Center for Basic Medical Research, Medical School of Nantong University, Nantong, 226001, Jiangsu, China.
Key Laboratory of Neuroregeneration of Jiangsu and the Ministry of Education, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, 226001, Jiangsu, China.
J Neuroinflammation. 2022 Feb 2;19(1):32. doi: 10.1186/s12974-022-02405-1.
Peripheral nerve injury (PNI) is a public health concern that results in sensory and motor disorders as well as neuropathic pain and secondary lesions. Currently, effective treatments for PNI are still limited. For example, while nerve growth factor (NGF) is widely used in the treatment of PNI to promote nerve regeneration, it also induces pain. Maresin 1 (MaR1) is an anti-inflammatory and proresolving mediator that has the potential to regenerate tissue. We determined whether MaR1 is able to promote nerve regeneration as well as alleviating neuropathic pain, and to be considered as a putative therapeutic agent for treating PNI.
PNI models were constructed with 8-week-old adult male ICR mice and treated with NGF, MaR1 or saline by local application, intrathecal injection or intraplantar injection. Behavioral analysis and muscle atrophy test were assessed after treatment. Immunofluorescence assay was performed to examine the expression of ATF-3, GFAP, IBA1, and NF200. The expression transcript levels of inflammatory factors IL1β, IL-6, and TNF-α were detected by quantitative real-time RT-PCR. AKT, ERK, mTOR, PI3K, phosphorylated AKT, phosphorylated ERK, phosphorylated mTOR, and phosphorylated PI3K levels were examined by western blot analysis. Whole-cell patch-clamp recordings were executed to detect transient receptor potential vanilloid 1 (TRPV1) currents.
MaR1 demonstrated a more robust ability to promote sensory and motor function recovery in mice after sciatic nerve crush injury than NGF. Immunohistochemistry analyses showed that the administration of MaR1 to mice with nerve crush injury reduced the number of damaged DRG neurons, promoted injured nerve regeneration and inhibited gastrocnemius muscle atrophy. Western blot analysis of ND7/23 cells cultured with MaR1 or DRG neurons collected from MaR1 treated mice revealed that MaR1 regulated neurite outgrowth through the PI3K-AKT-mTOR signaling pathway. Moreover, MaR1 dose-dependently attenuated the mechanical allodynia and thermal hyperalgesia induced by nerve injury. Consistent with the analgesic effect, MaR1 inhibited capsaicin-elicited TRPV1 currents, repressed the nerve injury-induced activation of spinal microglia and astrocytes and reduced the production of proinflammatory cytokines in the spinal cord dorsal horn in PNI mice.
Application of MaR1 to PNI mice significantly promoted nerve regeneration and alleviated neuropathic pain, suggesting that MaR1 is a promising therapeutic agent for PNI.
周围神经损伤（PNI）是一种公共健康问题，可导致感觉和运动障碍以及神经病理性疼痛和继发性损伤。目前，PNI 的有效治疗方法仍然有限。例如，神经生长因子（NGF）广泛用于 PNI 的治疗，以促进神经再生，但它也会引起疼痛。maresin 1（MaR1）是一种抗炎和促解决的介质，具有组织再生的潜力。我们确定 MaR1 是否能够促进神经再生以及缓解神经病理性疼痛，并被认为是治疗 PNI 的潜在治疗剂。
使用 8 周龄雄性 ICR 小鼠构建 PNI 模型，并通过局部应用、鞘内注射或足底内注射给予 NGF、MaR1 或生理盐水。治疗后进行行为分析和肌肉萎缩试验。通过免疫荧光分析检测 ATF-3、GFAP、IBA1 和 NF200 的表达。通过定量实时 RT-PCR 检测炎症因子 IL1β、IL-6 和 TNF-α 的表达转录水平。通过 Western blot 分析检测 AKT、ERK、mTOR、PI3K、磷酸化 AKT、磷酸化 ERK、磷酸化 mTOR 和磷酸化 PI3K 水平。执行全细胞膜片钳记录以检测瞬时受体电位香草醛 1（TRPV1）电流。
MaR1 促进坐骨神经挤压损伤后小鼠感觉和运动功能恢复的能力强于 NGF。免疫组织化学分析显示，MaR1 给药可减少损伤的 DRG 神经元数量，促进损伤神经再生并抑制比目鱼肌萎缩。用 MaR1 或 MaR1 处理的小鼠的 DRG 神经元培养的 ND7/23 细胞的 Western blot 分析表明，MaR1 通过 PI3K-AKT-mTOR 信号通路调节轴突生长。此外，MaR1 剂量依赖性地减轻神经损伤引起的机械性痛觉过敏和热痛觉过敏。与镇痛作用一致，MaR1 抑制辣椒素诱导的 TRPV1 电流，抑制脊髓小胶质细胞和星形胶质细胞的神经损伤激活，并减少 PNI 小鼠脊髓背角促炎细胞因子的产生。
MaR1 应用于 PNI 小鼠可显著促进神经再生并缓解神经病理性疼痛，表明 MaR1 是 PNI 的一种有前途的治疗剂。
