Neurodegeneration induced by general anaesthetics in the developing brain: Mechanism and prevention
Author(s)
Shu, Yi
Type
Thesis
Abstract
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.
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.
Date Issued
2010-12
Date Awarded
2011-12
Copyright Statement
Attribution NoDerivatives 4.0 International Licence (CC BY-ND)
Advisor
Ma, Daqing
Maze, Mervyn
Sponsor
Oversea Research Student Award, Deputy Rector Scholarship and Kowk Foundation
Creator
Shu, Yi
Publisher Department
Surgery and Cancer
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)