Neurotrophin-3 as a promoter of spinal cord plasticity in a distal middle cerebral artery occlusion model of stroke

Student thesis: Doctoral ThesisDoctor of Philosophy

Abstract

Ischaemic stroke is a cause of locomotor disability and, in combination with other cardiovascular diseases, is the 3rd most common cause of death worldwide. It occurs when a region of the brain is deprived of oxygen and metabolites through occlusion of a blood vessel in the brain and as a result, the affected area of the brain is unable to perform normal functions. Stroke often leads to disability and neglect of the opposite side of the body, which requires effective, efficient treatments. This project used a model of large, permanent, ischaemic stroke to measure functional recovery in adult and elderly rats following treatment with neurotrophin-3. To do this, blood flow to the sensorimotor cortex was reduced through the use of a distal, permanent occlusion of the middle cerebral artery with the addition of common carotid artery occlusions, for a three-vessel occlusion model. The model was reproducible, permitting assessment of forelimb sensory or motor function. Additionally, the model was well tolerated in elderly rats, and indeed, produced more sustained deficits from which to measure functional repair. However, in most cases, there was substantial spontaneous recovery in adult rats, and NT3 treatment did not lead to any detectable benefit against this background of recovery. Neurotrophin-3 is essential during development, particularly for spinal reflexes involved in movement. Clinical trials using NT3 in other conditions have shown that systemic, high doses are well tolerated. The studies in this thesis show that neurotrophin-3 produces modest effects on behavioural recovery, in addition to reducing hyper-reflexia when treatment is initiated subcutaneously 24 hours after stroke, which is a feasible timeframe for delayed treatment in human beings. One objective of this project was to also identify recovery mechanisms behind improvement observed with or without neurotrophin-3 treatment. One way to do this was with the use of functional MRI techniques and measurement of spontaneous recovery networks of activity. From these data it was possible to identify brain regions important in spontaneous recovery. In addition, mRNA regulation was assessed with RNASeq of cervical dorsal root ganglia to determine changes in gene expression associated with neurotrophin-3 treatment after stroke. Genes were identified that could be involved in this mechanism, and could be important for future work in this field. This work shows that subcutaneous delivery of neurotrophin-3 improves function in elderly rats, when treatment is initiated 24 hours after a large ischaemic stroke. This adds to the existing literature on the use of this therapy following an ischaemic stroke.
Date of Award1 Mar 2017
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorLawrence Moon (Supervisor)

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