Cerium Oxide Nanoparticles Alleviate Neuropathic Pain by Modulating Macrophage Polarization in a Rat SCI Model

Abstract

Dexiang Ban,1,2,* Hao Yu,1,2,* Zhenyang Xiang,1,2,* Chao Li,1,2 Peng Yu,1,2 Jianhao Wang,1,2 Yang Liu1,2 1Department of Orthopaedic, Tianjin Medical University General Hospital, Tianjin, 300052, People’s Republic of China; 2International Science and Technology Cooperation Base of Spinal Cord Injury, Tianjin Key Laboratory of Spine and Spinal Cord Injury, Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin, 300052, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yang Liu, Department of Orthopaedic, Tianjin Medical University General Hospital, Anshan Road No. 154, Heping District, Tianjin, 300052, People’s Republic of China, Email [email protected]: Chronic neuropathic pain (NP) frequently occurs after spinal cord injury (SCI) but lacks effective therapeutic options in the clinic. Numerous evidence indicates the involvement of macrophages activation in the NP, and the modulation of macrophages is promising for NP treatment. In this study, we introduce Cerium oxide nanoparticles (CONPs) and aim to investigate whether it can relieve the NP by modulating macrophage polarization.Methods: CONPs were prepared using the hydrothermal method. In vitro, different concentrations of CONPs were used to cultivate macrophages (RAW 264.7). In vivo, the analgesic effect of CONPs was investigated in a contusive rat SCI model. Mechanical paw withdrawal threshold (PWT) and thermal paw withdrawal latency (PWL) were tested to evaluate pain behaviors. Immunofluorescence staining and real-time quantitative polymerase chain reaction were applied to assess macrophage phenotypes.Results: The synthesized CONPs were 6.8 ± 0.5 nm in size, presenting a cubic morphology. Live/dead staining showed that the relatively low concentrations of CONPs (less than 800 μg/mL) displayed good biocompatibility with macrophages. Intrathecal injection of CONPs could significantly increase the mechanical PWT and thermal PWL of SCI rats. Molecular experiments results showed the expression of M2 macrophage-related markers (CD206, Arg-1, IL-10) were significantly increased, while that of M1 macrophage-related markers (CD86, TNF-α, iNOS) were downregulated after CONPs treatment.Conclusion: Our study suggests that CONPs can relive the NP following SCI by promoting M2 macrophages polarization, which provides a novel insight for the treatment of SCI induced NP.Keywords: cerium oxide nanoparticles, spinal cord injury, neuropathic pain, neuroimmune, macrophages polarization

Keywords

• cerium oxide nanoparticles
• spinal cord injury
• neuropathic pain
• neuroimmune
• macrophages polarization