Stilbenes Against Alzheimer’s Disease: A Comprehensive Review of Preclinical Studies of Natural and Synthetic Compounds Combined with the Contributions of Developed Nanodrug Delivery Systems

Küpeli Akkol, Esra; Karatoprak, Gökçe Şeker; Dumlupınar, Berrak; Bahadır Acıkara, Özlem; Arıcı, Reyhan; Yücel, Çiğdem; Aynal, Leyli Can; Sobarzo Sánchez, Eduardo

doi:10.3390/molecules30091982

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Stilbenes Against Alzheimer’s Disease: A Comprehensive Review of Preclinical Studies of Natural and Synthetic Compounds Combined with the Contributions of Developed Nanodrug Delivery Systems

by

Esra Küpeli Akkol

^1,*

,

Gökçe Şeker Karatoprak

²

,

Berrak Dumlupınar

³

,

Özlem Bahadır Acıkara

⁴,

Reyhan Arıcı

⁵

,

Çiğdem Yücel

⁶,

Leyli Can Aynal

⁷ and

Eduardo Sobarzo Sánchez

^8,9,*

¹

Department of Pharmacognosy, Faculty of Pharmacy, Gazi University, Ankara 06330, Türkiye

²

Department of Pharmacognosy, Faculty of Pharmacy, Erciyes University, Kayseri 38039, Türkiye

³

Department of Nutrition and Dietetics, Faculty of Health Sciences, Istanbul Okan University, İstanbul 34959, Türkiye

⁴

Department of Pharmacognosy, Faculty of Pharmacy, Ankara University, Ankara 06560, Türkiye

⁵

Department of Pharmacognosy, Faculty of Pharmacy, Ankara Medipol University, Ankara 06570, Türkiye

⁶

Department of Pharmaceutical Technology, Faculty of Pharmacy, Erciyes University, Kayseri 38039, Türkiye

⁷

Etlik City Hospital, Department of Neurology, Ankara 06170, Türkiye

⁸

Centro de Investigación en Ingeniería de Materiales, Facultad de Medicina y Ciencias de la Salud, Universidad Central de Chile, Santiago 8330507, Chile

⁹

Department of Organic Chemistry, Faculty of Pharmacy, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain

^*

Authors to whom correspondence should be addressed.

Molecules 2025, 30(9), 1982; https://doi.org/10.3390/molecules30091982

Submission received: 3 March 2025 / Revised: 24 April 2025 / Accepted: 25 April 2025 / Published: 29 April 2025

(This article belongs to the Special Issue Discovery of New Natural Derived Compounds and Mechanisms for Chronic Diseases Therapy)

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Abstract

This review covers preclinical studies of stilbene derivative compounds (both natural and synthetic) with potential preventive and therapeutic effects against Alzheimer’s disease (AD). AD is a worldwide neurodegenerative disease characterized by the destruction of nerve cells in the brain and the loss of cognitive function due to aging. Stilbenes are a unique class of natural phenolic compounds distinguished by a C6-C2-C6 (1,2-diphenylethylene) structure and two aromatic rings connected by an ethylene bridge. Stilbenes’ distinct features make them an intriguing subject for pharmacological research and development. Several preclinical studies have suggested that stilbenes may have neuroprotective effects by reducing Aβ generation and oligomerization, enhancing Aβ clearance, and regulating tau neuropathology through the prevention of aberrant tau phosphorylation and aggregation, as well as scavenging reactive oxygen species. Synthetic stilbene derivatives also target multiple pathways involved in neuroprotection and have demonstrated promising biological activity in vitro. However, some properties of stilbenes, such as sensitivity to physiological conditions, low solubility, poor permeability, instability, and low bioavailability, limit their usefulness in clinical applications. To address this issue, current investigations have developed new drug delivery systems based on stilbene derivative molecules. This review aims to shed light on the development of next-generation treatment strategies by examining in detail the role of stilbenes in Alzheimer’s pathophysiology and their therapeutic potential.

Keywords: stilbene; Alzheimer’s disease; natural compound; structure–activity relationships; nanoformulation

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MDPI and ACS Style

Küpeli Akkol, E.; Karatoprak, G.Ş.; Dumlupınar, B.; Bahadır Acıkara, Ö.; Arıcı, R.; Yücel, Ç.; Aynal, L.C.; Sobarzo Sánchez, E. Stilbenes Against Alzheimer’s Disease: A Comprehensive Review of Preclinical Studies of Natural and Synthetic Compounds Combined with the Contributions of Developed Nanodrug Delivery Systems. Molecules 2025, 30, 1982. https://doi.org/10.3390/molecules30091982

AMA Style

Küpeli Akkol E, Karatoprak GŞ, Dumlupınar B, Bahadır Acıkara Ö, Arıcı R, Yücel Ç, Aynal LC, Sobarzo Sánchez E. Stilbenes Against Alzheimer’s Disease: A Comprehensive Review of Preclinical Studies of Natural and Synthetic Compounds Combined with the Contributions of Developed Nanodrug Delivery Systems. Molecules. 2025; 30(9):1982. https://doi.org/10.3390/molecules30091982

Chicago/Turabian Style

Küpeli Akkol, Esra, Gökçe Şeker Karatoprak, Berrak Dumlupınar, Özlem Bahadır Acıkara, Reyhan Arıcı, Çiğdem Yücel, Leyli Can Aynal, and Eduardo Sobarzo Sánchez. 2025. "Stilbenes Against Alzheimer’s Disease: A Comprehensive Review of Preclinical Studies of Natural and Synthetic Compounds Combined with the Contributions of Developed Nanodrug Delivery Systems" Molecules 30, no. 9: 1982. https://doi.org/10.3390/molecules30091982

APA Style

Küpeli Akkol, E., Karatoprak, G. Ş., Dumlupınar, B., Bahadır Acıkara, Ö., Arıcı, R., Yücel, Ç., Aynal, L. C., & Sobarzo Sánchez, E. (2025). Stilbenes Against Alzheimer’s Disease: A Comprehensive Review of Preclinical Studies of Natural and Synthetic Compounds Combined with the Contributions of Developed Nanodrug Delivery Systems. Molecules, 30(9), 1982. https://doi.org/10.3390/molecules30091982

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Stilbenes Against Alzheimer’s Disease: A Comprehensive Review of Preclinical Studies of Natural and Synthetic Compounds Combined with the Contributions of Developed Nanodrug Delivery Systems

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