Elucidating the Mechanism of Action of the Novel Remyelination Therapy Nefiracetam

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Title: Elucidating the Mechanism of Action of the Novel Remyelination Therapy Nefiracetam
Authors: Mc Donnell, Lisa
Permanent link: http://hdl.handle.net/10197/13023
Date: 2022
Online since: 2022-08-02T12:04:21Z
Abstract: Multiple sclerosis (MS) is a progressive neurodegenerative disorder which occurs when autoreactive T-lymphocytes infiltrate the central nervous system (CNS) and damage the oligodendrocytes responsible for maintaining the myelin sheath. Initially, the damage is repaired through the activation of a repair process called remyelination. However, as the disease progresses, remyelination begins to fail leaving the denuded axons vulnerable to damage and subsequent degeneration. The accumulating loss of chronically demyelinated axons causes a steady decline in neuronal activity, resulting in progressive disability. Current therapies target the immune component of MS but do not address the remyelination deficits underlying the disease progression. Thus, there is a need for therapies which actively encourage remyelination to improve treatment outcomes. Our group has found that the nootropic nefiracetam accelerates remyelination in vitro and in vivo. Moreover, in the experimental autoimmune encephalomyelitis (EAE) model, the gold standard model of MS, nefiracetam reduces white matter lesions in the spinal cord and, when used together with an immunosuppressant, restores normal motor function. In vitro studies with oligodendrocyte precursor cells (OPC) found that nefiracetam modulates key phases of remyelination, including OPC migration. Microarray analysis of corpus callosal tissue taken from the in vivo cuprizone model of demyelination highlighted several genes and pathways which may be central to nefiracetam’s effect on remyelination. In particular, the data implicated the regulation of glutamate signalling. Indeed, calcium-imaging studies with OPCs found that nefiracetam modulates glutamate receptor signalling in these cells. The aim of this thesis was to further elucidate the mechanism underlying nefiracetam-mediated acceleration of remyelination. We provide further evidence for the modulation of glutamate pathways by nefiracetam in OPCs. Notably, we found that the regulation of glutamate signalling is linked to its ability to accelerate OPC migration. Furthermore, RNA sequencing analysis of the cortex of cuprizone mice revealed additional pathways regulated by nefiracetam which may be relevant to its mechanism of action, including those related to immune cell migration, inflammation and extracellular matrix organisation. We found that nefiracetam directly modulates monocyte, macrophage and microglial signalling. To date, our in vitro studies exploring the mechanism of action of nefiracetam have predominantly focused on OPCs. As such, another aim was to explore the effect of nefiracetam on cells other than OPCs. We found that nefiracetam reduces the secretion of the pro-inflammatory cytokine TNF-a from macrophages and microglia. Nefiracetam also downregulates the expression of CD14, a toll-like receptor co-receptor that mediates pro-inflammatory signalling, in monocytes and macrophages. Furthermore, nefiracetam alters the expression of several matrix metalloproteinases known to be dysregulated in MS in macrophages. Overall, these results suggest that nefiracetam may also alter immune cell signalling within lesions to modulate remyelination. Finally, we identified two serum-based proteins which could be developed as a companion diagnostic for monitoring nefiracetam’s therapeutic effect. A barrier to the development of remyelination therapies is the lack of biomarkers which are specific and sensitive for myelin repair. The identification of biomarkers which reflect changes in myelin would assist in assessing the therapeutic efficacy of nefiracetam in subsequent clinical trials. Analysis of the serum of EAE mice detected changes in ceruloplasmin and Ig kappa chain V-II region 17S29.1 in response to nefiracetam. Interestingly, these proteins were dysregulated by the model before being normalised by nefiracetam; thus, they warrant further investigation as biomarkers of remyelination and/or nefiracetam’s therapeutic effect.
Type of material: Doctoral Thesis
Publisher: University College Dublin. School of Biomolecular and Biomedical Science
Qualification Name: Ph.D.
Copyright (published version): 2022 the Author
Keywords: MSDemyelinationRemyelinationTherapy
Language: en
Status of Item: Peer reviewed
This item is made available under a Creative Commons License: https://creativecommons.org/licenses/by-nc-nd/3.0/ie/
Appears in Collections:Biomolecular and Biomedical Science Theses

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