A phlorotannin isolated from Ecklonia radiata, Dibenzodioxin-fucodiphloroethol, inhibits neurotoxicity and aggregation of β-amyloid

•The phlorotannin dibenzodioxin-fucodiphloroethol was isolated from ecklonia radiata.•DFD elicited in vitro neuroprotective activity against amyloid β protein, Aβ1–42.•DFD inhibited Aβ1–42 aggregation, AChE activity and ROS formation in PC-12 cells.•DFD exerts neuroprotective effects through multiple pathways. The polyphenolic phlorotannins derived from brown macroalgae consist of complex polymers of phloroglucinol residues with diverse structures ascribed pleiotropic bioactivity. This study aimed to isolate and purify the phlorotannins from Ecklonia radiata and to investigate their neuroprotective activity in PC-12 cells. This study used high performance counter-current chromatography (HPCCC) combined with size exclusion chromatography to isolate and purify a phlorotannin from the marine brown algae Ecklonia radiata. Nuclear magnetic resonance (NMR) including 1H and 13C and 2D COZY, HSQC, HMBC (broad and band selective), and NOESY along with mass spectroscopy enabled us to identify the phlorotannin as dibenzodioxin-fucodiphloroethol (DFD). The compound was subsequently investigated for protective bioactivity against the neurotoxic β-amyloid protein Aβ1–42, and intracellular reactive oxygen species (ROS) scavenging activity in PC-12 cells along with in silico studies. DFD was nontoxic up to 50 µM in the neuronal PC-12 cell line and significantly prevented loss of cell viability in response to Aβ1–42 (0–1.5 µM). Furthermore, it significantly reduced the aggregation of Aβ1–42 as evidenced by transmission electron microscopy, while molecular docking studies revealed DFD binding to key Aβ1–42 residues associated with fibrillisation propensity. Additionally, DFD demonstrated moderate cholinesterase inhibitory activity (IC50 value of 41 µM), sharing similar interacting binding residues to donepezil in the crystallized structure, and was also able to significantly scavenge ROS in PC-12 cells. Collectively, DFD possesses neuroprotective actions mitigating several mechanisms ascribed to amyloid β neurotoxicity, making this macroalgal phlorotannin an excellent candidate for further studies targeting neurodegenerative pathways in Alzheimer's disease. [Display omitted]