Imaging the effects of inflammation and impulse activity on normal and demyelinated nerve tissue

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Although nerve fibres are clearly damaged by inflammation in a range of disorders such as multiple sclerosis and Guillain-Barre syndrome, little is known about the underlying mechanisms. Largely circumstantial evidence suggests that inflammation impairs mitochondrial metabolism and causes intra-axonal ion imbalance, but these effects are not accessible to direct study using existing morphological and electrophysiological techniques. In pilot studies, we have combined our expertise in multivariable confocal imaging of live cells (Duchen), and the generation of experimental inflammatory and demyelinating lesions (Smith), to examine in real time the effects of inflammation and demyelination on the physiology of inflamed intact peripheral nerves. Having demonstrated the feasibility of this unique approach, we propose to apply it to understand how inflammation and inflammatory mediators may impair mitochondrial metabolism, and cause ion imbalance in neural tissue, notably in normal, demyelinated and remyelinated axons, their ensheathing glial cells, and the invading inflammatory cells. In particular we will explore the mechanisms underlying our finding that impulse activity in axons exposed to nitric oxide can cause axonal degeneration. We have hypothesised that this combination results in axonal sodium loading which leads to calcium overload through the reverse activity of the sodium/calcium exchanger. The impact of such overload may be amplified by nitric oxide-mediated loss of mitochondrial function resulting in irreversible axonal injury. The hypothesis can now be tested in live tissue, thereby not only illuminating the mechanisms involved in axonal degeneration, but also potentially indicating novel strategies for axonal protection in inflammatory disorders of the nervous system.