Abstract
BackgroundPeripheral neuropathy is a common and progressive disorder in the elderly that interferes with daily activities. It is of importance to find efficient treatments to treat or delay this age-related neurodegeneration. Silencing macrophages by reducing foamy macrophages showed significant improvement of age-related degenerative changes in peripheral nerves of aged mice. We previously demonstrated that activation of the cholesterol sensor Liver X receptor (LXR) with the potent agonist, GW3965, alleviates pain in a diet-induced obesity model. We sought to test whether LXR activation may improve neuropathy in aged mice.Methods21-month-old mice were treated with GW3965 (25 mg/Kg body weight) for 3 months while testing for mechanical allodynia and thermal hyperalgesia. At termination, flow cytometry was used to profile dorsal root ganglia and sciatic nerve cells. Immune cells were sorted and analyzed for cholesterol and gene expression. Nerve fibers of the skin from the paws were analyzed. Some human sural nerves were also evaluated. Comparisons were made using either t test or one-way ANOVA.ResultsTreatment with GW3965 prevented the development of mechanical hypersensitivity and thermal hyperalgesia over time in aged mice. We also observed change in polarization and cholesterol content of sciatic nerve macrophages accompanied by a significant increase in nerve fibers of the skin.ConclusionsThese results suggest that activation of the LXR may delay the PNS aging by modifying nerve-immune cell lipid content. Our study provides new potential targets to treat or delay neuropathy during aging.
Highlights
Peripheral neuropathy is a common and progressive disorder in the elderly that interferes with daily activities
We observed a significant decrease in both Intraepidermal nerve fibers (IENF) (Fig. 2C, E) (n = 4–6/group) and Sub-basal nerve plexus (SBNP) (Fig. 2D, E) (n = 4–6/group) density in 24 month-old mice compared to 6-month-old mice demonstrating that aging led to distal sensory neuropathy
There was not a significant change in proportions of any macrophage phenotype in the dorsal root ganglia (DRG) (Fig. 5A) (n = 8/group), we did observe a significant increase in percentage of both pro-inflammatory (CD45 + IAIE +) M1 macrophages and anti-inflammatory (CD45 + Cluster of dif‐ ferentiation 206 (CD206) +) M2 macrophages in the sciatic nerve (SN) of mice treated with GW3965 (Fig. 5B) (n = 8/group)
Summary
Peripheral neuropathy is a common and progressive disorder in the elderly that interferes with daily activities. Silenc‐ ing macrophages by reducing foamy macrophages showed significant improvement of age-related degenerative changes in peripheral nerves of aged mice. Aging-related peripheral neuropathy and neuropathic pain contributes significantly to decreased quality of life in the elderly. The peripheral nervous system (PNS) undergoes pathophysiological changes that are observed in people suffering with neuropathy, such. For example in Guillain–Barre syndrome, macrophages penetrate myelinating fibers at the nodes of Ranvier and promote axonal damage [25], while endoneurial macrophages are activated by Schwann cells and damage nerve fibers in a model of charcot-marie-tooth [26]. Targeting macrophages as an approach to treating age-related neuropathy is suggested by a report that macrophage silencing, achieved by blocking a cytokine receptor, reduced endoneurial foamy macrophages and significantly improved age-related degenerative changes in peripheral nerves of 24-month-old mice [6]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
