Advertisement

Neurotoxicity Research

, Volume 27, Issue 3, pp 314–327 | Cite as

Protective Effects of a Piperazine Derivative [N-{4-[4-(2-methoxy-phenyl)-piperazin-1-yl]-phenyl} Carbamic Acid Ethyl Ester] Against Aluminium-Induced Neurotoxicity: Insights From In Silico and In Vivo Studies

  • Poonam Meena
  • Apra Manral
  • Vikas Saini
  • Manisha TiwariEmail author
Original Article

Abstract

The cholinergic hypothesis associated with Alzheimer’s disease has spurred the development of numerous structural classes of compounds with different pharmacological profiles aimed at increasing central cholinergic neurotransmission. In the present study, six synthetic piperazine derivatives D1–D6 were screened for their efficacy as acetylcholinesterase inhibitors (AChEIs) through in silico and in vitro studies. Compound D2 was found to be a potential AChEI with adequate pharmacokinetic properties, as supported by in silico study. Further, in vivo studies were designed to examine the protective effect of piperazine derivative D2 (3 and 5 mg/kg for 6 weeks) in ameliorating the alterations induced by aluminium chloride (AlCl3) on behavioural and neurochemical indices. Behavioural tests (Morris water maze and elevated plus maze) revealed significant alterations in the short-term memory and anxiety levels in rats treated with AlCl3, which was further improved after D2 treatment. Further, D2 treatment attenuated the neurotoxic effects of AlCl3 as shown by the improvement in rats performance in Water maze test and in lowering AChE activity. Besides preventing lipid peroxidation and protein damage, changes in the levels of endogenous antioxidant enzymes (GST, GPx, GR and GSH) associated with AlCl3 administration were also restored upon treatment with D2. Thus, our results support the neuroprotective potential of compound D2, thus validating its use in alleviating toxic effects of aluminium.

Keywords

Acetylcholinesterase Molecular docking Aluminium Neurotoxicity Oxidative stress Neuroprotective 

Notes

Acknowledgments

The authors wish to acknowledge the financial assistance provided by the Department of Science & Technology, Government of India and the facilities provided by University of Delhi. The author Ms. Poonam Meena wishes to acknowledge the award of the Rajiv Gandhi National Fellowship from the University Grants Commission. Scientific contributions from Prof. Vani Brahmachari are gratefully acknowledged. The authors wish to acknowledge the Bioinformatics facility of ACBR.

Conflict of interest

The authors declare that there is no conflict of interest.

References

  1. Andersson CD, Forsgren N, Akfur C, Allgardsson A, Berg L, Engdahl C, Qian W, Ekström F, Linusson A (2013) Divergent structure–activity relationships of structurally similar acetylcholinesterase inhibitors. J Med Chem 56:7615–7624CrossRefPubMedGoogle Scholar
  2. Aviv P, Qiong X, Harry MG, Wei F, Yun T, Yun T, Israel S, Zhuibai Q, Joel LS (2009) The crystal structure of a complex of acetylcholinesterase with a bis-(-)- nor-meptazinol derivative reveals disruption of the catalytic triad. J Med Chem 52(8):2543–2549CrossRefGoogle Scholar
  3. Benzi G, Marzatico F, Pastoris O, Villa RF (1989) Relationship between aging, drug treatment and the cerebral enzymatic antioxidant system. Exp Gerontol 24(2):137–148CrossRefPubMedGoogle Scholar
  4. Berkheij M (2005) Synthesis of 2-substituted piperazines via direct α-lithiation. Tetrahedron Lett 46:2369–2371CrossRefGoogle Scholar
  5. Bhalla P, Garg ML, Dhawan DK (2010) Protective role of lithium during aluminum-induced neurotoxicity. Neurochem Int 56(2):256–262CrossRefPubMedGoogle Scholar
  6. Bihaqi SW, Sharma M, Singh AP, Tiwari M (2009) Neuroprotective role of Convolvulus Pluricaulis on aluminium induced neurotoxicity. J Ethnopharmacol 124(3):409–415CrossRefPubMedGoogle Scholar
  7. Bolognesi ML, Andrisano V, Bartolini M, Cavalli A, Minarini A, Recanatini M, Rosini M, Tumiatti V, Melchiorre C (2005) Heterocyclic inhibitors of AChE acylation and peripheral sites. II Farmaco 60:465–473CrossRefGoogle Scholar
  8. Butterfield DA, Lauderback CM (2002) Lipid peroxidation and protein oxidation in Alzheimer’s disease brain: potential causes and consequences involving amyloid β-peptide-associated free radical oxidative stress. Free Radic Biol Med 32(11):1050–1060CrossRefPubMedGoogle Scholar
  9. Carlberg I, Mannervik B (1975) Purification and characterization of the flavoenzyme glutathione reductase from rat liver. J Biol Chem 250(14):5475–5480PubMedGoogle Scholar
  10. Carli M, Balducci C, Millan MJ, Bonalumi P, Samanin R (1999) S:15535, a benzodioxopiperazine acting as presynaptic agonist and postsynaptic 5-HT1A receptor antagonist, prevents the impairment of spatial learning caused by intrahippocampal scopolamine. Br J Pharmacol 128(6):1207–1214CrossRefPubMedCentralPubMedGoogle Scholar
  11. Chaudhary P, Kumar R, Verma AK et al (2006) Synthesis and antimicrobial activity of N-alkyl and N-aryl piperazine derivatives. Bioorg Med Chem 14(6):1819–1826CrossRefPubMedGoogle Scholar
  12. Cumming J, Babu S, Huang Y, Carrol C, Chen X, Favreau L, Greenlee W et al (2010) Piperazine sulfonamide BACE1 inhibitors:design, synthesis, and in vivo characterization. Bioorg Med Chem Lett 20(9):2837–2842CrossRefPubMedGoogle Scholar
  13. Dorronsoro I, Castro A, Martinez A (2003) Peripheral and dual binding site inhibitors of acetylcholinesterase as neurodegenerative disease-modifying agents. Exp Opin Ther Patents 13(11):1725–1732Google Scholar
  14. Dua R, Gill KD (2001) Aluminum phosphide exposure: implications on rat brain lipid peroxidation and antioxidant defence system. Pharmacol Toxicol 89(6):315–319CrossRefPubMedGoogle Scholar
  15. Edwin HR, Boris B, Harry MG, Dawn MW, David S, Larry DW, Paul RC, Yuan-Ping P, Israel S, Joel LS (2006) Complexes of alkylene-linked tacrine dimers with Torpedo californica acetylcholinesterase: Binding of bis(5)-tacrine produces a dramatic rearrangement in the active-site gorge. J Med Chem 49(18):5491–5500CrossRefGoogle Scholar
  16. Ellman GL, Courtney KD, Andres V Jr, Feather-Stone RM (1961) A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 7(2):88–90CrossRefPubMedGoogle Scholar
  17. Farlow M (2002) A clinical overview of cholinesterase inhibitors in Alzheimer’s disease. Int Psychogeriatr 14:93–126CrossRefPubMedGoogle Scholar
  18. Flohe L, Gunzler W (1984) Assays of glutathione peroxidase. In: Packer L (ed) Methods in Enzymology, vol 105. Academic Press, New York, pp 14–120Google Scholar
  19. Francis PT, Palmer AM, Snape M, Wilcock GK (1999) The cholinergic hypothesis of Alzheimer’s disease: a review of progress. J Neurol Neurosurg Psychiatry 66:137–147CrossRefPubMedCentralPubMedGoogle Scholar
  20. Gandhi S, Abramov AY (2012) Mechanism of oxidative stress in neurodegeneration. Oxid Med Cell Longev 428010:11Google Scholar
  21. García-Alberca JM, Lara JP, Berthier ML (2011) Anxiety and depression in caregivers are associated with patient and caregiver characteristics in Alzheimer’s disease. Int J Psychiatry Med 41:57–69CrossRefPubMedGoogle Scholar
  22. Gulya K, Rakonczay Z, Kasa P (1990) Cholinotoxic effects of aluminum in rat brain. J Neurochem 54(3):1020–1026CrossRefPubMedGoogle Scholar
  23. Habig WH, Pabst MJ, Jakoby WB (1974) Glutathione-S-transferase: the first enzymatic step in mercapturic acid formation. J Biol Chem 249(22):7130–7139PubMedGoogle Scholar
  24. Harel M, Schalk I, Ehret-Sabatier L, Bouet F, Goeldner M, Hirth C, Axelsen PH, Silman I, Sussman JL (1993) Quaternary ligand binding to aromatic residues in the active-site gorge of acetylcholinesterase. Proc Natl Acad Sci USA 90(19):9031–9035CrossRefPubMedCentralPubMedGoogle Scholar
  25. Jhon V, Lieberburg I, Thorsett ED (1993) Alzheimer’s Disease:current therapeutic approaches. Annu Rep Med Chem 28:197–206CrossRefGoogle Scholar
  26. Jollow DJ, Mitchell JR, Zampaglione N, Gillette JR (1974) Bromobenzene-induced liver necrosis. Protective role of glutathione and evidence for 3,4-bromobenzene oxide as the hepatotoxic metabolite. Pharmacology 11:151–169CrossRefPubMedGoogle Scholar
  27. Kelder J, Grootenhuis PDJ, Bayada DM, Delbressine LPC, Ploemen JP (1999) Polar molecular surface as a dominating determinant for oral absorption and brain penetration of drugs. Pharm Res 16(10):1514CrossRefPubMedGoogle Scholar
  28. Khatri M, Rai SK, Alam S, Vij A, Tiwari M (2009) Synthesis and pharmacological evaluation of new arylpiperazines N-[4-[4-(aryl) piperazine-1-yl]-phenyl]-amine derivatives: putative role of 5-HT1A receptors. Bioorg Med Chem 17(5):1890–1897CrossRefPubMedGoogle Scholar
  29. Khatri M, Rai SK, Ranbhor R, Kishore K, Tiwari M (2012) Synthesis and pharmacological evaluation of [(4-Arylpiperazin-1-yl)-alkyl]-carbamic acid ethyl ester derivatives as potential anxiolytic agents. Arch Pharm Res 35(7):1143CrossRefPubMedGoogle Scholar
  30. Kumar V, Gill KD (2009) Aluminium neurotoxicity: neurobehavioural and oxidative aspects. Arch Toxicol 83(11):965–978. doi: 10.1007/s00204-009-0455-6 CrossRefPubMedGoogle Scholar
  31. Kumar A, Prakash A, Dogra S (2011) Neuroprotective effect of carvedilol against aluminium induced toxicity: possible behavioral and biochemical alterations in rats. Pharmacol Rep 63(4):915–923CrossRefPubMedGoogle Scholar
  32. Laras Y, Garino C, Dessolin J, Weck C, Moret V, Rolland A, Kraus JL (2009) New N4-substituted piperazine naphthamide derivatives as BACE-1 inhibitors. J Enzyme Inhib Med Chem 24(1):181–187CrossRefPubMedGoogle Scholar
  33. Levine RL, Garland D, Oliver CN, Amici A, Climent I, Lenz AG, Ahn BW, Shaltiel S, Stadtman ER (1990) Determination of carbonyl content in oxidatively modified proteins. Methods Enzymol 186:464–478CrossRefPubMedGoogle Scholar
  34. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (2001) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Del Rev 46:3–26CrossRefGoogle Scholar
  35. Lister RG (1987) The use of a plus-maze to measure anxiety in the mouse. Psychopharmacology 92(2):180–185CrossRefPubMedGoogle Scholar
  36. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with folin phenol reagent. J Biol Chem 193:265–275PubMedGoogle Scholar
  37. Luo Y, Nie J, Gong QH, Lu YF, Wu Q, Shi JS (2007) Protective effects of icariin against learning and memory deficits induced by aluminium in rats. Clin Exp Pharmacol Physiol 34(8):792–795CrossRefPubMedGoogle Scholar
  38. Mallesha L, Mohana KN (2011) Synthesis, antimicrobial and antioxidant activities of 1-(1, 4-benzodioxane-2-carbonyl) piperazine derivatives. Eur J Chem 2(2):193–199CrossRefGoogle Scholar
  39. Matsuoka N, Aigner TG (1997) FK960 [N-(4-acetyl-1-piperazinyl)- p-fluorobenzamide monohydrate], a novel potential antidementia drug, improves visual recognition memory in rhesus monkeys: comparison with physostigmine. J Pharmacol Exp Ther 280:1201–1209PubMedGoogle Scholar
  40. Matsuoka N, Satoh M (1998) FK960, a novel potential antidementia drug, augments long-term potentiation in mossy fiber-CA3 pathway of guinea-pig hippocampal slices. Brain Res 794(2):248–254CrossRefPubMedGoogle Scholar
  41. Meiri H, Banin E, Roll M, Rousseau A (1993) Toxic effects of aluminium on nerve cells and synaptic transmission. Prog Neurobiol 40(1):89–121CrossRefPubMedGoogle Scholar
  42. Meister A, Tate SS (1976) Glutathione and related γ-glutamyl compounds: biosynthesis and utilization. Annu Rev Biochem 45:559–604CrossRefPubMedGoogle Scholar
  43. Miezan Ezoulin JM, Shao BY, Xia Z, Xie Q, Li J, Cui YY, Wang H et al (2009) Novel piperazine derivative PMS1339 exhibits tri-functional properties and cognitive improvement in mice. Int J Neuropsychopharmacol 12(10):1409–1419CrossRefPubMedGoogle Scholar
  44. Morris R (1984) Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods 11(1):47–60CrossRefPubMedGoogle Scholar
  45. Nehru B, Bhalla P, Garg A (2007) Further evidence of centrophenoxine mediated protection in aluminium exposed rats by biochemical and light microscopy analysis. Food Chem Toxicol 45(12):2499–2505CrossRefPubMedGoogle Scholar
  46. Okhawa H, Ohishi N, Yaga K (1979) Assay of lipid peroxides in animal tissue by thiobarbituric acid reaction. Anal Biochem 95(2):351–358CrossRefGoogle Scholar
  47. Poroikov VV, Filimonov DA, Ihlenfeld WD, Gloriozova TA, Lagunin AA, Borodina YuV, Stepanchikova AV, Nicklaus MC (2003) PASS biological activity spectrum predictions in the enhanced open NCI database browser. J Chem Inf Comput Sci 43(1):228–236CrossRefPubMedGoogle Scholar
  48. Prakash A, Kumar A (2009) Effect of N-acetyl cysteine against aluminium-induced cognitive dysfunction and oxidative damage in rats. Basic Clin Pharmacol Toxicol 105(2):98–104CrossRefPubMedGoogle Scholar
  49. Querfurth HW, LaFerla FM (2010) Alzheimer’s Disease. N Engl J Med 362:329–344CrossRefPubMedGoogle Scholar
  50. Rankin J, Sedowofia K, Clayton R, Manning A (1993) Behavioral effects of gestational exposure to aluminum. Am Ist Super Sanita 29(1):147–152Google Scholar
  51. Rossen K, Weissman SA, Sager J et al (1995) Asymmetric hydrogenation of tetrahydropyrazines : synthesis of (S)-piperazine-2-tert-butylcarboxamide, an intermediate in the preparation of the HIV protease inhibitor indinavir. Tetrahedron Lett 36(36):6419–6422CrossRefGoogle Scholar
  52. Sadashiva CT, Narendra Sharath Chandra JN, Ponnappa KC, Veerabasappa Gowda T, Rangappa KS (2006) Synthesis and efficacy of 1-[bis(4-fluorophenyl)-methyl]piperazine derivatives for acetylcholinesterase inhibition, as a stimulant of central cholinergic neurotransmission in Alzheimer’s disease. Bioorg Med Chem Lett 16(15):3932–3936CrossRefPubMedGoogle Scholar
  53. Seignourel PJ, Kunik ME, Snow L, Wilson N, Stanley M (2008) Anxiety in dementia: a critical review. Clin Psychol Rev 28(7):1071–1082CrossRefPubMedCentralPubMedGoogle Scholar
  54. Shen L, Liu G, Tang Y (2007) Molecular docking and 3D-QSAR studies of 2-substituted 1-indanone derivatives as acetylcholinesterase inhibitors. Acta Pharmacol Sin 28:2053–2063CrossRefPubMedGoogle Scholar
  55. Sood A, Warren Beach J, Webster SJ, Terry AV, Buccafusco JJ (2007) The effects of JWB1-84-1 on memory-related task performance by amyloid Aβ transgenic mice and by young and aged monkeys. Neuropharmacology 53(5):588–600CrossRefPubMedGoogle Scholar
  56. Thirunavukkarasu SV, Venkataraman S, Raja S, Upadhyay L (2012) Neuropro-tective effect of Manasamitra vatakam against aluminium induced cognitive impairment and oxidative damage in the cortex and hippocampus of rat brain. Drug Chem Toxicol 35(1):104–115CrossRefPubMedGoogle Scholar
  57. Upadhayaya RS, Sinha N, Jain S, Kishore N, Chandra R, Arora SK (2004) Optically active antifungal azoles: synthesis and antifungal activity of (2R,3S)-2-(2,4-difluorophenyl)-3-(5-2-[4-aryl-piperazin-1-yl]-ethyl-tetrazol-2-yl/1-yl)-1-[1,2,4] triazol-1-yl-butan-2-ol. Bioorg Med Chem 12(9):2225–2238CrossRefPubMedGoogle Scholar
  58. Wimo A, Winblad B, Jonsson L (2010) The worldwide societal costs of dementia: estimates for 2009. Alzheimers Dement 6(2):98–103CrossRefPubMedGoogle Scholar
  59. Winkler J, Thal L, Gage F, Fisher LJ (1998) Cholinergic strategies for Alzheimer’s disease. J Mol Med 76(8):555–567CrossRefPubMedGoogle Scholar
  60. Yellamma K, Saraswathamma S, Kumar BN (2010) Cholinergic system under aluminium toxicity in rat brain. Toxicol Int 17(2):106–112CrossRefPubMedCentralPubMedGoogle Scholar
  61. Yokel RA (2000) The toxicology of aluminum in the brain: a review. Neurotoxicology 21:813–828PubMedGoogle Scholar
  62. Zatta P, Lucchini R, van Rensburg SJ, Taylor A (2003) The role of metals in neurodegenerative processes: aluminum, manganese, and zinc. Brain Res Bull 62(1):15–28CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Poonam Meena
    • 1
  • Apra Manral
    • 1
  • Vikas Saini
    • 1
  • Manisha Tiwari
    • 1
    Email author
  1. 1.Bio-Organic Chemistry Laboratory, Dr. B. R. Ambedkar Centre for Biomedical ResearchUniversity of DelhiDelhiIndia

Personalised recommendations