Ischaemic injury and protection of the mammalian
central white matter.
Doctoral thesis, UCL (University College London).
Ischaemic injury of the central white matter (IICWM) has been relatively little studied despite its contribution to the pathology of several neurological diseases, including stroke and vascular dementia. Research has been hampered by a lack of suitable experimental models. Here, a new model of IICWM has been developed in the rat spinal cord in vivo, and the model has been used to explore the value of agents that block voltage-gated sodium channels, or the sodium/calcium exchanger (NCX). Endothelin-1 (ET-1, a potent vasoconstrictor) was injected into the spinal cord to induce local ischaemia, and hence injury to the spinal white matter as demonstrated by blockade of axonal conduction and change of axonal morphology. The sodium channel blocking agent phenytoin was found to improve axonal conduction during the first 4.5 hours post ET-1 injection. Importantly, the protection provided by phenytoin (fosphenytoin as prodrug) persisted for at least 3 days (the longest interval studied) in animals allowed to recover from anaesthesia. The selective reverse-mode blocker of the NCX, KB-R7943 was also found to improve axonal conduction during the first 4.5 hours post ET-1 injection. Another reverse-mode blocker of the NCX, SEA0400 was also neuroprotective. Furthermore, in the longer term, KB-R7943 protected axons at 3 days post ET-1 injection. None of the study agents (phenytoin, KB-R7943 and SEA0400) diminished the severity of ET-1-induced ischaemia, revealing the effect to be a true neuroprotection, rather than an unintended diminution of the ischaemic insult. The findings are consistent with an interpretation that intracellular sodium accumulation, probably via open sodium channels, may play a role in mediating IICWM in vivo, perhaps by promoting the lethal importation of calcium ions via the reverse-mode operation of the NCX. It is concluded that partial blockade of sodium channels, or the NCX, may be effective in protecting central axons from ischaemic injury.
|Title:||Ischaemic injury and protection of the mammalian central white matter|
|Additional information:||Authorisation for digitisation not received. For further information please contact Fengfeng Bei <email@example.com> or Kenneth J. Smith <firstname.lastname@example.org>|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Neurology > IoN - Neuroinflammation|
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