U-78517F: a potent inhibitor of lipid peroxidation with activity in experimental brain injury and ischemia.

Abstract

U-78517F (2-[4-[2,6-di-(1-pyrrolidinyl)-4-pyridinyl)-1-piperazinyl] methyl]-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol, dihydrochloride), which combines the antioxidant ring portion of alpha-tocopherol together with the amine of the previously described 21-aminosteroids (e.g., U-74006F), is a novel inhibitor of iron-catalyzed lipid peroxidation. U-78517F was found to have a 50% inhibitory concentration (IC50) of 0.6 microM against 200 microM ferrous chloride-initiated lipid peroxidation in rat brain homogenates, compared to 8 microM for U-74006F, 28 microM for alpha-tocopherol and 43 microM for the ring portion of alpha-tocopherol (i.e., trolox). Both stereoisomers of the racemic U-78517F proved to be equally active antioxidants. Against lipid peroxidation initiated by xanthine/xanthine oxidase, U-78517F was even more potent, with an IC50 of 0.01 microM. U-78517F was also observed to protect cultured mouse spinal neurons against iron-induced damage, with an IC50 of approximately 0.5 microM. When administered to male CF-1 mice i.v. at 5 min after a severe concussive head injury. U-78517F produced a dose-related improvement in the 1-hr neurological recovery. The minimum effective i.v. dose was 1.0 micrograms/kg. Measurement of U-78517 concentrations in the brains of mice after administration of a 10-mg/kg i.v. dose revealed effective antioxidant levels for as long as 2 hr. Evidence of an in vivo antioxidant action was provided by the attenuation of iron-induced blood-brain barrier disruption (i.e., Evans' blue extravasation) in rats pretreated with U-78517F.(ABSTRACT TRUNCATED AT 250 WORDS)

• Authors: E D Hall, J M Braughler, P A Yonkers, S L Smith, K L Linseman, E D Means, H M Scherch, P F Von Voigtlander, R A Lahti, E J Jacobsen
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 258 Issue 2 Pg. 688-94 (Aug 1991) ISSN: 0022-3565 [Print] United States
• PMID: 1865365 (Publication Type: Journal Article)

Chemical References

• Chromans
• Free Radical Scavengers
• Piperazines
• U 78517F
• Vitamin E
• Iron

Topics

• Animals
• Blood-Brain Barrier (drug effects)
• Brain (drug effects, metabolism)
• Brain Injuries (metabolism)
• Brain Ischemia (metabolism)
• Cells, Cultured
• Chromans (pharmacology)
• Free Radical Scavengers
• Gerbillinae
• In Vitro Techniques
• Iron (pharmacology)
• Lipid Peroxidation (drug effects)
• Male
• Mice
• Piperazines (pharmacology)
• Rats
• Spinal Cord (metabolism)
• Vitamin E (pharmacology)