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 Aβ1-42 with homocysteine (Hcy) seeds. Molecular docking analysis further demonstrated hydrophobic interactions and hydrogen bonds between phloroglucinol and Aβ1-42/α-syn. Furthermore, phloroglucinol inhibited amyloid aggregates-induced cytotoxicity in neuronal cells and prevented Aβ1-42 + 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.