Traversal of the Blood–Brain Barrier by Cleavable l-Lysine Conjugates of Apigenin

• DOI: 10.1021/acs.jafc.8b01187
• Publication Date: 2018-06-20T09:19:09Z
• Authors: Tsung-Yun Wong; Ming-Shian Tsai; Lih-Ching Hsu; Shu-Wha Lin; Pi-Hui Liang
• Keywords: Male; 0301 basic medicine; Molecular Structure; Plant Extracts; Lysine; Brain; 3. Good health; Mice, Inbred C57BL; Kinetics; Mice; 03 medical and health sciences; Blood-Brain Barrier; Animals; Humans; Petroselinum; Apigenin; Apium

Apigenin, a flavone abundant in parsley and celery, is known to act on several CNS receptors, but its very poor water solubility (<0.001 mg/mL) impedes its absorption in vivo and prevents clinical use. Herein, apigenin was directly conjugated with glycine, l-phenylalanine, and l-lysine to give the corresponding carbamate derivatives, all of which were much more soluble than apigenin itself (0.017, 0.018, and 0.13 mg/mL, respectively). The Lys-apigenin carbamate 10 had a temporary sedative effect on the mice within 5 min of intraperitoneal administration (single dose of 0.4 mg/g) and could be detected in the mice brain tissues at a concentration of 0.82 μg/g of intact Lys-apigenin carbamate 10 and 0.42 ug/g of apigenin at 1.5 h. This study accomplished the delivery of apigenin across the BBB in a manner that might be applicable to other congeners, which should inform the future development of BBB-crossing flavonoids.