Lai Zhenzhen, Ke Long, Zhao Wei
Department of Neurology, Tiantai People's Hospital of Zhejiang Province, Tiantai Branch of Zhejiang Provincial People's Hospital, Hangzhou Medical College, Taizhou, Zhejiang, China.
Department of Health Examination, The Third Affiliated Hospital of Shanghai University, Wenzhou No. 3 Clinical Institute Affiliated to Wenzhou Medical University, Wenzhou People's Hospital, Wenzhou, China.
Front Aging Neurosci. 2025 Aug 15;17:1647967. doi: 10.3389/fnagi.2025.1647967. eCollection 2025.
Alzheimer's disease (AD) remains a major neurodegenerative disorder characterized by progressive cognitive decline, amyloid- (Aβ) aggregation, tau pathology, oxidative stress, and chronic neuroinflammation. In recent years, the dietary flavonoid naringenin, abundant in citrus fruits, has gained attention as a multi-target neuroprotective agent with potential application in AD therapy. Preclinical studies demonstrate that naringenin exhibits robust antioxidant activity, notably through activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway, which reduces ROS and preserves mitochondrial integrity. Furthermore, naringenin upregulates AMPK-mediated autophagy, aiding in the clearance of toxic Aβ peptides and promoting neuronal survival. Inflammatory cascades are significantly downregulated following naringenin treatment. Additionally, naringenin modulates estrogen receptor and PI3K/Akt signaling, contributing to enhanced neuronal viability and reduced apoptosis. Notably, its ability to inhibit acetylcholinesterase suggests promise for restoring cholinergic neurotransmission. Despite these benefits, naringenin's poor solubility and limited oral bioavailability hinder clinical translation. To address these challenges, advanced nanocarrier-based delivery systems have been engineered to facilitate blood-brain barrier penetration and sustained brain targeting, markedly improving cognitive outcomes in animal models. Safety profiles in rodents indicate low toxicity at therapeutic doses, reinforcing its viability as a candidate compound. This review highlights the multifaceted mechanisms and delivery strategies of naringenin in AD, and underscores the need for well-designed clinical trials to confirm its efficacy and safety in humans.
阿尔茨海默病（AD）仍然是一种主要的神经退行性疾病，其特征为进行性认知衰退、淀粉样蛋白（Aβ）聚集、tau蛋白病变、氧化应激和慢性神经炎症。近年来，柑橘类水果中富含的膳食类黄酮柚皮素，作为一种具有多靶点神经保护作用的药物，在AD治疗中具有潜在应用价值，从而受到关注。临床前研究表明，柚皮素具有强大的抗氧化活性，特别是通过激活核因子红细胞2相关因子2（Nrf2）/抗氧化反应元件（ARE）信号通路，减少活性氧（ROS）并维持线粒体完整性。此外，柚皮素上调AMPK介导的自噬，有助于清除有毒的Aβ肽并促进神经元存活。柚皮素治疗后炎症级联反应显著下调。此外，柚皮素调节雌激素受体和PI3K/Akt信号传导，有助于提高神经元活力并减少细胞凋亡。值得注意的是，其抑制乙酰胆碱酯酶的能力表明有望恢复胆碱能神经传递。尽管有这些益处，但柚皮素的低溶解度和有限的口服生物利用度阻碍了其临床转化。为应对这些挑战，已设计出先进的基于纳米载体的递送系统，以促进血脑屏障穿透和持续的脑靶向，显著改善动物模型中的认知结果。啮齿动物的安全性研究表明，治疗剂量下毒性较低，增强了其作为候选化合物的可行性。本综述强调了柚皮素在AD中的多方面作用机制和递送策略，并强调需要设计良好的临床试验来证实其在人体中的疗效和安全性。
