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

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

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159 Scopus citations


U-78517F {2-[4-[2,6-di-(1-pyrrolidinyl)-4-pyrimidinyl)-1-piperazinyl]-3,4 -dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol, dihydrochloride}, which combines the antioxidant ring portion of α-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 μM against 200 μM ferrous chloride-initiated lipid peroxidation in rat brain homogenates, compared to 8 μM for U-74006F, 28 μM for α-tocopherol and 43 μM for the ring portion of α-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 μM. U-78517F was also observed to protect cultured mouse spinal neurons against iron-induced damage, with an IC50 of approximately 0.5 μM. 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 μg/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. When administered to male gerbils at an i.p. dose of 10 mg/kg at 10 min before, and again at the end of a 3-hr period of unilateral carotid artery occlusion, U-78517F was shown to decrease 24-hr postischemic cortical neuronal necrosis. In the medial portion of the cortex, neuronal density was increased from 34.2% of normal in vehicle-treated animals to 86.3% in the U-78517F-treated animals. In the lateral cortical area, the vehicle group showed only 3.3% neuronal survival vs. 48.2% in the drug-treated group. U-78517F neither exhibited hypothermic activity nor antagonized excitatory amino acid (e.g., N-methyl-D-aspartate, kainate, quisqualate)-induced seizures in mice. Moreover, it showed no significant interaction with known neurotransmitter receptors (e.g., acetylcholine, norepinephrine, dopamine, 5-hydroxytryptamine, opiate and benzodiazepine). These results document the cerebroprotective efficacy of a novel and potent inhibitor of iron-catalyzed lipid peroxidation, and further support a key role of oxygen radicals in post-traumatic and postischemic pathophysiology.

Original languageEnglish
Pages (from-to)688-694
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number2
StatePublished - 1991

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology


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