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Title: Neurodegeneration induced by general anaesthetics in the developing brain : mechanism and prevention
Author: Shu, Yi
ISNI:       0000 0004 2713 3225
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2011
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In the early development of brain, there is an important period called the synaptogenesis period (also known as the brain growth-spurt period) which occurs in different mammalian species at different times relative to birth. In rodents, it begins a day or two before birth and ends 2 weeks after birth, whereas in humans it starts at the beginning of the third trimester and ends several years after birth. This is a critical period during neural development as neurons are establishing communications with their environment and other neurons to ensure that they develop and function appropriately; disruption at this stage by toxic agents including anaesthetic agents may compromise the normal neuronal development of the central nervous system. During the course of my PhD study, I found that inhalational agents isoflurane (ISO) alone or in combination with nitrous oxide (N2O) caused a wide spread neurodegeneration in the brain including the cingulated cortex, hippocampus, substantia nigra and basal forebrain in postnatal day 7 Sprague-Dawley rat pups. In those brain regions, the cells involved included glutamatergic, GABAergic and dopaminergic neurons. However, the cholinergic neurons in the basal forebrain were spared from anaesthesia-induced neuroapoptosis. My studies also showed that the neurodegeneration was not only confined to the higher centres, but was also observed in the spinal cord. These data indicated that the anaesthetics studied acted at molecular level and induced neuronal apoptosis by activating the intrinsic apoptotic pathway. It has been well documented that preconditioning with hypoxia or other interventions including pharmacological agents can protect against subsequent brain injury induced by hypoxia/ischemia. However, my data showed that hypoxic preconditioning exacerbated N2O+ISO-induced neonatal neurodegeneration, while xenon preconditioning protected against anaesthetics-induced neuroapoptosis and subsequent neurocognitve impairment. Most studies in this field including my own study described above are more relevant to the clinical situation where neonates are managed in the critical care unit, i.e. in the absence of surgery. For this reason, I implemented another experimental setting to mimic the clinical situation in the operating room where neonates receiving anaesthetic drugs are also subjected to nociceptive surgical stimuli. Therefore, in another experiment, rat pups in addition to receiving anaesthetic drugs were also subjected to standardised nociceptive stimuli. The results suggested that nociceptive stimuli enhanced neuronal apoptosis induced by anaesthetic drugs in the brain and the spinal cord and consequently impaired neurological function. Were the data reported in my thesis to be extrapolated to the clinical setting, it would have very important implications for the clinical management of paediatric population receiving general anaesthesia.
Supervisor: Ma, Daqing ; Maze, Mervyn Sponsor: Overseas Research Student Award ; Deputy Rector Scholarship ; Kowk Foundation
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral