Phloroglucinol, a clinical-used antispasmodic, inhibits amyloid aggregation and degrades the pre-formed amyloid proteins.

Amyloid proteins, such as β-amyloid (Aβ) and α-synuclein (α-syn), could form neurotoxic aggregates during the progression of neurodegenerative disorders. Phloroglucinol, a clinical-used drug for treating spasmodic pain, was predicted to cross the blood brain-barrier and possesses neuroprotective potential. In this study, we have found, for the first time, that phloroglucinol inhibited the formation of amyloid aggregates, and degraded pre-formed amyloid aggregates with the similar efficacy as curcumin, a widely known amyloid aggregation inhibitor. Moreover, phloroglucinol decreased the seeding during aggregation process and inhibited the aggregation of Aβ with homocysteine (Hcy) seeds. Molecular docking analysis further demonstrated hydrophobic interactions and hydrogen bonds between phloroglucinol and Aβ/α-syn. Furthermore, phloroglucinol inhibited amyloid aggregates-induced cytotoxicity in neuronal cells and prevented Aβ + Hcy aggregates-induced cognitive impairments in mice. All these results suggested that phloroglucinol possesses the ability to degrade pre-formed amyloid aggregates, to inhibit the seeding during amyloid aggregation, and to reduce the neurotoxicity, indicating the reposition possibility of phloroglucinol as a novel drug for treating neurodegenerative disorders.