Abstract
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.
Highlights
Nerve damage resulting from a peripheral nerve injury (PNI) can be highly debilitating to a patient causing life-long loss or disturbance to end-organ function [1]
This review explores how the Rho/Rho-associated kinase (ROCK) pathway could be modulated in PNI, in particular via the peroxisome proliferator-activated receptor gamma (PPAR-γ)
This review has focused on targeting PPAR-γ in the peripheral nervous system (PNS), there are studies that have explored targeting PPAR-γ in the central nervous system (CNS) [76,77,78,79]
Summary
Nerve damage resulting from a peripheral nerve injury (PNI) can be highly debilitating to a patient causing life-long loss or disturbance to end-organ function [1]. The current treatment for PNI is surgical intervention, with a primary repair between the proximal and distal stump being the gold standard therapy for transection injuries with no tension, and microsurgical autografts for long gap repair [5] They do not address the complexity of cellular and molecular events occurring along the entire length of the nerve [5] and adequate functional improvement is not always achieved, there is a clear clinical need to find new therapeutic approaches. Unlike the central nervous system (CNS) the peripheral nervous system (PNS) does have some innate regenerative capacity, the rate of this regeneration is remarkably slow (~1 mm/day) [8,9] This delay increases the likelihood of Schwann cell degeneration or senescence in denervated distal nerve segments leading to a loss of their supportive role towards the regenerating axon and poor functional outcomes [10,11]. The study of PPAR-γ in other nervous system disorders is important; this review focuses on peripheral nerve regeneration and functional recovery
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