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Investigating small molecule therapeutics to improve regeneration and functional recovery following peripheral nerve damage

Rayner, Melissa Lucy Doreen; (2019) Investigating small molecule therapeutics to improve regeneration and functional recovery following peripheral nerve damage. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Peripheral nerve injury (PNI) can be debilitating and results in loss of function, coupled with slow neuron regeneration. Microsurgical treatments remain the gold standard therapy, with no drug therapies currently available. Effective pharmacological treatments could potentially maintain neuronal viability, encourage axonal growth, improve axonal specificity to targets and reduce neuropathic pain. Some drugs and targets have been identified but challenges remain with clinical translation. Advancements in understanding the molecular and cellular events occurring following PNI identifies signalling pathways that could be targeted with drug therapies. The failure in drug therapies reaching PNI clinical trials may be due to the lack of effective in vitro and in vivo pre-clinical models. This study developed and applied models to be used as effective screening tools to address this need. Many compounds demonstrated positive effects on neurite growth when screened in a 3D-engineered co-culture model. NSAIDs (ibuprofen and sulindac sulfide) demonstrated beneficial effects and were studied further in two injury models demonstrating increased axonal growth and improved function. Local controlled-release drug delivery systems have become more attractive because of the drawbacks in conventional drug treatments. This study investigated drug release from various biomaterials in order to obtain an optimal material for implantation and sustained drug delivery. Suitable biomaterials were implanted in vivo to deliver ibuprofen or sulindac sulfide. Both drugs demonstrated beneficial effects on axonal regeneration and functional recovery. Embedding drugs into biocompatible and bio-degradable materials provides effective delivery systems for future translation. Studying NSAIDs revealed a previously unreported relationship between PPAR-γ affinity and regeneration. A NSAID derivative demonstrated the greatest effects on neurite growth in vitro at lower doses than other compounds tested. In summary, this work has identified therapeutic targets to aid the development of novel compounds, as well as, drug repurposing, and effective tools for the pre-clinical screening of these drugs.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Investigating small molecule therapeutics to improve regeneration and functional recovery following peripheral nerve damage
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2019. 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
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 Institute of Prion Diseases
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Institute of Prion Diseases > UCL Institute of Prion Diseases Support
URI: https://discovery.ucl.ac.uk/id/eprint/10070085
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