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Repurposing Small Molecules to Target PPAR-γ as New Therapies for Peripheral Nerve Injuries

The slow rate of neuronal regeneration that follows peripheral nerve repair results in poor recovery, particularly where reinnervation of muscles is delayed, leading to atrophy and permanent loss of function. There is a clear clinical need to develop drug treatments that can accelerate nerve regener...

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Autores principales: Rayner, Melissa L. D., Healy, Jess, Phillips, James B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8465622/
https://www.ncbi.nlm.nih.gov/pubmed/34572514
http://dx.doi.org/10.3390/biom11091301
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author Rayner, Melissa L. D.
Healy, Jess
Phillips, James B.
author_facet Rayner, Melissa L. D.
Healy, Jess
Phillips, James B.
author_sort Rayner, Melissa L. D.
collection PubMed
description The slow rate of neuronal regeneration that follows peripheral nerve repair results in poor recovery, particularly where reinnervation of muscles is delayed, leading to atrophy and permanent loss of function. There is a clear clinical need to develop drug treatments that can accelerate nerve regeneration safely, restoring connections before the target tissues deteriorate irreversibly. The identification that the Rho/Rho-associated kinase (ROCK) pathway acts to limit neuronal growth rate is a promising advancement towards the development of drugs. Targeting Rho or ROCK directly can act to suppress the activity of this pathway; however, the pathway can also be modulated through the activation of upstream receptors; one of particular interest being peroxisome proliferator-activated receptor gamma (PPAR-γ). The connection between the PPAR-γ receptor and the Rho/ROCK pathway is the suppression of the conversion of inactive guanosine diphosphate (GDP)-Rho to active guanosine triphosphate GTP-Rho, resulting in the suppression of Rho/ROCK activity. PPAR-γ is known for its role in cellular metabolism that leads to cell growth and differentiation. However, more recently there has been a growing interest in targeting PPAR-γ in peripheral nerve injury (PNI). The localisation and expression of PPAR-γ in neural cells following a PNI has been reported and further in vitro and in vivo studies have shown that delivering PPAR-γ agonists following injury promotes nerve regeneration, leading to improvements in functional recovery. This review explores the potential of repurposing PPAR-γ agonists to treat PNI and their prospective translation to the clinic.
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spelling pubmed-84656222021-09-27 Repurposing Small Molecules to Target PPAR-γ as New Therapies for Peripheral Nerve Injuries Rayner, Melissa L. D. Healy, Jess Phillips, James B. Biomolecules Review The slow rate of neuronal regeneration that follows peripheral nerve repair results in poor recovery, particularly where reinnervation of muscles is delayed, leading to atrophy and permanent loss of function. There is a clear clinical need to develop drug treatments that can accelerate nerve regeneration safely, restoring connections before the target tissues deteriorate irreversibly. The identification that the Rho/Rho-associated kinase (ROCK) pathway acts to limit neuronal growth rate is a promising advancement towards the development of drugs. Targeting Rho or ROCK directly can act to suppress the activity of this pathway; however, the pathway can also be modulated through the activation of upstream receptors; one of particular interest being peroxisome proliferator-activated receptor gamma (PPAR-γ). The connection between the PPAR-γ receptor and the Rho/ROCK pathway is the suppression of the conversion of inactive guanosine diphosphate (GDP)-Rho to active guanosine triphosphate GTP-Rho, resulting in the suppression of Rho/ROCK activity. PPAR-γ is known for its role in cellular metabolism that leads to cell growth and differentiation. However, more recently there has been a growing interest in targeting PPAR-γ in peripheral nerve injury (PNI). The localisation and expression of PPAR-γ in neural cells following a PNI has been reported and further in vitro and in vivo studies have shown that delivering PPAR-γ agonists following injury promotes nerve regeneration, leading to improvements in functional recovery. This review explores the potential of repurposing PPAR-γ agonists to treat PNI and their prospective translation to the clinic. MDPI 2021-09-01 /pmc/articles/PMC8465622/ /pubmed/34572514 http://dx.doi.org/10.3390/biom11091301 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Rayner, Melissa L. D.
Healy, Jess
Phillips, James B.
Repurposing Small Molecules to Target PPAR-γ as New Therapies for Peripheral Nerve Injuries
title Repurposing Small Molecules to Target PPAR-γ as New Therapies for Peripheral Nerve Injuries
title_full Repurposing Small Molecules to Target PPAR-γ as New Therapies for Peripheral Nerve Injuries
title_fullStr Repurposing Small Molecules to Target PPAR-γ as New Therapies for Peripheral Nerve Injuries
title_full_unstemmed Repurposing Small Molecules to Target PPAR-γ as New Therapies for Peripheral Nerve Injuries
title_short Repurposing Small Molecules to Target PPAR-γ as New Therapies for Peripheral Nerve Injuries
title_sort repurposing small molecules to target ppar-γ as new therapies for peripheral nerve injuries
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8465622/
https://www.ncbi.nlm.nih.gov/pubmed/34572514
http://dx.doi.org/10.3390/biom11091301
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