Download PDF
Arzneimittelforschung 2010; 60(6): 299-306
DOI: 10.1055/s-0031-1296291
CNS-active Drugs · Hypnotics · Psychotropics · Sedatives
Editio Cantor Verlag Aulendorf (Germany)

Investigation into the in vivo effects of five novel tacrine/ferulic acid and β-carboline derivatives on scopolamine-induced cognitive impairment in rats using radial maze paradigm

Christian Fleck
1   Institute of Pharmacology and Toxicology, Friedrich Schiller University, Jena, Germany
,
Dorothea Appenroth
1   Institute of Pharmacology and Toxicology, Friedrich Schiller University, Jena, Germany
,
Lei Fang
2   Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University, Jena, Germany
3   School of Chemistry and Chemical Engineering, South-East University, Nanjing, P. R. China
,
Yvonne Schott
2   Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University, Jena, Germany
,
Jochen Lehmann
2   Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University, Jena, Germany
,
Michael Decker
2   Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University, Jena, Germany
› Author Affiliations
Further Information

Publication History

Publication Date:
02 December 2011 (online)

    Permissions and Reprints

Abstract

Two tacrine-ferulic acid hybrids (1 A, 1 B) and three β-carboline derivatives (BCs;2 A, 2B, 2C) were tested in vivo on 3-month-old female rats as multi-potent anti-Alzheimer drug candidates. In vitro, the two tacrine-ferulic acid hybrids show higher acetylcholinesterase (AChE) inhibitory activity and comparable butyrylcholinesterase (BChE) inhibitory activity compared to tacrine (CAS 1684-40-8). However, in vivo both substances have no beneficial effect on scopolamine (CAS 51-34-3) induced cognition impairment. Onthe contrary, 1B even worsen the scopolamine induced cognition impairment The β-carboline derivatives 2 A, 2B, and 2 C, the inhibitory potency of which at AChE reaching tacrine activity does not antagonize scopolamine induced impairment of cognition in rats measured in radial maze paradigm. Compounds 2A and1 B might act as positive allosteric modulators of scopolamine action at the mus-carinic acetylcholine receptors. On the basis of these results it can be concluded that both ferulic acid- (CAS 537-98-4) and BC-derivatives are not qualified as cognition improving drugs and further studies in this field should be focussed on other pharmaceutical leads to find effective anti-Alzheimer drugs.

Key words

Anti-Alzheimer drugs - Antioxidants - b-Carbolines - Cholinesterase inhibitors - Ferulic acid, hybrid molecule,rat - Tacrine, hybrid molecule, rat
 

  • References

  • 1 Appenroth D, Decker M, Lehmann J, Fleck C. In vivo-in-vestigations on the cholinesterase-inhibiting effects of tricyclic quinazolinimines: Scopolamine-induced cognitive impairments in rats are attenuated at low dosage and reinforced at higher dosage. Pflügers Arch Eur J Physiol. 2008; 455: 895-901
    PubMedGoogle Scholar
  • 2 Appenroth D, Fleck C. Influence of age on cognition and scopolamine induced memory impairment in rats measured in the radial maze paradigm. Arzneimittelforschung. 2010; 60 (6) 293-8
    Article in Thieme ConnectPubMedGoogle Scholar
  • 3 Bassant MH, Jazat-Poindessous F, Lamour Y. Effects of metrifonate, a cholinesterase inhibitor, on local cerebral glucose utilization in young and aged rats. J Cereb Blood Flow Metab. 1996; 16: 1014-25
    PubMedGoogle Scholar
  • 4 Buccafusco JJ. The revival of scopolamine reversal for the assessment of cognition-enhancing drugs. In: Frontiers in neuroscience. Methods of behavior analysis in neuroscience. Buccafusco JJ. editor. Boca Raton (USA): CRC Press; 2009: 329-344
    Google Scholar
  • 5 Cavalli A, Bolognesi ML, Minarini A, Rosini M, Tumiatti V, Recanatini M et al Multi-target-directed ligands to com-bat neurodegenerative diseases. J Med Chem. 2008; 51: 347-72
    CrossrefPubMedGoogle Scholar
  • 6 Dávalos A, Gómez-Cordovés C, Bartolomé B. Extending applicability of the oxygen radical absorbance capacity (ORAC-Fluorescein) assay. J Agric Food Chem. 2004; 52: 48-54
    CrossrefPubMedGoogle Scholar
  • 7 Decker M. Recent advances in the development of hybrid molecules/designed multiple compounds with antiamnesic properties. Mini Rev Med Chem. 2007; 7: 221-9
    CrossrefPubMedGoogle Scholar
  • 8 Doraiswamy PM. Non-cholinergic strategies for treating and preventing Alzheimer’s disease. CNS Drugs. 2002; 16: 811-24
    CrossrefPubMedGoogle Scholar
  • 9 Eckerman DA, Gordon WA, Edwards JD, McPhail R, Gage MI. Effects of scopolamine, pentobarbital, and amphetamine on radial arm maze performance in the rat. Pharmacol Biochem Behav. 1980; 12: 595-602
    CrossrefPubMedGoogle Scholar
  • 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: 2905-9
    CrossrefPubMedGoogle Scholar
  • 11 Fisher A, Hanin I. Potential animal models for senile dementia of Alzheimer’s type, with emphasis on AF64A-induced cholinotoxicity. Ann Rev Pharmacol Toxicol. 1986; 26: 161-81
    CrossrefPubMedGoogle Scholar
  • 12 Fleck C, Appenroth D, Decker M, Lehmann J. A new way of data interpretation for cognition tests in rats used to characterise six choline esterase inhibitors with heterocyclic nitrogen bridgehead structure: application for Alzheimer therapy. Arzneimittelforschung. 2008; 58 (11) 543-50
    Article in Thieme ConnectPubMedGoogle Scholar
  • 13 Francis PT, Palmer AM, Snape A, Wilcock GK. The cholinergic hypothesis of Alzheimer’s disease: a review of progress. J Neurol Neurosurg Psychiatry. 1999; 66: 137-47
    CrossrefPubMedGoogle Scholar
  • 14 Ghosal S, Bhattacharya SK, Mehta R. Naturally occurring and synthetic β-carbolines as cholinesterase inhibitors. Pharm Sci. 1972; 61: 808-10
    CrossrefPubMedGoogle Scholar
  • 15 Giacobini E. Drugs that target cholinesterases. In: Buccafusco JJ. editor. Cognitive Enhancing Drugs. Basle-Boston-Berlin: Birkhäuser; 2004: 11-36
    CrossrefGoogle Scholar
  • 16 Graf E. Antioxidant potential of ferulic acid. Free Radic Biol Med. 1992; 13: 435-48
    CrossrefPubMedGoogle Scholar
  • 17 Griffin WS, Mrak RE. Interleukin-1 in the genesis and progression of and risk for development of neuronal degeneration in Alzheimer’s disease. J Leukoc Biol. 2002; 72: 233-8
    PubMedGoogle Scholar
  • 18 Heilmann J, Çalis I, Kirmizbekmez H, Schühly W, Harput S, Sticher O. Radical scavenger activity of phenylethanoid glycosides in FMLP stimulated human polymorphonuclear leukocytes: structure-activity relationships. Planta Med. 2000; 66: 746-8
    Article in Thieme ConnectPubMedGoogle Scholar
  • 19 Holzgrabe U, Kapkova P, Alptuezuen V, Scheiber J, Kugel-mann E. Targeting acetylcholinesterase to treat neurode-generation. Expert Opin Ther Targets. 2007; 11: 161-79
    CrossrefPubMedGoogle Scholar
  • 20 Johnson G, Moore SW. The peripheral anionic site of acetylcholinesterase: Structure, functions and potential role in rational drug design. Curr PharmDesign. 2006; 12: 217-25
    PubMedGoogle Scholar
  • 21 Kanski J, Aksenova M, Stoyanova A, Butterfield DA. Ferulicacid antioxidant protection against hydroxyl and peroxyl radical oxidation in synaptosomal and neuronal cell culture systems in vitro : structure-activity studies. J Nutr Biochem. 2002; 13: 273-81
    CrossrefPubMedGoogle Scholar
  • 22 Kikuzaki H, Hisamoto M, Hirose K, Akiyama K, Taniguchi H. Antioxidant properties of ferulic acid and its related compounds. J Agric Food Chem. 2002; 50: 2161-8
    CrossrefPubMedGoogle Scholar
  • 23 Kim HS, Cho JY, Kim DH, Yan JJ, Lee HK, Suh HW et al Inhibitory effects of long-term administration of ferulic acid on microglial activation induced by intracerebroven-tricular injection of β-amyloid peptide (1–42) in mice. Biol Pharm Bull. 2004; 27: 120-1
    CrossrefPubMedGoogle Scholar
  • 24 Matsubara K, Kobayashi S, Kobayashi. Yamashita K, Koide H, Hatta M et al Beta-carbolinium cations, endogenous MPP++ analogs, in the lumbar cerebrospinal fluid of patients with Parkinson’s disease. Neurology. 1995; 45: 2240-5
    CrossrefPubMedGoogle Scholar
  • 25 Messer Jr JS. Drugs that target muscarinic cholinergic receptors. In: Buccafusco JJ. editor. Cognitive Enhancing Drugs. Basle-Boston-Berlin: Birkhäuser; 2004: 37-49
    CrossrefGoogle Scholar
  • 26 Mrak RE, Griffin WS. Interleukin-1, neuroinflammation,and Alzheimer’s disease. Neurobiol Aging. 2001; 22: 903-8
    CrossrefPubMedGoogle Scholar
  • 27 Ni JW, Matsumoto K, Li HB, Murakami Y, Watanabe H. Neuronal damage and decrease of central acetylcholine level following permanent occlusion of bilateral common carotid arteries in rat. Brain Res. 1995; 673: 290-96
    CrossrefPubMedGoogle Scholar
  • 28 Nordberg A. Mechanisms behind the neuroprotective actions of cholinesterase inhibitors in Alzheimer’s disease. Alzheimer Dis Assoc Disorders. 2006; 20: S12-8
    CrossrefPubMedGoogle Scholar
  • 29 Nunomura A, Castellani RJ, Zhu X, Moreira PI, Perry G, Smith MA. Involvement of oxidative stress in Alzheimer disease. J Neuropathol Exp Neurol. 2006; 65: 631-41
    CrossrefPubMedGoogle Scholar
  • 30 Ogiwara T, Satoh K, Kadoma Y, Muratami Y, Unten S, Atsumi T et al Radical scavenging activity and cytotoxicity of ferulic acid. Anticancer Res. 2002; 22: 2711-7
    PubMedGoogle Scholar
  • 31 Park CH, Lee YJ, Lee SH, Choi SH, Kim H-S, Jeong SJ et al Dehydroevodiamine HCl prevents impairment of learning and memory and neuronal loss in rat models of cognitive disturbance. J Neurochem. 2000; 74: 244-53
    PubMedGoogle Scholar
  • 32 Picone P, Bondi ML, Montana G, Bruno A, Pitarresi G, Giammona G et al Ferulic acid inhibits oxidative stress and cell death induced by Ab oligomers: Improved delivery by solid lipid nanoparticles. Free Radical Res. 2009; 43: 1133-45
    CrossrefPubMedGoogle Scholar
  • 33 Rawlins JNP, Deacon RMJ. Further developments of maze procedures. In: Sahgal A. editor Behavioural Neuroscience. Vol. I: A Practical Approach. Oxford: IRL Press; 1993: 95-122
    Google Scholar
  • 34 Rush DK. Scopolamine amnesia of passive avoidance: a deficit of information acquisition. Behav Neural Biol. 1988; 50: 255-74
    CrossrefPubMedGoogle Scholar
  • 35 Schott Y, Decker M, Rommelspacher H, Lehmann J. 6-Hy-droxy- and 6-methoxy-b-carbolines as acetyl- and butyrylcholinesterase inhibitors. Bioorg Med Chem Lett. 2006; 16: 5840-3
    Google Scholar
  • 36 Schubert P, Ogata T, Marchini C, Ferroni S. Glia-related pathomechanisms in Alzheimer’s disease: a therapeutic target?. Mech Ageing Dev. 2001; 123: 47-57
    CrossrefPubMedGoogle Scholar
  • 37 Smith MA, Rottkamp CA, Nunomura A, Raina AK, Perry G. Oxidative stress in Alzheimer’s disease. Biochim Biophys Acta. 2000; 1502: 139-44
    CrossrefPubMedGoogle Scholar
  • 38 Trombino S, Serini S, DiNicuolo F, Celleno L, Ando S, Picci N et al Antioxidant effect of ferulic acid in isolated membranes and intact cells: synergistic interactions with alpha-tocopherol, beta-carotene, and ascorbic acid. J Agric Food Chem. 2004; 528: 2411-20
    PubMedGoogle Scholar
  • 39 Wang T, Tang XC. Reversal of scopolamine-induced deficits in radial-arm maze performance by (–)huperizine A: comparison with E2020 and tacrine. Eur J Pharmacol. 1998; 349: 137-42
    CrossrefPubMedGoogle Scholar
  • 40 Watkins PB, Zimmerman HJ, Knapp MJ, Gracon SI, Lewis KW. Hepatotoxic effects of tacrine administration in patients with Alzheimer’s disease. J Am Med Assoc. 1994; 271: 992-8
    CrossrefPubMedGoogle Scholar
  • 41 Wirsching BA, Beninger RJ, Jhamandas K, Boegman RJ, El Defrawy SR. Differential effects of scopolamine on working and reference memory of rats in the radial maze. Pharmacol Biochem Behav. 1984; 20: 659-62
    CrossrefPubMedGoogle Scholar
  • 42 Yamaguchi Y, Higashi M, Matsuno T, Kawashima S. Ameliorative effects of azaindolizinone derivative ZSET845 on scopolamine-induced deficits in passive avoidance and ra-dial-arm maze learning in the rat. Jpn J Pharmacol. 2001; 87: 240-44
    CrossrefPubMedGoogle Scholar
  • 43 Yan J, Cho J, Kim H, Kim K, Jung J, Huh S et al Protection against β-amyloid peptide toxicity in vivo with long-term administration of ferulic acid. Br J Pharmacol. 2001; 133: 89-96
    CrossrefPubMedGoogle Scholar
  • 44 Lei Fang, Jumpertz S, Yihua Zhang, Appenroth D, Fleck C, Mohr K et al Hybrid molecules from xanomeline and tacrine: enhanced tacrine actions on cholinesterases and muscarine M1 receptors. J Med Chem. Forthcoming 2010
    PubMedGoogle Scholar