Functional recovery in young adult and aged rats following delayed, intramuscular treatment with neurotrophin-3 after focal stroke injury.

    Student thesis: Doctoral ThesisDoctor of Philosophy


    Stroke is a currently the major cause of locomotor disability and the 3rd most common cause of death worldwide. It occurs when a region of the brain is damaged due to compromised cerebral blood flow either from a clot or rupture of a blood vessel and as a result, the affected area of the brain is unable to perform its normal functions. Stroke often leads to arm disability and neglect of the opposite side of the body, for which there is an urgent need for effective, efficient treatment. This thesis utilises an endothelin-1 model of focal ischemic stroke to evaluate functional recovery in adult and aged rats following treatment with neurotrophin-3 (NTS). Endothelin-1 produces a reduction in local blood flow to levels that produce ischemic injury when applied to areas of the brain. Due to the reproducible nature and location of this injury, we can qualitatively and quantitatively monitor any increase in forelimb sensory or motor function. NT3 is essential for the development and function of locomotor networks and clinical trials for other conditions have shown that systemic, high doses of NT3 are well tolerated. Here we show in three independent, randomised, blinded studies that NT3 reverses sensory neglect and arm disability in rats, when treatment is initiated 24 hours after stroke (a clinically-feasible time-frame). This thesis demonstrates that NT3 induces spinal and supraspinal neuroplasticity: brain imaging during forearm stimulation shows reorganisation upon treatment. Recovery was associated with neuroanatomical plasticity in the spinal cord of spared corticospinal and serotonergic pathways, which express receptors for NTS. Nerve recording during CST stimulation of both hemispheres showed that NTS enhances motor output. We find no evidence that NTS causes pain by lack of sprouting of nociceptive related fibres or no change to cold allodynia responses.
    This thesis shows that intramuscular injection of AAV-NT3 improves function in elderly rats as well as in young rats, and that intramuscular infusion of recombinant NTS protein improves function in young adult rats, even when treatment is initiated 24 hours after stroke. Furthermore, it provides additional evidence for the beneficial use of NTS following CNS insult and provides novel evidence s for the use of this therapy following an ischemic stroke.
    Date of Award1 Sept 2012
    Original languageEnglish
    Awarding Institution
    • King's College London
    SupervisorLawrence Moon (Supervisor) & Marzia Malcangio (Supervisor)

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