ShengHui Decoction mitigates oxidative stress and neuroinflammation in AlCl3-induced AD zebrafish via activating Nrf2/HO-1 and inhibiting NF-κB signaling pathway

Ethnopharmacological relevance ShengHui decoction (SHD), a traditional Chinese herbal formula, has long been used clinically to mitigate Alzheimer’s disease (AD), demonstrating significant efficacy in alleviating cognitive impairment. However, its molecular mechanisms remain insufficiently understood. Aim of the study To clarify the effects of SHD on oxidative stress–related markers and inflammatory cytokines in an aluminum chloride (AlCl 3 )-induced zebrafish model of AD and as well as uncover its underlying mechanisms in alleviating oxidative stress and neuroinflammation.. Materials and methods Ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS) was employed to identify the bioactive constituents of SHD. Behavioral tests and histopathological analyses were then conducted to evaluate the effects of SHD (0.74, 1.48, and 2.96 mg/mL) on apoptosis and amyloid-beta (Aβ) deposition in an AlCl 3 -induced AD zebrafish model. Biochemical assays and enzyme-linked immunosorbent assay were used to quantify superoxide dismutase (SOD), malondialdehyde (MDA), glutathione peroxidase (GSH-Px), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), IL-1 beta (IL-1β), and IL-18.. Western blot analysis was performed to determine the protein expression of nuclear factor erythroid 2–related factor 2 (Nrf2), heme oxygenase-1 (HO-1), NAD(P)H quinone dehydrogenase 1 (NQO1), nuclear factor-kappa B p65 (NF-κB p65), phosphorylated NF-κB p65 (p–NF-κB p65), and NOD-like receptor family pyrin domain containing 3 (NLRP3). Results UPLC–MS/MS profiling identified phenolic acids, saponins, lignans/coumarins, flavonoids, and aliphatic alcohols as the main constituents of SHD. SHD significantly ameliorated cognitive deficits and histopathological abnormalities in AlCl 3 -induced zebrafish. Moreover, SHD attenuated oxidative stress by upregulating Nrf2, HO-1, and NQO1 expression, while downregulating AlCl 3 -induced levels of NF-κB p65, p–NF-κB p65, NLRP3 and pro-inflammatory factors. Conclusions SHD effectively improved cognitive performance and reduced AD-like pathological lesions in AlCl 3 -induced zebrafish. Importantly, SHD exhibits both antioxidant and anti-inflammatory activities by activating the Nrf2/HO-1 axis and inhibiting NF-κB signaling, thereby alleviating oxidative stress and neuroinflammatory responses in AD. These findings provide experimental evidence supporting SHD as a potential therapeutic agent for AD, and substantiate the traditional Chinese medicine principle of tonifying the kidney and replenishing essence in the treatment of AD.