LXR agonist improves peripheral neuropathy and modifies PNS immune cells in aged mice

Abstract

Background Peripheral 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. Methods 21-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. Results Treatment 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. Conclusions These 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.

Age‐Associated Changes in Knee Osteoarthritis, Pain‐Related Behaviors, and Dorsal Root Ganglia Immunophenotyping of Male and Female Mice

“…This result is consistent with a previous report in a partial meniscectomy model of OA, in which young female mice developed pain-like behavior at the same time as young male mice despite reduced chondropathy in the female mice compared to the male mice (32). Peripheral neuropathy may also partially explain increased mechanical sensitivity with age; however, previous studies have reported that the decline in epidermal innervation occurs in C57BL/6 mice older than the mice chosen for this study (33,34). There are many types of immune cells involved in neuroimmune cross-talk and function (11), including dendritic cells, macrophages, and T cells.…”

Osteoarthritis Pain in Old Mice Aggravates Neuroinflammation and Frailty: The Positive Effect of Morphine Treatment

“…While the presence of neuroinflammation in the aged brain has been largely confirmed [ 55 ], less is known about cytokines and neuroinflammatory markers in the peripheral nervous system and spinal cord during aging. In healthy old mice, we observed that TNFα was higher in all tissue, in agreement with what was reported by other authors [ 56 , 57 , 58 ], and confirming the existence of an age-associated proinflammatory phenotype. This state is more evident in the spinal cord, where microglial-related markers CD68 and CD11b are upregulated, sustaining the presence of primed microglia in aging [ 15 , 59 , 60 ].…”

The Pathological Links between Adiposity and the Carpal Tunnel Syndrome

“…The same group found also that activation of LXR can reduce pain in diet-induced obesity. In the presence of a powerful agonist of LXR, the lipid content of the macrophages from peripheral nerves was reduced with a consequent decline in inflammation and the slower progression of the nerve lesions [ 81 ]. All the above suggest that LXR could explain symptoms of obesity-associated CTS, and should be investigated for their therapeutically potential.…”