Abstract
Neurodegenerative diseases (NDDs), characterized by a progressive neuronal loss that leads to cognitive and motor deficits, both pose a significant global health challenge and have limited treatment options. This review explores the therapeutic potential of gastrodin (GAS) and gastrodigenin (HBA), which are the key bioactive constituents of Gastrodia elata Blume (GEB). These compounds demonstrate significant neuroprotective effects across various NDD models which include Alzheimer's disease (AD) and Parkinson's disease (PD). Their mechanisms involve multi-target actions such as inhibiting pathological protein aggregation (Aβ, tau, α-synuclein), attenuating neuroinflammation via the TLR4/NF-κB and NLRP3 pathways, reducing oxidative stress through Nrf2 activation, mitigating mitochondrial dysfunction, inhibiting ferroptosis, and counteracting glutamate excitotoxicity. While pharmacokinetic studies reveal favorable brain distribution for HBA, its clinical translation faces challenges including blood-brain barrier penetration and the need for human trials. Advances in delivery systems, like focused ultrasound, show promise. This review both synthesizes the current evidence on GAS and HBA to highlight their multifaceted mechanisms and potential as multi-target agents for NDD intervention, and outlines future research directions for their clinical development.