Inhibition of Cyclophilin A-Metalloproteinase-9 Pathway Alleviates the Development of Neuropathic Pain by Promoting Repair of the Blood-Spinal Cord Barrier

Yu Wang; Chenchen Wang; Xuli Yang; Kun Ni; Li Jiang; Li Xu; Qi Liu; Xuan Xu; Xiaoping Gu; Yue Liu; Zhengliang Ma

doi:10.1213/ANE.0000000000006705

Inhibition of Cyclophilin A-Metalloproteinase-9 Pathway Alleviates the Development of Neuropathic Pain by Promoting Repair of the Blood-Spinal Cord Barrier

Anesth Analg. 2023 Nov 23. doi: 10.1213/ANE.0000000000006705. Online ahead of print.

Authors

Yu Wang¹, Chenchen Wang¹, Xuli Yang¹, Kun Ni¹, Li Jiang², Li Xu¹, Qi Liu¹, Xuan Xu¹, Xiaoping Gu¹, Yue Liu¹, Zhengliang Ma¹

Affiliations

¹ From the Department of Anesthesiology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
² Department of Anesthesiology, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, China.

PMID: 38009963
DOI: 10.1213/ANE.0000000000006705

Abstract

Background: Dysfunction of the blood-spinal cord barrier (BSCB) contributes to the occurrence and development of neuropathic pain (NP). Previous studies revealed that the activation of cyclophilin A (CypA)-metalloproteinase-9 (MMP9) signaling pathway can disrupt the integrity of the blood-brain barrier (BBB) and aggravate neuroinflammatory responses. However, the roles of CypA-MMP9 signaling pathway on BSCB in NP have not been studied. This study aimed to investigate the effect of CypA on the structure and function of the BSCB and pain behaviors in mice with NP.

Methods: We first created the mouse chronic constriction injury (CCI) model, and they were then intraperitoneally injected with the CypA inhibitor cyclosporine A (CsA) or vehicle. Pain behaviors, the structure and function of the BSCB, the involvement of the CypA-MMP9 signaling pathway, microglia activation, and expression levels of proinflammatory factors in mice were examined.

Results: CCI mice presented mechanical allodynia and thermal hyperalgesia, impaired permeability of the BSCB, downregulated tight junction proteins, activated CypA-MMP9 signaling pathway, microglia activation, and upregulated proinflammatory factors, which were significantly alleviated by inhibition of CypA.

Conclusions: Collectively, the CypA-MMP9 signaling pathway is responsible for CCI-induced NP in mice by impairing the structure and function of the BSCB, and activating microglia and inflammatory responses.