Cell and Molecular Physiology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, 60153, USA.
Departement of Internal Medicine, Division of Cardiology, Loyola University Medical Center, Maywood, IL, 60153, USA.
J Neuroinflammation. 2022 Feb 26;19(1):57. doi: 10.1186/s12974-022-02423-z.
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.
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.
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.
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.
周围神经病变是老年人常见且进行性的疾病，会干扰日常活动。寻找有效的治疗方法来治疗或延缓这种与年龄相关的神经退行性变非常重要。通过减少泡沫状巨噬细胞来沉默巨噬细胞，可显著改善老年小鼠周围神经的与年龄相关的退行性变化。我们之前证明，用强效激动剂 GW3965 激活胆固醇传感器肝 X 受体 (LXR) 可减轻饮食诱导肥胖模型中的疼痛。我们试图测试 LXR 激活是否可以改善老年小鼠的周围神经病变。
21 月龄的小鼠用 GW3965（25mg/Kg 体重）处理 3 个月，同时测试机械性痛觉过敏和热痛觉过敏。在终止时，使用流式细胞术对背根神经节和坐骨神经细胞进行分析。对免疫细胞进行分选和分析胆固醇和基因表达。分析来自爪子皮肤的神经纤维。还评估了一些人类的腓肠神经。使用 t 检验或单因素方差分析进行比较。
GW3965 的治疗可预防老年小鼠机械性超敏反应和热痛觉过敏随时间的发展。我们还观察到坐骨神经巨噬细胞的极化和胆固醇含量发生变化，同时皮肤神经纤维显著增加。
这些结果表明，LXR 的激活可能通过改变神经-免疫细胞的脂质含量来延缓 PNS 衰老。我们的研究为治疗或延缓衰老过程中的周围神经病变提供了新的潜在靶点。
