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A neuroprotective strategy to reduce acute and chronic disability, and slowly progressive central nervous system atrophy in a new model of multiple sclerosis

Aguzzi, Erika Antuanette; (2021) A neuroprotective strategy to reduce acute and chronic disability, and slowly progressive central nervous system atrophy in a new model of multiple sclerosis. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Multiple sclerosis (MS) is a neuroinflammatory demyelinating disease of the central nervous system that causes severe neurological deficits, starting in young adulthood. Early in the course of disease the deficits usually manifest as temporary ‘attacks’, or relapses, but later in the disease they manifest as a slowly progressive, irreversible worsening. Relapses are primarily due to impaired neuro/axonal function in the short term, whereas the progressive deficits are principally due to the slow accumulation of neuro/axonal degeneration and tissue atrophy. Regarding therapy, current evidence suggests that the acute neurological deficit can arise from inflammation, even in the absence of demyelination, although the mechanism(s) remain uncertain. Equally uncertain, is the cause of the slowly progressive degeneration and atrophy. Current disease-modifying treatments for MS can reduce the frequency of relapses, but, when they occur, they can still be severe. Steroids can shorten the duration of relapses, but any benefit regarding disability in the long-term is negligible. There are no very effective therapies to prevent progressive disease, and developing a therapy is hampered by the lack of an accepted animal model. Here, we introduce a new animal model of MS which causes severe neurological deficits with a time course similar to that in MS. Thus, acute deficits arise in young adulthood from CNS inflammation in the absence of demyelination, and chronic, progressive deficits accumulate throughout life due to neurodegeneration and atrophy. In MS, damage to the grey matter, particularly that of the spinal cord, correlates more precisely with the progression of disability than damage to the white matter, and here we describe a new animal model that leads to post-inflammatory, slowly progressive disability resulting from damage to the spinal grey matter. We aim to use the model to explore the mechanisms responsible for both acute and chronic deficit, and to identify a rational and effective strategy for neuroprotection. The lesion is induced in the rat spinal cord by the unilateral, intraspinal injection of pro- inflammatory lipopolysaccharide (LPS, or saline control) into the ventral horn at the 13th thoracic vertebra. The lesion consists of a period of acute inflammation, characterized by oedema and local tissue hypoxia, which peaks at 48 hours post-injection, subsiding within 4 days. The inflammatory lesion is accompanied by the expression of a neurological deficit, namely hind limb and tail weakness, both of which subside within 4 days. Interestingly, the acute inflammatory lesion is gradually replaced over the lifetime by a slowly progressive degeneration of the previously inflamed grey matter, resembling the slow and progressive grey matter degeneration in MS. The progressive degeneration is accompanied by the return of the neurological deficit which gradually worsens over the following months, surpassing the disability observed in the acute stage of the disease, and modelling the slow, relentless accumulation of disability seen in progressive MS. We have used the histological characteristics of the acute inflammatory lesion, including the evidence of hypoxia, to devise a potential therapeutic strategy based on maintaining adequate tissue oxygenation. Two therapies have been explored, namely increasing respiratory oxygen, and use of the vasodilating agent nimodipine. The therapies have been applied acutely, just during the initial period of inflammatory hypoxia. Both therapies were effective in reducing the acute disability, indicating a potential therapy for relapses in MS. Remarkably, both therapies were also effective in reducing both the slowly progressive accumulation of permanent disability and the accompanying atrophy, indicating a therapeutic opportunity to avoid the severity of progressive MS. These observations illuminate the important question in MS of whether the degeneration and atrophy that accompany progressive disease are due to contemporaneous events, or whether they are the delayed consequences of events occurring long before, in the acute inflammatory lesion. In summary, we introduce a new animal model of MS that illuminates the mechanisms contributing to both acute and chronic disability and use the model to identify therapies effective in reducing both acute and chronic disability, and the underlying pathology. The therapies are safe and inexpensive, and are suitable for testing in clinical trial in MS.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: A neuroprotective strategy to reduce acute and chronic disability, and slowly progressive central nervous system atrophy in a new model of multiple sclerosis
Event: UCL
Language: English
Additional information: Copyright © The Author 2021. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
URI: https://discovery.ucl.ac.uk/id/eprint/10120070
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