Regulation of microglial polarization via notch signaling pathway by intrathecal administration of tanshinone IIA-PLGA sustained-release microspheres to promote neurological recovery after spinal cord injury

Secondary injuries following spinal cord injury (SCI) are closely associated with the activation of microglia and neuroinflammation. Tanshinone IIA (TIIA), a traditional Chinese medicine monomer with anti-inflammatory and antioxidant properties, has shown neuroprotective effects after SCI. Our previous studies indicated that TIIA exhibited inhibitory effects on early inflammatory responses and microglial activation after SCI, but its underlying mechanisms remained unclear. Due to TIIA’s poor water solubility and low bioavailability, its sulfonated derivative, sodium tanshinone IIA sulfonate (STS), was developed to address these issues. However, STS still faced challenges in crossing the blood-spinal cord barrier and exhibited poor stability. In this study, we utilized an emulsion electrospinning technique to load TIIA into poly (lactic-co-glycolic) acid (PLGA) microspheres, creating TIIA-loaded PLGA sustained-release microspheres (TIIA-PLGA SRMs). A single injection of an adequate amount of TIIA-PLGA SRMs was administered into the subarachnoid space through the atlanto-occipital membrane, and its regulatory effects on microglia after SCI were compared with a traditional continuous intraperitoneal injection of STS. Our experimental results demonstrated that intrathecal injection of TIIA-PLGA SRMs effectively promoted the transition of microglial phenotypes from M1 to M2 in the early stages in rats after SCI, alleviating neuroinflammation and improving motor dysfunction and neuropathic pain after SCI. Furthermore, the efficacy of TIIA-PLGA SRMs was superior to the traditional continuous intraperitoneal injection of STS. Additionally, our experiments suggested that the mechanism underlying TIIA-PLGA SRMs in regulating microglial polarization after SCI may be associated with the inhibition of the Notch signaling pathway.