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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

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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.

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References

  • 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 56:7615–7624

    Article  CAS  PubMed  Google Scholar 

  • 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):2543–2549

    Article  Google Scholar 

  • Benzi G, Marzatico F, Pastoris O, Villa RF (1989) Relationship between aging, drug treatment and the cerebral enzymatic antioxidant system. Exp Gerontol 24(2):137–148

    Article  CAS  PubMed  Google Scholar 

  • Berkheij M (2005) Synthesis of 2-substituted piperazines via direct α-lithiation. Tetrahedron Lett 46:2369–2371

    Article  CAS  Google Scholar 

  • Bhalla P, Garg ML, Dhawan DK (2010) Protective role of lithium during aluminum-induced neurotoxicity. Neurochem Int 56(2):256–262

    Article  CAS  PubMed  Google Scholar 

  • Bihaqi SW, Sharma M, Singh AP, Tiwari M (2009) Neuroprotective role of Convolvulus Pluricaulis on aluminium induced neurotoxicity. J Ethnopharmacol 124(3):409–415

    Article  CAS  PubMed  Google Scholar 

  • 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 60:465–473

    Article  CAS  Google Scholar 

  • 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):1050–1060

    Article  CAS  PubMed  Google Scholar 

  • Carlberg I, Mannervik B (1975) Purification and characterization of the flavoenzyme glutathione reductase from rat liver. J Biol Chem 250(14):5475–5480

    CAS  PubMed  Google Scholar 

  • 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):1207–1214

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • 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):1819–1826

    Article  CAS  PubMed  Google Scholar 

  • 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):2837–2842

    Article  CAS  PubMed  Google Scholar 

  • 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):1725–1732

    CAS  Google Scholar 

  • Dua R, Gill KD (2001) Aluminum phosphide exposure: implications on rat brain lipid peroxidation and antioxidant defence system. Pharmacol Toxicol 89(6):315–319

    Article  CAS  PubMed  Google Scholar 

  • 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):5491–5500

    Article  Google Scholar 

  • Ellman GL, Courtney KD, Andres V Jr, Feather-Stone RM (1961) A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 7(2):88–90

    Article  CAS  PubMed  Google Scholar 

  • Farlow M (2002) A clinical overview of cholinesterase inhibitors in Alzheimer’s disease. Int Psychogeriatr 14:93–126

    Article  PubMed  Google Scholar 

  • Flohe L, Gunzler W (1984) Assays of glutathione peroxidase. In: Packer L (ed) Methods in Enzymology, vol 105. Academic Press, New York, pp 14–120

    Google Scholar 

  • Francis PT, Palmer AM, Snape M, Wilcock GK (1999) The cholinergic hypothesis of Alzheimer’s disease: a review of progress. J Neurol Neurosurg Psychiatry 66:137–147

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Gandhi S, Abramov AY (2012) Mechanism of oxidative stress in neurodegeneration. Oxid Med Cell Longev 428010:11

    Google Scholar 

  • 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 41:57–69

    Article  PubMed  Google Scholar 

  • Gulya K, Rakonczay Z, Kasa P (1990) Cholinotoxic effects of aluminum in rat brain. J Neurochem 54(3):1020–1026

    Article  CAS  PubMed  Google Scholar 

  • Habig WH, Pabst MJ, Jakoby WB (1974) Glutathione-S-transferase: the first enzymatic step in mercapturic acid formation. J Biol Chem 249(22):7130–7139

    CAS  PubMed  Google Scholar 

  • 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):9031–9035

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Jhon V, Lieberburg I, Thorsett ED (1993) Alzheimer’s Disease:current therapeutic approaches. Annu Rep Med Chem 28:197–206

    Article  Google Scholar 

  • 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 11:151–169

    Article  CAS  PubMed  Google Scholar 

  • 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):1514

    Article  CAS  PubMed  Google Scholar 

  • 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):1890–1897

    Article  CAS  PubMed  Google Scholar 

  • 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):1143

    Article  CAS  PubMed  Google Scholar 

  • Kumar V, Gill KD (2009) Aluminium neurotoxicity: neurobehavioural and oxidative aspects. Arch Toxicol 83(11):965–978. doi:10.1007/s00204-009-0455-6

    Article  CAS  PubMed  Google Scholar 

  • 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):915–923

    Article  CAS  PubMed  Google Scholar 

  • 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):181–187

    Article  CAS  PubMed  Google Scholar 

  • 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 186:464–478

    Article  CAS  PubMed  Google Scholar 

  • 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 46:3–26

    Article  CAS  Google Scholar 

  • Lister RG (1987) The use of a plus-maze to measure anxiety in the mouse. Psychopharmacology 92(2):180–185

    Article  CAS  PubMed  Google Scholar 

  • Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with folin phenol reagent. J Biol Chem 193:265–275

    CAS  PubMed  Google Scholar 

  • 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):792–795

    Article  CAS  PubMed  Google Scholar 

  • Mallesha L, Mohana KN (2011) Synthesis, antimicrobial and antioxidant activities of 1-(1, 4-benzodioxane-2-carbonyl) piperazine derivatives. Eur J Chem 2(2):193–199

    Article  CAS  Google Scholar 

  • 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 280:1201–1209

    CAS  PubMed  Google Scholar 

  • 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):248–254

    Article  CAS  PubMed  Google Scholar 

  • Meiri H, Banin E, Roll M, Rousseau A (1993) Toxic effects of aluminium on nerve cells and synaptic transmission. Prog Neurobiol 40(1):89–121

    Article  CAS  PubMed  Google Scholar 

  • Meister A, Tate SS (1976) Glutathione and related γ-glutamyl compounds: biosynthesis and utilization. Annu Rev Biochem 45:559–604

    Article  CAS  PubMed  Google Scholar 

  • 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):1409–1419

    Article  CAS  PubMed  Google Scholar 

  • Morris R (1984) Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods 11(1):47–60

    Article  CAS  PubMed  Google Scholar 

  • 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):2499–2505

    Article  CAS  PubMed  Google Scholar 

  • Okhawa H, Ohishi N, Yaga K (1979) Assay of lipid peroxides in animal tissue by thiobarbituric acid reaction. Anal Biochem 95(2):351–358

    Article  Google Scholar 

  • 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):228–236

    Article  CAS  PubMed  Google Scholar 

  • 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):98–104

    Article  CAS  PubMed  Google Scholar 

  • Querfurth HW, LaFerla FM (2010) Alzheimer’s Disease. N Engl J Med 362:329–344

    Article  CAS  PubMed  Google Scholar 

  • Rankin J, Sedowofia K, Clayton R, Manning A (1993) Behavioral effects of gestational exposure to aluminum. Am Ist Super Sanita 29(1):147–152

    CAS  Google Scholar 

  • 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):6419–6422

    Article  CAS  Google Scholar 

  • 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):3932–3936

    Article  CAS  PubMed  Google Scholar 

  • Seignourel PJ, Kunik ME, Snow L, Wilson N, Stanley M (2008) Anxiety in dementia: a critical review. Clin Psychol Rev 28(7):1071–1082

    Article  PubMed Central  PubMed  Google Scholar 

  • 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 28:2053–2063

    Article  CAS  PubMed  Google Scholar 

  • 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):588–600

    Article  CAS  PubMed  Google Scholar 

  • 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):104–115

    Article  PubMed  Google Scholar 

  • 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):2225–2238

    Article  CAS  PubMed  Google Scholar 

  • Wimo A, Winblad B, Jonsson L (2010) The worldwide societal costs of dementia: estimates for 2009. Alzheimers Dement 6(2):98–103

    Article  PubMed  Google Scholar 

  • Winkler J, Thal L, Gage F, Fisher LJ (1998) Cholinergic strategies for Alzheimer’s disease. J Mol Med 76(8):555–567

    Article  CAS  PubMed  Google Scholar 

  • Yellamma K, Saraswathamma S, Kumar BN (2010) Cholinergic system under aluminium toxicity in rat brain. Toxicol Int 17(2):106–112

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Yokel RA (2000) The toxicology of aluminum in the brain: a review. Neurotoxicology 21:813–828

    CAS  PubMed  Google Scholar 

  • 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):15–28

    Article  CAS  PubMed  Google Scholar 

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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.

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The authors declare that there is no conflict of interest.

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  1. Bio-Organic Chemistry Laboratory, Dr. B. R. Ambedkar Centre for Biomedical Research, University of Delhi, Delhi, 110007, India

    Poonam Meena, Apra Manral, Vikas Saini & Manisha Tiwari

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  1. Poonam Meena
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Correspondence to Manisha Tiwari.

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Meena, P., Manral, A., Saini, V. et al. 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. Neurotox Res 27, 314–327 (2015). https://doi.org/10.1007/s12640-014-9499-3

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