reduced lupus-like cognitive dysfunction and neuroinflammation in preclinical models by restoring autophagy signaling.
Evidence
This animal and cell study tested paeoniflorin in imiquimod-induced C57BL/6J lupus-model mice and LPS-injured HT22 hippocampal neuronal cells.
Caveat
The findings are limited to short-course mouse and cell models, so they do not establish human efficacy or clinical safety.
Simplified
PURPOSE: This research was designed to systematically assess the neuroprotective efficacy of 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 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.
Key numbers
20, 60, and 100 mg/kg
Decrease in autoantibody levels
Dosages of administered to mice with .
100 mg/kg
Improvement in cognitive function
Effective dosage of for cognitive improvement in behavioral tests.
TNF-α, , and IL-1β
Reduction in pro-inflammatory cytokines
Cytokines measured in the hippocampal parenchyma post-treatment.
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