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Antenatal brain injury and prospects for neuroprotection

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thesis
posted on 13.01.2017, 01:19 by Saglam, Burcu
There is a growing body of evidence to suggest that intrauterine infection contributes to the pathogenesis of fetal brain injury. Infants born from pregnancies that have been complicated by intrauterine infection are at increased risk of neurological damage such as periventricular leukomalacia, the main aetiology behind cerebral palsy. Epidemiological and clinical studies have been useful in postulating a causal link between infection and hypoxia and brain injury but the mechanisms that translate infection to brain injury have not been well-understood, thus limiting the strategies for intervention. Recently, studies using animal models have assisted in our understanding of the mechanisms by which this injury can occur, providing a basis on which therapeutic strategies can be developed. Experimentally, endotoxins including lipopolysaccharide (LPS) have been used to mimic the effects of bacteria. LPS is a component of the cell wall in Gram-negative bacteria and is a potent inflammatory agent that initiates components of the innate immune response, including increased concentrations of pro-inflammatory mediators and cardiovascular changes ultimately resulting in systemic hypoxia. Extensive studies show that the antenatal administration of LPS to pregnant animals or the fetuses from different species results in neurological damage to the offspring. The first study of this thesis was conducted to establish a novel model of studying intrauterine infection-inflammation by utilising twin-pregnant ewes. In this model, low-dose LPS (100 ng/kg) was administered daily for 3 days directly into the circulation of one twin while the co-twin was administered with saline, and served as an internal control. While the saline-administered co-twins remained unaffected, the LPS-administered co-twins elicited the well-documented acute-phase responses to LPS, including transient hypoxia, acidaemia, hypercapnia, increased levels of pro-inflammatory mediators (cytokines, prostaglandins), markers of oxidative stress (MDA), cardiovascular changes and diffuse brain injury (including demyelination, astrocyte activation, BBB breakdown, lipid peroxidation and cell death).

History

Principal supervisor

Euan Wallace

Year of Award

2010

Department, School or Centre

Obstetrics and Gynaecology

Campus location

Australia

Course

Doctor of Philosophy

Degree Type

DOCTORATE

Faculty

Faculty of Medicine Nursing and Health Sciences