Paeoniflorin modulates AGEs/RAGE/P38MAPK/ERK/mTOR autophagy pathway to improve cognitive dysfunction in MRL/lpr mice.

Objective: The objective of this study was to investigate the therapeutic effects of paeoniflorin (PA) on cognitive impairment and to elucidate its potential mechanisms in MRL/lpr mice, a model of systemic lupus erythematosus-associated cognitive dysfunction.

Method: Cognitive performance and behavioral responses were assessed using a comprehensive battery of tests, including the Morris water maze, the Novel object recognition test, and the Y maze. Neuropathological changes in the hippocampal regions were visualized through Nissl, HE and Immunohistochemistry staining. Protein expression levels of receptor for advanced glycation end-products (RAGE) and LC3B were quantified by immunofluorescence, while the ultrastructure of autophagic organelles was examined using transmission electron microscopy (TEM). Inflammatory cytokines, namely tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6) were quantified in both serum and hippocampal homogenates by enzyme-linked immunosorbent assay (ELISA). The hippocampal expression of advanced glycation end-products (AGEs), RAGE, p62, Beclin-1, and key proteins involved in the mitogen-activated protein kinase (MAPK) pathways, including p38MAPK, ERK, and mTOR were analyzed by Western blotting.

Result: Paeoniflorin ameliorates cognitive dysfunction, neuronal damage, pro-inflammatory cytokine production in MRL/lpr mice. Paeoniflorin suppresses RAGE and autophagy levels and P38 MAPK/ERK/mTOR signaling pathway activation in the hippocampus of MRL/lpr mice.

Conclusion: Paeoniflorin may exert its neuroprotective effects by modulating the AGEs/RAGE/P38MAPK/ERK/mTOR autophagy signaling pathway.