Phlorotannins of the edible brown seaweed Ecklonia cava Kjellman induce sleep via positive allosteric modulation of gamma-aminobutyric acid type A–benzodiazepine receptor: A novel neurological activity of seaweed polyphenols

The primary objective was to investigate whether seaweeds have hypnotic activity. Methanol extracts of 30 seaweeds were screened for their binding activity at the GABA type A–benzodiazepine (GABAA–BZD) receptor, a well-characterised molecular target for sedative–hypnotics. The most active seaweed was Ecklonia cava Kjellman (ECK). An ethanol extract of ECK (ECK-E) significantly potentiated pentobarbital-induced sleep in mice. In four solvent fractions separated from ECK-E, hypnotic activity was proportional to contents of total phenols and total phlorotannins, known as seaweed polyphenols. Major phlorotannins of the ethyl acetate (EtOAc) fraction with the highest activity were eckol, eckstolonol, dieckol, and triphlorethol-A, and their Ki (binding affinity, μM) values for [3H]-flumazenil binding were 1.070, 1.491, 3.072, and 4.419, respectively. Hypnotic effects of ECK-E and the EtOAc fraction were fully inhibited by flumazenil, a specific GABAA–BZD receptor antagonist. These results imply that phlorotannins of ECK induce sleep by positive allosteric modulation of the GABAA–BZD receptor.