Phosphodiesterase 2A as a Therapeutic Target for Relieving Mechanical Allodynia and Modulating Microglial Polarization in Neuropathic Pain Models Following Spinal Cord Injury

Wen-Jie Yang; Jie Han; Zhen-Xin Cao; Lei Yang; Jun-Nan Wang; Tao Sun

doi:10.1021/acschemneuro.5c00169

Phosphodiesterase 2A as a Therapeutic Target for Relieving Mechanical Allodynia and Modulating Microglial Polarization in Neuropathic Pain Models Following Spinal Cord Injury

ACS Chem Neurosci. 2025 Jun 28. doi: 10.1021/acschemneuro.5c00169. Online ahead of print.

Authors

Wen-Jie Yang¹, Jie Han², Zhen-Xin Cao³, Lei Yang⁴, Jun-Nan Wang⁵, Tao Sun⁵

Affiliations

¹ Department of Anesthesiology and Perioperative Medicine, Shandong Public Health Clinical Center, Jinan 250102 Shandong, China.
² Department of Anesthesiology, Qilu Hospital of Shandong University, Jinan 250012 Shandong, China.
³ Department of Anesthesiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021 Shandong, China.
⁴ Department of Pain Management, Weihai Municipal Hospital,Shandong University, Weihai, Shandong 264200, China.
⁵ Department of Pain Management, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021 Shandong, China.

PMID: 40580118
DOI: 10.1021/acschemneuro.5c00169

Abstract

Spinal cord injury (SCI) is a severe clinical condition often accompanied by multiple complications, with neuropathic pain (NP) being one of the most persistent and difficult conditions to treat. The underlying mechanisms of NP remain unclear, and effective clinical treatments are lacking. Some studies suggest that phosphodiesterase 2A (PDE2A) may contribute to the development of NP. This study aims to investigate the role of PDE2A inhibitor Bay 60-7550 in alleviating NP in a rat model of SCI. Male Sprague-Dawley rats were randomly allocated into four groups: sham, SCI, SCI + Bay 60-7550, and SCI + vehicle. Mechanical thresholds were assessed using the von Frey test from 1 day prior to surgery through postoperative day 21. PDE2A expression in the spinal cord was quantified via qRT-PCR, Western blotting, and immunohistochemistry. Microglial polarization (M1/M2) was analyzed using flow cytometry and qRT-PCR. Downstream biomarkers, including IL-6, IL-1β, IL-10, TGF-β, CCL2, and CCL3, were also quantified via qRT-PCR. Additionally, enzyme-linked immunosorbent assay (ELISA) was performed to determine the levels of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Intrathecal administration of the PDE2A inhibitor Bay 60-7550 significantly alleviated mechanical allodynia in rats following SCI. PDE2A expression was notably elevated in the spinal dorsal horn post-SCI, an effect that was suppressed by Bay 60-7550 treatment. In addition, Bay 60-7550 administration reduced the expression of pro-inflammatory cytokines (IL-6, IL-1β), increased anti-inflammatory cytokines (IL-10, TGF-β), and decreased mRNA levels of CCL2 and CCL3 in the spinal cord. Consistently, treatment with Bay 60-7550 elevated the levels of cGMP and cAMP in the spinal cord and shifted microglial polarization by increasing the proportion of M2-type cells while reducing M1-type cells in SCI rats. Inhibiting PDE2A overexpression may mitigate the progression of NP in rats following SCI by modulating microglial polarization. Therefore, PDE2A represents a promising therapeutic target for the management of neuropathic pain after SCI.

Keywords: microglia; neuropathic pain; phosphodiesterase 2A; polarization; spinal cord injury.