Abstract
PURPOSE: This research was designed to systematically assess the neuroprotective efficacy of paeoniflorin and clarify the molecular mechanisms using two complementary models: a TLR-7 agonist imiquimod-induced murine lupus model and lipopolysaccharide-injured HT22 hippocampal neuronal cells. METHODS: A lupus-like phenotype was induced in C57BL/6J mice through topical administration of 1.25 mg 5% (w/w) imiquimod cream to the posterior auricular region three times a week for eight consecutive weeks, paeoniflorin by gavage for 7 days, and dexamethasone by intraperitoneal injection for 7 days. Animal behavioral experiments were performed at the end of the modeling. Subsequent execution of animals for biochemical analysis and histopathological examinations to evaluate the effects of paeoniflorin. RESULTS: Paeoniflorin ameliorated cognitive deficits, reduced autoantibody generation production, and hippocampal neuronal were observed in the SLE induced by the TLR-7 agonist imiquimod, accompanied by amelioration of blood-brain barrier damage. Subsequently, paeoniflorin activated autophagy and upregulated autophagy flux-related protein levels in mice with SLE induced by the TLR-7 agonist imiquimod. Interestingly, LPS-induced autophagy levels in HT22 cells were downregulated, but paeoniflorin pretreatment restored its autophagy inhibitory effect and attenuated the secretion of pro-inflammatory cytokines. Paeoniflorin activated the PI3K/AKT/mTOR pathway to restore autophagy, and using 3-methyladenine further confirmed the mechanism of paeoniflorin's role in regulating autophagy. CONCLUSION: Paeoniflorin plays a critical neuroprotective role as demonstrated in the TLR-7 agonist imiquimod-induced murine lupus model, mediated through activation of autophagic flux via modulation of the PI3K/AKT/mTOR signaling axis.