Paeoniflorin attenuates neuropathic Pain-associated depression by modulating microglial M1 polarization and...

Neuropathic pain (NP) is increasingly recognized as a chronic stressor contributing to the development of depressive comorbidities through neuroimmune dysregulation. However, the mechanistic interplay between microglial polarization states and kynurenine pathway (KP) metabolism in this process remains incompletely understood. The present study investigated the therapeutic potential of paeoniflorin (PF), a bioactive monoterpene glycoside, in alleviating NP-associated depression by modulating the M1 microglial M1 polarization-kynurenine 3-monooxygenase (KMO) pathway. Using a chronic constriction injury (CCI) rat model, we demonstrate that CCI induces sustained hippocampal microglial M1 polarization, accompanied by upregulation of KMO, ultimately leading to quinolinic acid (QUIN)-mediated neuronal apoptosis and depression-like behaviors. Systemic administration of PF reduced microglial M1 polarization and KMO enzymatic activity, consequently decreasing QUIN levels and alleviating hippocampal neuronal damage. The pharmacological blockade of M1 polarization (minocycline) or KMO activity (Ro 61-8048) replicated PF's antidepressant effects, thereby supporting the critical role of this neuroimmune-metabolic pathway. In vitro experiments revealed that PF inhibited the LPS/IFN-γ-induced M1 polarization in BV-2 cells by downregulating the signal transducer and activator of transcription 1 (STAT1). These findings identify PF as a multi-target modulator of neuroimmune-metabolic crosstalk, suggesting a novel therapeutic approach for NP-associated depression through disruption of the STAT1-M1-KMO pathway.