ESR study on the antioxidant activity of TAK-218 in biological model membranes

TAK-218 has a 2,3-dihydrobenzofuran-5-amine (coumaran) structure which rese mbles alpha-tocopherol, and is a promising candidate as an agent for centra l nervous system (CNS) trauma and ischemia, The radical scavenging activity of TAK-218 was studied using electron spin resonance (ESR) spectroscopy. TAK-218 exhibited a more potent scavenging activity towards the hydroxyl ra dical than did the well-known hydroxyl radical scavengers, mannitol and dim ethylsulfoxide. Towards the superoxide radical, TAK-218 showed equal potenc y to glutathione. TAK-218 reacted rapidly with stable radicals, such as gal vinoxyl and 2,2-diphenyl-1-picrylhydrazyl hydrate (DPPH), and gave the quin one as a two-electron oxidized product in analogy with alpha-tocopherol. To exhibit an excellent antioxidative activity in living systems, the compo unds should not only have the intrinsic radical scavenging activity but als o good distribution in the biological lipid-bilayer membrane. To examine th e antioxidant activity of TAK-218, the inhibition of lipid peroxidation by alpha-tocopherol and TAK-218 in liposomal membranes was studied using an ES R spin-label technique, Both alpha-tocopherol and TAK-218 completely inhibited lipid peroxidation b y radicals generated in an aqueous layer using a water-soluble radical init iator, 2.2'-azobis-(2-amidinopropane) hydrochloride (AAPH). At a high incub ation temperature (45 degrees C), alpha-tocopherol scavenged radicals more effectively than TAK-218 on the surface of the membrane, while TAK-218 scav enged radicals more effectively in the interior of the membrane. The differ ence between TAK-218 and alpha-tocopherol for radical scavenging in the mem brane system derives from the different distribution pattern of these compo unds. TAK-218 can penetrate the membrane freely and can scavenge the radica l in the membrane interior. Furthermore, TAK-218 was shown to inhibit lipid peroxidation initiated by a lipid soluble radical initiator, 2,2'-azobis-(2,4-dimethylvaleronitrile) ( AMVN). in a membrane more effectively than alpha-tocopherol.