Neuropathic pain, a debilitating nerve injury-induced condition, remains a significant clinical challenge. This study evaluates the effect of histone deacetylase 6 (HDAC6) inhibition in a spared nerve injury (SNI) mouse model. Systemic administration of the selective HDAC6 inhibitor ACY-1215 (20 mg/kg/day, 14 days), alleviated SNI-induced pain in mice of both sexes. ACY-1215 increased acetylated signal transducer and activator of transcription 3 (Ac-STAT3) and reduced phosphorylated STAT3 (p-STAT3) in the lumbar spinal cord of SNI mice. HDAC6 and p-STAT3 were expressed in spinal dorsal horn neurons, and SNI-enhanced HDAC6/STAT3 interaction was reversed by ACY-1215. Neuronal STAT3 overexpression induced pain hypersensitivity and elevated p-STAT3, tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β), effects suppressed by ACY-1215. Cytokine profiling identified CC-chemokine ligand 7 (CCL7) as a key downstream effector of the HDAC6/STAT3 axis, with ACY-1215 attenuating SNI-induced CCL7 upregulation. HDAC6 knockdown in neurons reduced p-STAT3, while HDAC6 or STAT3 knockdown diminished CCL7 production. These findings demonstrate that ACY-1215 mitigates neuropathic pain by modulating STAT3 acetylation/phosphorylation and suppressing HDAC6/STAT3-driven CCL7 and cytokine release. This study underscores the role of the HDAC6/STAT3/CCL7 signaling axis in neuropathic pain and highlights the therapeutic potential of HDAC6 inhibitors for pain management.
Chronic inflammatory pain (CIP) poses a significant medical challenge, with current pharmacological treatments often associated with considerable side effects. The identification of effective therapeutic targets and the development of novel agents remain major hurdles. Exploring neuroimmune interactions and utilizing network pharmacology to uncover compounds capable of simultaneously modulating pain and inflammation presents a promising strategy. In this study, the therapeutic efficacy, potential targets, and underlying mechanisms of isoliquiritigenin (ISL) were investigated in a mouse model of CIP induced by complete Freund's adjuvant (CFA) paw pad injection. Single-dose ISL (20 or 60 mg/kg) attenuated CFA-induced hypersensitivity in an acute screening experiment, after which we investigated sustained efficacy using ISL (10 mg/kg) once daily for 7 days. ISL treatment significantly reduced paw swelling, mechanical allodynia, and thermal hyperalgesia. Additionally, ISL lowered the levels of IL-6, TNF-α, and VCAM-1 in both dorsal root ganglia (DRG) and skin tissues, along with a significant reduction in ERK phosphorylation. Network pharmacology analysis and molecular docking suggested CCR2 as a potential target of ISL. Further investigation revealed that ISL attenuated CCL7-induced CCR2 signaling activation. To validate the involvement of CCR2, siRNA-mediated knockdown of CCR2 was performed via DRG injection. This intervention suppressed ISL's analgesic and anti-inflammatory effects in CIP mice and CCL7 paw pad injection-induced pain and inflammation. Moreover, activation of ERK using tert-butylhydroquinone in CCR2 knockdown mice exacerbated CFA-induced inflammatory responses. These findings suggest that ISL alleviates CIP by targeting the CCL7/CCR2 axis and suppressing ERK-mediated inflammation.
危险品化学品经营许可证（带存储）