Efficacy and molecular mechanisms of hesperidin in mitigating Alzheimer's disease: A systematic review

Hesperidin, a flavonoid glycoside, is a natural phenolic compound that has broad biological effects. Increasing evidence suggests that hesperidin inhibits the occurrence and development of neurodegenerative diseases, including Alzheimer's disease (AD). This article reviews the neuropharmacological mechanisms of hesperidin in the prevention and treatment of AD through in vitro and in vivo studies. A systematic review of preclinical studies was conducted using PubMed, Web of Science, Scopus, and Google Scholar (up to July 1, 2024). The neuroprotective potential of hesperidin was mediated through mechanisms such as inhibition of β-amyloid (Aβ) aggregation, enhancement of endogenous antioxidant defense functions, reduction of neuroinflammation and apoptosis, improvement of mitochondrial dysfunction, regulation of autophagy, and promotion of neurogenesis. Despite various preclinical studies on the role of hesperidin in AD, its exact effects on humans remain unclear. Few clinical trials have indicated that dietary supplements rich in hesperidin can improve cerebral blood flow, cognition, and memory performance. The neuroprotective effect of hesperidin may be exerted via regulating different molecular pathways, including the RAGE/NF-κB, Akt/Nrf2, and AMPK/BDNF/CREB pathways. However, further clinical trials are needed to confirm the neuroprotective effects of this natural flavonoid compound and to assess its safety.