龙胆酸通过靶向氧化应激、神经炎症和蛋白质聚集，在实验性阿尔茨海默病中提供多模式神经保护
Gentisic acid confers multimodal neuroprotection in experimental Alzheimer's disease by targeting oxidative stress, neuroinflammation, and protein aggregation.
摘要(中文译文)
阿尔茨海默病（AD）是一种进行性神经退行性疾病，以认知功能下降为特征，并与氧化应激、神经炎症、胆碱能功能障碍以及β-淀粉样蛋白（Aβ）和过度磷酸化tau蛋白（p-tau）的积累相关。鉴于AD的多因素性质，具有多靶点药理特性的植物化学物质日益受到治疗关注。龙胆酸（GA；2,5-二羟基苯甲酸）具有已确立的抗氧化和抗炎活性；然而，其在AD中的潜在相关性尚未得到全面评估。本研究采用体外和体内整合实验模型，探讨了龙胆酸对阿尔茨海默病样病理的神经保护潜力。本研究开展了一项临床前实验研究，结合了基于细胞的实验以及由氯化铝（AlCl₃）和D-半乳糖（D-Gal）诱导的AD样神经退行性变大鼠模型。采用PAMPA-BBB实验评估了GA的血脑屏障（BBB）通透性。在暴露于AlCl₃的SH-SY5Y细胞中检测了神经保护作用。在体内，Wistar大鼠接受AlCl₃和D-Gal以诱导认知和生化改变，随后给予口服GA治疗。采用旷场实验、Morris水迷宫、新物体识别、高架十字迷宫和Y迷宫等行为学范式评估空间学习、识别记忆和焦虑样行为。对氧化应激标志物、抗氧化酶、乙酰胆碱酯酶活性、单胺能神经递质、脑源性神经营养因子（BDNF）、促炎细胞因子、β-淀粉样蛋白和过度磷酸化tau蛋白水平进行了定量检测。对海马和皮质区域进行了组织病理学评估。GA表现出充分的血脑屏障通透性，并在SH-SY5Y细胞中对AlCl₃诱导的细胞毒性具有浓度依赖性的保护作用。在大鼠模型中，GA（10、30和100 mg/kg，口服（p.o.））改善了认知表现并减轻了焦虑样行为。GA治疗降低了脂质过氧化（丙二醛），恢复了抗氧化防御（超氧化物歧化酶、过氧化氢酶和还原型谷胱甘肽），抑制了乙酰胆碱酯酶活性，并使单胺能神经递质（5-羟色胺和多巴胺）正常化。GA还升高了BDNF水平并抑制了促炎细胞因子（肿瘤坏死因子-α和白细胞介素-1β）。值得注意的是，GA减少了脑内Aβ和p-tau的积累，并保护了海马和皮质的组织结构。在AD实验模型中，龙胆酸发挥了多模式神经保护作用，包括抗氧化、抗炎、抗胆碱酯酶和抗淀粉样蛋白生成作用。这些发现支持其作为植物化学候选物用于AD预防或辅助管理的进一步开发潜力。
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline associated with oxidative stress, neuroinflammation, cholinergic dysfunction, and accumulation of amyloid-β (Aβ) and hyperphosphorylated tau (p-tau). Given the multifactorial nature of AD, phytochemicals with multi-target pharmacological properties are of growing therapeutic interest. Gentisic acid (GA; 2,5-dihydroxybenzoic acid) possesses established antioxidant and anti-inflammatory activities; however, its potential relevance in AD has not been comprehensively evaluated. This study investigated the neuroprotective potential of gentisic acid against Alzheimer-like pathology using integrated in vitro and in vivo experimental models. A preclinical experimental study combining cell-based assays and an aluminium chloride (AlCl) and D-galactose (D-Gal)-induced rat model of AD-like neurodegeneration was conducted. Blood-brain barrier (BBB) permeability of GA was assessed using a PAMPA-BBB assay. Neuroprotective effects were examined in AlCl₃-exposed SH-SY5Y cells. In vivo, Wistar rats received AlCl₃ and D-Gal to induce cognitive and biochemical alterations, followed by oral GA treatment. Behavioral paradigms such as open field, Morris water maze, novel object recognition, elevated plus maze and Y-maze tests were employed to assess spatial learning, recognition memory, and anxiety-like behavior. Oxidative stress markers, antioxidant enzymes, acetylcholinesterase activity, monoaminergic neurotransmitters, brain-derived neurotrophic factor (BDNF), pro-inflammatory cytokines, amyloid beta, and hyperphosphorylated tau protein levels were quantified. Histopathological evaluation of hippocampal and cortical regions was performed. GA demonstrated adequate BBB permeability and concentration-dependent protection against AlCl₃-induced cytotoxicity in SH-SY5Y cells. In the rat model, GA (10, 30, and 100 mg/kg, per oral (p.o.) improved cognitive performance and attenuated anxiety-like behavior. Treatment with GA reduced lipid peroxidation (malondialdehyde), restored antioxidant defenses (superoxide dismutase, catalase and reduced glutathione), inhibited acetylcholinesterase activity, and normalized monoaminergic neurotransmitters (serotonin and dopamine). GA further elevated BDNF levels and suppressed pro-inflammatory cytokines (tumor necrosis factor-alpha and interleukin-1 beta). Notably, GA decreased cerebral Aβ and p-tau accumulation and preserved hippocampal and cortical architecture. Gentisic acid exerts multi-modal neuroprotective effects, including antioxidant, anti-inflammatory, anti-cholinesterase, and anti-amyloidogenic actions, in experimental models of AD. These findings support its potential as a phytochemical candidate for further development in the prevention or adjunctive management of AD.
如何引用
AMA
Urvashi Soni, Rohini Pujari. Gentisic acid confers multimodal neuroprotection in experimental Alzheimer's disease by targeting oxidative stress, neuroinflammation, and protein aggregation.. Phytomedicine : international journal of phytotherapy and phytopharmacology. 2026; doi:10.1016/j.phymed.2026.158276.
APA
Urvashi Soni, Rohini Pujari (2026). Gentisic acid confers multimodal neuroprotection in experimental Alzheimer's disease by targeting oxidative stress, neuroinflammation, and protein aggregation.. Phytomedicine : international journal of phytotherapy and phytopharmacology. https://doi.org/10.1016/j.phymed.2026.158276
GB/T 7714
Urvashi Soni, Rohini Pujari. Gentisic acid confers multimodal neuroprotection in experimental Alzheimer's disease by targeting oxidative stress, neuroinflammation, and protein aggregation.[J]. Phytomedicine : international journal of phytotherapy and phytopharmacology, 2026 doi:10.1016/j.phymed.2026.158276.
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