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Cerebral haemodynamics and the role of nitric oxide production following transient cerebral ischaemia in the developing brain

Marks, Kyla-Anna; (1997) Cerebral haemodynamics and the role of nitric oxide production following transient cerebral ischaemia in the developing brain. Doctoral thesis (M.D), UCL (University College London). Green open access

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Abstract

Birth asphyxia is associated with mortality and long-term neurodevelopmental sequelae in the survivors. The clinical features of hypoxic-ischaemic encephalopathy are well recognised in the days following resuscitation and reflect the pathophysiological processes that are occurring. There is substantial evidence from asphyxiated infants and animal models of perinatal hypoxia- ischaemia that cerebral injury during and following ischaemia is biphasic: early and delayed. Many neurons recover from the early ischaemic insult, but succumb later by a cascade of processes that culminate in delayed derangements in cerebral energetics. An understanding of the mechanisms that precede and accompany delayed cerebral injury is critical to the management of perinatal hypoxia ischaemia. In this thesis, some of the mechanisms implicated were investigated. The changes in cerebral perfusion and oxygenation were investigated in the fetal sheep preparation of severe transient cerebral ischaemia, in which a biphasic increase in cortical impedance (CI) reflects the presence of cytotoxic oedema. Near infrared spectroscopy (NIRS) was employed to measure continuously changes in oxyhaemoglobin (HbO2), deoxyhaemoglobin (Hb), and their sum total cerebral haemoglobin (tHb), and oxidised cytochrome oxidase (CytO2). There was an early and delayed increase in [tHb], and a progressive fall in [CytO2]. The delayed increase in [tHb] preceded and accompanied the delayed increase in CI. The extent of these changes related to histological outcome. Nitric oxide (NO), an ubiquitous gas generated from L-arginine by several isoforms of the enzyme NO synthase (NOS) produces neuronal death in cell culture through the production of highly potent oxidants, in particular peroxynitrite; but as a potent vasodilator has also been shown to improve cerebral perfusion following cerebral ischaemia. The role of NO was examined by first demonstrating the presence of NOS isoforms in the ischaemic fetal sheep brain using immunohistochemical techniques. Next, the effect of NOS inhibition on the delayed increase in cerebral perfusion following transient cerebral ischaemia was investigated using LG-nitro-L-arginine. NOS inhibition attenuated the delayed increase in cerebral perfusion and was associated with an increase in the extent of cerebral injury. In summary, by combining the technique of MRS with those measuring CI in an animal model of perinatal cerebral ischaemia, the changes in cerebral perfusion and oxygenation were temporally related to the development of delayed cerebral injury. Further study of the role of NO revealed important information on the pathogenesis of hypoxic-ischaemic brain injury.

Type: Thesis (Doctoral)
Qualification: M.D
Title: Cerebral haemodynamics and the role of nitric oxide production following transient cerebral ischaemia in the developing brain
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Biological sciences
URI: https://discovery.ucl.ac.uk/id/eprint/10103623
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