Neuroprotective Effect of Isorhapontigenin (ISO) Against LPS-Induced Neurodegenerative Condition via TLR4/RAGE-Mediated p-NF-kB Activation

초록

Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by persistent neuroinflammation, oxidative imbalance, cognitive decline, A beta buildup, tau phosphorylation, and synaptic dysfunction. Despite progress in understanding AD's development, effective treatments are still limited. Isorhapontigenin (ISO), a methoxylated stilbenoid similar to resveratrol, shows neuroprotective, anti-inflammatory, and antioxidative effects. In this study, we explored ISO's therapeutic potential in a mouse model of AD-like pathology induced by LPS, focusing on TLR4/RAGE-triggered NF-kappa B signaling pathway and related neuroinflammatory responses, oxidative stress, GSK3 beta signaling, tau pathology, A beta accumulation, glial activation, and synaptic health. Western blot and immunofluorescence techniques were used to measure the levels of TLR4/RAGE signaling components, glial markers (GFAP and Iba-1), p-NF-kappa B signaling pathway activation, proinflammatory cytokines ( TNF-alpha, COX-2, and IL-1 beta), oxidative stress indicators (Nrf2 and HO-1), neurodegeneration markers (p-GSK3 beta, p-tau, and A beta), and synaptic proteins (PSD-95, SNAP-23, and SYP). Nissl staining helped assess neuronal density and structure. BV2 microglial cells were treated similarly in vitro, followed by viability tests and Apotox-Glo (TM) triplex assays, along with protein expression analysis. The levels of TLR4, RAGE, GFAP, and Iba-1 increased in the LPS-treated group, along with proinflammatory mediators, ROS, LPO, and neurodegenerative markers. Yet, ISO treatment significantly reduced their expression. Moreover, LPS lowered Nrf2 and HO-1 levels, reduced p-GSK3 beta, and decreased synaptic proteins, indicating oxidative damage and synaptic failure. ISO reversed these changes by restoring p-GSK3 beta, activating Nrf2/HO-1, and boosting synaptic protein levels, followed by behavioral improvement as evidenced by reduced escape latency and increased spontaneous alternations in the Morris water maze (MWM) and Y-maze tests. Additionally, ISO preserved neuronal and synaptic integrity and provided consistent neuroprotection in BV2 cells. Overall, these results demonstrate that ISO reduces LPS-induced AD-like pathology by activating TLR4/RAGE-driven p-NF-kappa B, decreasing neuroinflammation, enhancing Nrf2/HO-1 activity, inhibiting GSK3 beta, lowering A beta and p-Tau accumulation, preserving synaptic health, and prominent improvement in spatial memory, emphasizing its potential as an AD treatment.

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