M: Plasticity in the neonatal brain following hypoxic-ischaemic injury. Neural Plast 2016
- Lafemina MJ, Sheldon RA, Ferriero DM: Acute hypoxia-ischemia results in hydrogen peroxide accumulation in neonatal but not adult mouse brain. Pediatr Res 2006, 59:680–3
- Teshima Y, Akao M, Li RA, Chong TH, Baumgartner WA, Johnston M V, Marbán E: Mitochondrial ATP-sensitive potassium channel activation protects cerebellar granule neurons from apoptosis induced by oxidative stress. Stroke 2003, 34:1796–802
- Blomgren K, Hagberg H: Free radicals, mitochondria, and hypoxia-ischemia in the developing brain. Free Radic Biol Med 2006, 40:388–97