Planta Med 2002; 68(3): 217-220
DOI: 10.1055/s-2002-23145
Original Paper
Pharmacology
© Georg Thieme Verlag Stuttgart · New York

Schisandrin B Protects Against Tacrine- and Bis(7)-tacrine-Induced Hepatotoxicity and Enhances Cognitive Function in Mice

S. Y. Pan1, 3 , Y. F. Han1 , P. R. Carlier2, 5 , Y. P. Pang4 , D. H. F. Mak1 , B. Y. H. Lam1 , K. M. Ko1
  • 1Department of Biochemistry and
  • 2Department of Chemistry, Hong Kong University of Science & Technology, Hong Kong, China
  • 3Department of Pharmacology, Beijing University of Traditional Chinese Medicine, Beijing, China
  • 4Mayo Clinic Cancer Center, Department of Pharmacology, Mayo Clinic, Rochester, MN, USA
  • 5Present Address: Department of Chemistry, Virginia Tech, Blacksburg, VA, USA
Further Information

Publication History

March 16, 2001

September 30, 2001

Publication Date:
25 March 2002 (online)

Abstract

Intragastric administration (100 - 200 μmol/kg) of tacrine (THA) or bis(7)-THA could cause an acute and dose-dependent increase in plasma alanine aminotransferases activity in mice at 6 h after the drug administration. The increase in plasma enzyme activity was associated with an increase in hepatic malondialdehyde level, an indirect index of oxidative tissue damage. Pretreating mice with schisandrin B (Sch B), an active dibenzocyclooctadiene derivative isolated from the fruit of Schisandra chinensis, at a daily dose of 0.125 - 0.5 mmol/kg for 3 days protected against the THA/bis(7)-THA induced hepatic oxidative damage in a dose-dependent manner.  Sch B treatment (0.025 - 0.5 mmol/kg/day × 5) also enhanced the passive avoidance-response in mice as assessed by the step-through task experiment. The ensemble of results suggests that Sch B may be useful for reducing the potential hepatotoxicity of THA/bis(7)-THA in anti-Alzheimer’s therapy.

Abbreviations

ALT:alanine aminotransferases

MDA:malondialdehyde

Sch B:schisandrin B

THA:tetrahyroaminoacridine

VE:α-tocopherol

References

  • 1 Kristofikova Z, Fales E, Majer E, Klaschka J. (3H)Hemicholinium-3 binding sites in postmortem brains of human patients with Alzheimer’s disease and multi-infarct dementia.  Experimental Gerontology. 1995;  30 125-36
  • 2 Lawrence A D, Sahakian B J. The cognitive psychopharmacology of Alzheimer’s disease: Focus on cholinergic systems.  Neurochemical Research. 1998;  23 787-94
  • 3 Rocca W A, Amaducci L A, Schoenberg B S. Epidemiology of clinically diagnosed Alzheimer’s disease.  Annals of Neurology. 1986;  19 415-24
  • 4 Marquis J K. Pharmacological significance of acetylcholinesterase inhibition by tetrahydroaminoacridine.  Biochemical Pharmacology. 1990;  40 1071-6
  • 5 Freeman S E, Dawson R M. Tacrine: a pharmacological review.  Progress in Neurobiology. 1991;  36 257-77
  • 6 Watkins P B, Zimmerman H J, Knapp M J, Gracon S I, Lewis K W. Hepatotoxic effects of tacrine administration in patients with Alzheimer’s disease.  Journal of American Medical Association.. 1994;  271 992-8
  • 7 O’Brien J T, Eagger S, Levy R. Effects of tetrahydroaminoacridine on liver function in patients with Alzheimer’s disease.  Age and Aging. 1991;  20 129-31
  • 8 Pang Y P, Quiram P, Jelacic T, Hong F, Brimijoin S. Highly potent, selective, and low cost bis-tetrahydroaminoacrine inhibitors of acetylcholinesterase.  Journal Biological Chemistry. 1996;  271 23 646-9
  • 9 Hancke J L, Burgos R A, Ahumada F. Schisandra chinensis (Turcz.) Baill.  Fitoterapia. 1999;  70 451-71
  • 10 Pang Y P, Hong F, Quiram P, Jelacic T, Brimijoin S. Synthesis of alkylene linked bis-THA and alkylene linked benzyl-THA as highly potent and selective inhibitors and molecular probes of acetylcholinesterase.  Journal of Chemical Society Perkin Transactions. 1997;  1 171-6
  • 11 Ip S P, Poon M KT, Wu S S, Che C T, Ng K H, Kong Y C, Ko K M. Effect of schisandrin B on hepatic glutathione antioxidant system in mice: Protection against carbon tetrachloride toxicity.  Planta Medica. 1995;  61 398-401
  • 12 Young I S, Trimble E R. Measurement of malondialdehyde in plasma by high performance liquid chromatography with fluorimetric detection.  Annals of Clinical Biochemistry. 1991;  28 504-8
  • 13 Summers W K, Koehler A L, Marsh G M, Tachiki K, Kling A. Long-term hepatotoxicity of tacrine.  Lancet. 1989;  1 729
  • 14 Monteith D K, Emmerling M R, Garvin J, Theiss J C. Cytotoxicity study of tacrine, structurally and pharmacologically related compounds using rat hepatocytes.  Drug and Chemical Toxicology. 1996;  19 71-84
  • 15 Madden S, Woolf T F, Pool W F, Park B K. An investigation into the formation of stable, protein-reactive and cytotoxic metabolites from tacrine in vitro. Studies with human and rat liver microsomes.  Biochemical Pharmacology. 1993;  46 13-20
  • 16 Woolf T F, Pool W F, Bjorge S M, Chang T, Goel O P, Purchase CF 2 nd, Schroeder M C, Kunze K L, Trager W F. Bioactivation and irreversible binding of the cognition activator tacrine using human and rat liver microsomal preparations. Species difference.  Drug Metabolism and Disposition. 1993;  21 874-82
  • 17 Monteith D K, Theiss J C. The role of metabolism in the cytotoxicity of tetrahydroaminoacridine in hepatocytes.  The Toxicologist. 1993;  13 139 (abstract)
  • 18 Wang H, Carlier P R, Ho W L, Wu D C, Lee N TK, Li C PL. et al . Effects of bis(7)-tacrine, a novel anti-Alzheimer’s agent, on rat brain ache.  NeuroReport. 1999;  10 789-93
  • 19 Stachlewitz R F, Arteel G E, Raleigh J A, Connor H D, Mason R P, Thurman R G. Development and characterization of a new model of tacrine-induced hepatotoxicity: role of the sympathetic nervous system and hypoxia-reoxygenation.  Journal of Pharmacology and Experimental Therapeutics. 1997;  282 1591-9
  • 20 Schemmer P, Connor H D, Arteel G E, Raleigh J A, Bunzendahl H, Mason R P. et al . Reperfusion injury in livers due to gentle in situ organ manipulation during harvest involves hypoxia and free radicals.  Journal of Pharmacology and Experimental Therapeutics. 1999;  290 235-40
  • 21 Dogterom P, Nagelkerke J F, Mulder G J. Hepatotoxicity of terahydroaminoacridine in isolated rat hepatocytes: Effect of glutathione and vitamin E.  Biochemical Pharmacology. 1988;  7 2311-3
  • 22 Mak D HF, Ip S P, Li P C, Poon M KT, Ko K M. Effects of schisandrin B and α-tocopherol on lipid peroxidation, in vitro and in vivo .  Molecular and Cellular Biochemistry. 1997;  165 161-5
  • 23 Chang H M, But P PH. Pharmacology and Applications of Chinese Materia Medica. Vol. 1 Singapore; World Scientific 1986: 199-209

Dr. Robert K.M. Ko

Department of Biochemistry

Hong Kong University of Science & Technology

Clear Water Bay, Hong Kong

China

Email: bcrko@ust.hk

Fax: +852-2358 1552