Tacrine-silibinin codrug shows neuro- and hepatoprotective effects in vitro and pro-cognitive and hepatoprotective effects in vivo

Journal of Medicinal Chemistry

Volumn 55, Issue 11, 2012, Pages 5231-5242

  Chen, Xinyu ^a   Zenger, Katharina ^a   Lupp, Amelie ^b   Kling, Beata ^a   Heilmann, Jörg ^a   Fleck, Christian ^b   Kraus, Birgit ^a   Decker, Michael ^a  

^a UNIVERSITY OF REGENSBURG   (Germany)

^b JENA UNIVERSITY HOSPITAL   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

ACETYLCHOLINESTERASE; CHOLINESTERASE; CYTOCHROME P450; GLUTAMIC ACID; SCOPOLAMINE; SILIBININ; TACRINE; TACRINE SILIBININ COMPLEX; UNCLASSIFIED DRUG;

ANIMAL BEHAVIOR; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CELL VIABILITY; COGNITION; COGNITIVE DEFECT; CONTROLLED STUDY; DRUG ACTIVITY; DRUG EFFECT; ENZYME INHIBITION; HUMAN; HUMAN CELL; IN VITRO STUDY; IN VIVO STUDY; LIVER PROTECTION; LIVER TOXICITY; MALE; MEMORY DISORDER; NERVE CELL CULTURE; NEUROPROTECTION; NEUROTOXICITY; NONHUMAN; RAT; STELLATE CELL;

ACETYLCHOLINESTERASE; ALLOSTERIC REGULATION; ANIMALS; BUTYRYLCHOLINESTERASE; CELL COUNT; CELL LINE; CELL SURVIVAL; CHOLINESTERASE INHIBITORS; COGNITION; EELS; FEMALE; GLUTAMIC ACID; HEPATIC STELLATE CELLS; HORSES; LIPID PEROXIDATION; LIVER; MAZE LEARNING; MICE; NEURONS; NEUROPROTECTIVE AGENTS; RATS; RATS, WISTAR; SILYMARIN; TACRINE;

EID: 84862279415     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm300246n     Document Type: Article

References (60)

1. Ballard, C.; Gauthier, S.; Corbett, A.; Brayne, C.; Aarsland, D.; Jones, E. Alzheimer's disease Lancet 2011, 377, 1019-1031
2. Knapp, M. J.; Knopman, D. S.; Solomon, P. R.; Pendlebury, W. W.; Davis, C. S.; Gracon, S. I. A 30-week randomized controlled trial of high-dose tacrine in patients with Alzheimer's disease J. Am. Med. Assoc. 1994, 271, 985-991
3. Takeda, A.; Loveman, E.; Clegg, A.; Kirby, J.; Picot, J.; Payne, E. C. A systematic review of the clinical effectiveness of donepezil, rivastigmine and galantamine on cognition, quality of life and adverse events in Alzheimer's disease Int. J. Geriatr. Psych. 2006, 21, 17-28
4. Watkins, P. B.; Zimmermann, H. J.; Knapp, M. J.; Gracon, S. I.; Lewis, K. W. Hepatotoxic effects of tacrine administration in patients with Alzheimer's disease J. Am. Med. Assoc. 1994, 271, 992-998
5. Gracon, S. I.; Knapp, M. J.; Berghoff, W. G.; Pierce, M.; DeJong, R.; Lobbestael, S. J.; Symons, J.; Dombey, S. L.; Luscombe, F. A.; Kraemer, D. Safety of tacrine: clinical trials, treatment IND, and postmarketing experience Alzheimer Dis. Ass. Disord. 1998, 12, 93-101
6. Tumiatti, V.; Minarini, A.; Bolognesi, M. L.; Milelli, A.; Rosini, M.; Melchiorre, C. Tacrine derivatives and Alzheimer's disease Curr. Med. Chem. 2010, 17, 1825-1838
7. Musial, A.; Bajda, M.; Malawska, B. Recent developments in cholinesterases inhibitors for Alzheimer's disease treatment Curr. Med. Chem. 2007, 14, 2654-2679
8. Lange, J. H. M.; Coolen, H. K. A. C.; van der Neut, M. A. W.; Borts, A. J. M.; Sork, B.; Verveer, P. C.; Kruse, C. G. Design, synthesis, biological properties, and molecular modeling investigations of novel tacrine derivatives with a combination of acetylcholinesterase inhibition and cannabinoid CB1 receptor antagonism J. Med. Chem. 2010, 53, 1338-1346
9. 1 receptors J. Med. Chem. 2010, 53, 2094-2103
10. Fang, L.; Kraus, B.; Lehmann, J.; Heilmann, J.; Zhang, Y.; Decker, M. Design and synthesis of tacrine-ferulic acid hybrids as multi-potent anti-Alzheimer drug candidates Bioorg. Med. Chem. Lett. 2008, 18, 2905-2909
11. Lupp, A.; Appenroth, D.; Fang, L.; Decker, M.; Lehmann, J.; Fleck, C. Tacrine-NO and tacrine-ferulic acid hybrid molecules as new anti-Alzheimer agents: Hepatotoxicity and influence on the cytochrome P450 system in comparison to tacrine Arzneim.-Forsch. 2010, 60, 229-237
12. Fleck, C.; Appenroth, D.; Fang, L.; Schott, Y.; Lehmann, J.; Decker, M. Investigation into the in vivo effects of five newly synthesized tacrine/ferulic acid and β-carboline derivatives on scopolamine-induced cognitive impairments in rats using radial maze experiments Arzneim.-Forsch. 2010, 60, 299-306
13. Fang, L.; Appenroth, D.; Decker, M.; Kiehntopf, M.; Roegler, C.; Deufel, T.; Fleck, C.; Peng, S.; Zhang, Y.; Lehmann, J. Synthesis and biological evaluation of NO-donor-tacrine hybrids as hepatoprotective anti-Alzheimer drug candidates J. Med. Chem. 2008, 51, 713-716
14. Fang, L.; Appenroth, D.; Decker, M.; Kiehntopf, M.; Lupp, A.; Peng, S.; Fleck, C.; Zhang, Y.; Lehmann, J. NO-Donating tacrine hybrid compounds improve scopolamine-induced cognition impairment and show less hepatotoxicity J. Med. Chem. 2008, 51, 7666-7669
15. Gažák, R.; Walterová, D.; Kŕen, V. Silybin and silymarin: new and emerging applications in medicine Curr. Med. Chem. 2007, 14, 315-338 and references therein
16. Yang, L. X.; Huang, K. X.; Li, H. B.; Gong, J. X.; Wang, F.; Feng, Y. B.; Tao, Q. F.; Wu, Y. H.; Li, X. K.; Wu, X. M.; Zeng, S.; Spencer, S.; Zhao, Y.; Qu, J. Design, synthesis, and examination of neuron protective properties of alkenylated and amidated dehydro-silybin derivatives J. Med. Chem. 2009, 52, 7732-7752
17. Gažák, R.; Svobodová, A.; Psotová, J.; Sedmera, P.; Přikrylová, V.; Walterová, D.; Křen, V. Oxidised derivatives of silybin and their antiradical and antioxidant activity Bioorg. Med. Chem. 2004, 12, 5677-5687
18. Nencinia, C.; Giorgia, G.; Micheli, L. Protective effect of silymarin on oxidative stress in rat brain Phytomedicine 2007, 14, 129-135
19. Loguericio, C.; Festi, D. Silybin and the liver: From basic research to clinical practice World J. Gastroenterol. 2011, 17, 2288-2301 and references therein.
20. Decker, M. Hybrid molecules incorporating natural products: Applications in cancer therapy, neurodegenerative disorders and beyond Curr. Med. Chem. 2011, 18, 1464-1475
21. R. Gažák, R.; Valentová, K.; Fuksová, K.; Marhol, P.; Kuzma, M.; Medina, M. á.; Orborná, I.; Ulrichová, J.; Křen, V. Synthesis and antiangiogenic activity of new silybin galloyl esters J. Med. Chem. 2011, 54, 7397-7407
22. Decker, M.; Kraus, B.; Heilmann, J. Design, synthesis and pharmacological evaluation of hybrid molecules out of quinazolinimines and lipoic acid lead to highly potent and selective butyrylcholinesterase inhibitors with antioxidant properties Bioorg. Med. Chem. 2008, 16, 4252-4261
23. Budzik, B.; Garzya, V.; Shi, D.; Walker, G.; Woolley-Roberts, M.; Pardoe, J.; Lucas, A.; Tehan, B.; Rivero, R. A.; Langmead, C. J.; Watson, J.; Wu, Z.; Forbes, I. T.; Jin, J. Novel N -substituted benzimidazolones as potent, selective, CNS-penetrant, and orally active M1 mAChR agonists ACS Med. Chem. Lett. 2010, 1, 244-248
24. Hu, M. K.; Lu, C. F. A facile synthesis of bis-tacrine isosteres Tetrahedron Lett. 2000, 41, 1815-1818
25. Frideling, A.; Faure, R.; Galy, J.-P.; Kenz, A.; Alkorta, I.; Elguero, J. Tetrahydroacridin-9-ones, 9-chlorotetrahydroacridines, 9-amino- tetrahydroacridines and 9-(pyrazol-1-yl)-tetrahydroacridines derived from chiral cyclanones Eur. J. Med. Chem. 2004, 39, 37-48
26. Wang, F.; Huang, K.; Yang, L.; Gong, J.; Tao, Q.; Li, H.; Zhao, Y.; Zeng, S.; Wu, X.; Stöckigt, J.; Li, X.; Qu, J. Preparation of C-23 esterified silybin derivatives and evaluation of their peroxidation inhibitory and DNA protective properties Bioorg. Med. Chem. 2009, 17, 6380-6389
27. Lee, D. Y. W.; Zhang, X.; Ji, X. S. Preparation of tritium-labeled silybin: A protectant for common liver diseases J. Labelled Compd. Radiopharm. 2006, 49, 1125-1130
28. Ellman, G. L.; Courtney, K. D.; Andres, V.; Featherstone, R. M. A new and rapid colorimetric determination of acetylcholinesterase activity Biochem. Pharmacol. 1961, 7, 88-95
29. Decker, M. Novel inhibitors of acetyl- and butyrylcholinesterase derived from the alkaloids dehydroevodiamine and rutaecarpine Eur. J. Med. Chem. 2005, 40, 305-313
30. Çokuǧraş, A. N. Butyrylcholinesterase: Structure and physiological function Turk. J. Biochem. 2003, 28, 54-62
31. Guillozet, A. L.; Smiley, J. F.; Mash, D. C.; Mesulam, M. M. Butyrylcholinesterase in the life cycle of amyloid plaques Ann. Neurol. 1997, 42, 909-918
32. Greig, N. H.; Utsuki, T.; Ingram, D. K.; Wang, Y.; Pepeu, G.; Scali, C.; Yu, Q. S.; Mamczarz, J.; Holloway, H. W.; Giordano, T.; Chen, D.; Furukawa, K.; Sambamurti, K.; Brossi, A.; Lahiri, D. K. Selective butyrylcholinesterase inhibition elevates brain acetylcholine, augments learning, and lowers Alzheimer beta-amyloid peptide in rodent Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 17213-17218
33. Mesulam, M. M.; Guillozet, A.; Shaw, P.; Levey, A.; Duysen, E. G.; Lockridge, O. Acetylcholinesterase knockouts establish central cholinergic pathways and can use butyrylcholinesterase to hydrolyze acetylcholine Neuroscience 2002, 110, 627-639
34. Montiel, T.; Quiroz-Baez, R.; Massieu, L.; Arias, C. Role of oxidative stress on β-amyloid neurotoxicity elicited during impairment of energy in the hippocampus: protection by antioxidants Exp. Neurol. 2006, 200, 496-508
35. Palmer, A. M. Neuroprotective therapeutics for Alzheimer's disease: progress and prospects Trends Pharmacol. Sci. 2011, 32, 141-147
36. Koufaki, M.; Tsatsaroni, A.; Alexi, X.; Guerrand, H.; Zerva, S.; Alexis, M. N. Isoxazole substituted chromans against oxidative stress-induced neuronal damage Bioorg. Med. Chem. 2011, 19, 4841-4859
37. Lee, K. Y.; Hwang, L.; Jeong, E. J.; Kim, S. H.; Kim, Y. C.; Sung, S. H. Effect of neuroprotective flavonoids of Agrimonia eupatoria on glutamate-induced oxidative injury to HT22 hippocampal cells Biosci. Biotechnol. Biochem. 2010, 74, 1704-1706
38. Yang, H.; Sung, S. H.; Kim, J.; Kim, Y. C. Neuroprotective diarylheptanoids from the leaves and twigs of Juglans sinensis against glutamate-induced toxicity on HT22 cells Planta Med. 2011, 77, 841-845
39. Choi, D. W. Glutamate neurotoxicity and diseases of the nervous system Neuron 1988, 1, 623-634
40. Murphy, T. H.; Miyamoto, M.; Sastre, A.; Schnaar, R. L.; Coyle, J. T. Glutamate toxicity in a neuronal cell line involves inhibition of cystine transport leading to oxidative stress Neuron 1989, 2, 1547-1558
41. Maher, P.; Davies, J. B. The role of monoamine metabolism in oxidative glutamate toxicity J. Neurosci. 1996, 16, 6394-6401
42. Tan, S.; Wood, M.; Maher, P. Oxidative stress induces a form of programmed cell death with characteristics of both apoptosis and necrosis in neuronal cells J. Neurochem. 1998, 71, 95-105
43. Tan, S.; Schubert, D.; Maher, P. Oxytosis: a novel form of programmed cell death Curr. Top. Med. Chem. 2001, 1, 497-506
44. Behl, C. Vitamin E protects neurons against oxidative cell death in vitro more effectively than 17-beta estradiol and induces the activity of the transcription factor NF-kappaB J. Neural. Transm. 2000, 107, 393-407
45. Ishige, K.; Schubert, D.; Sagara, Y. Flavonoids protect neuronal cells from oxidative stress by three distinct mechanisms Free Radical Biol. Med. 2001, 30, 433-446
46. Schnabl, B.; Choi, Y. H.; Olsen, J. C.; Hagedorn, C. H.; Brenner, D. A. Immortal activated human hepatic stellate cells generated by ectopic telomerase expression Lab. Invest. 2002, 82, 323-33
47. Gillies, R. J.; Didier, N.; Denton, M. Determination of cell number in monolayer cultures Anal. Biochem. 1986, 159, 109-113
48. Jaeschke, H.; Gores, G. G.; Cederbaum, A. I.; Hinson, J. A.; Pessayre, D.; Lemasters, J. J. Mechanisms of hepatotoxicity Toxicol. Sci. 2002, 65, 166-176
49. Berson, A.; Renault, S.; Lettéron, P.; Robin, M.-A.; Fromenty, B; Fau, D.; Le Bot, M. A.; Riché, C.; Durand-Schneider, A.-M.; Feldmann, G.; Pessayre, D. Uncoupling of rat and human mitochondria: a possible explanation for tacrine-induced liver dysfunction Gastroenterolgy 1996, 110, 1878-1890
50. Lemasters, J. J.; Quian, T.; Bradham, C. A.; Brenner, D. A.; Cascio, W. E.; Trost, L. C.; Nishimura, Y.; Nieminen, A.-L.; Herman, B. Mitochondrial dysfunction in the pathogenesis of necrotic and apoptotic cell death J. Bioenerg. Biomembr. 1999, 31, 305-319
51. Rasola, A; Bernardi, P. The mitochondrial permeability transition pore and its involvement in cell death and in disease pathogenesis Apoptosis 2007, 12, 815-833
52. Oh, H.; Kim, J.-S.; Song, E.-K.; Cho, H.; Kim, D.-H.; Park, S.-E.; Lee, H.-S.; Kim, Y.-C. Sesquiterpenes with hepatoprotective activity from Cnidium monnieri on tacrine-induced cytotoxicity in Hep G2 cells Planta Med. 2002, 68, 748-749
53. Mimica, N.; Presecki, P. Side effects of approved antidementives Psychiatr. Danub. 2009, 21, 108-113
54. Sedky, K.; Nazir, R.; Joshi, A.; Kaur, G.; Lippmann, S. Which psychotropic medications induce hepatotoxicity? Gen. Hosp. Psychiatry 2012, 34, 53-61
55. Letteron, P.; Labbe, G.; Degott, C.; Berson, A.; Fromenty, B.; Delaforge, M.; Larrey, D.; Pessayre, D. Mechanism for the protective effects of silymarin against carbon tetrachloride-induced lipid peroxidation and hepatotoxicity in mice. Evidence that silymarin acts both as an inhibitor of metabolic activation and as a chain-breaking antioxidant Biochem. Pharmacol. 1990, 39, 2027-2034
56. Raskovic, A.; Stilinovic, N.; Kolarovic, J; Vasovic, V.; Yukmirovic, S.; Mikov, M. The protective effects of silymarin against doxorubicin-induced cardiotoxicity and hepatotoxicity in rats Molecules (Basel) 2011, 16, 8601-8613
57. Rawlins, J. N. P.; Deacon, R. M. J. Further Developments of Maze Procedures. In Behavioural Neuroscience, Vol. I: A Practical Approach.; Sahgal, A., Ed.; IRL Press: Oxford, U.K., 1993; pp 95-122
58. Appenroth, D.; Decker, M.; Lehmann, J.; Tränkle, C.; Mohr, K.; Fleck, C. In vivo-investigations on the cholinesterase-inhibiting effects of tricyclic quinazolinimines: Scopolamine-induced cognitive impairments in rats are attenuated at low dosage and reinforced at higher dosage Pfluegers Arch. 2008, 455, 895-901
59. Mosmann, T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays J. Immunol. Methods 1983, 65, 55-63
60. Kraus, B.; Wolff, H.; Elstner, E. F.; Heilmann, J. Hyperforin is a modulator of inducible nitric oxide synthase and phagocytosis in microglia and macrophages Naunyn-Schmiedeberg's Arch. Pharmacol. 2010, 381, 541-553