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Journal of Pharmacology and Experimental Therapeutics

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Abstract

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 and E J Jacobsen
Journal of Pharmacology and Experimental Therapeutics August 1991, 258 (2) 688-694;
E D Hall
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J M Braughler
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P A Yonkers
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S L Smith
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K L Linseman
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E D Means
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H M Scherch
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P F Von Voigtlander
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R A Lahti
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E J Jacobsen
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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)

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Journal of Pharmacology and Experimental Therapeutics
Vol. 258, Issue 2
1 Aug 1991
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Abstract

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 and E J Jacobsen
Journal of Pharmacology and Experimental Therapeutics August 1, 1991, 258 (2) 688-694;

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Abstract

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 and E J Jacobsen
Journal of Pharmacology and Experimental Therapeutics August 1, 1991, 258 (2) 688-694;
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