Skip to main content

Advertisement

SpringerLink
Log in

DADS Analogues Ameliorated the Cognitive Impairments of Alzheimer-Like Rat Model Induced by Scopolamine

  • Original Article
  • Published:
Neurotoxicity Research Aims and scope Submit manuscript

Abstract

The development of agents that affect two or more relevant targets has drawn considerable attention in treatment of AD. Diallyl disulfide (DADS), an active principle of garlic, has been reported to prevent APP processing by amyloidogenic pathway. Recently, we have reported a new series of DADS derivatives and our findings revealed that compound 7k and 7l could provide good templates for developing new multifunctional agents for AD treatment. Thus, the present study was constructed to investigate the neuroprotective effect of DADS analogues (7k and 7l) against Aβ-induced neurotoxicity in SH-SY5Y human neuroblastoma cells and in ameliorating the cognition deficit induced by scopolamine in rat model. The results indicated that compound 7k and 7l significantly inhibited Aβ1–42-induced neuronal cell death by inhibiting ROS generation. Moreover, they prevented apoptosis, in response to ROS, by restoring normal Bax/Bcl-2 ratio. Furthermore, it was observed that scopolamine-induced memory impairment was coupled by alterations in neurotransmitters, acetylcholinesterase activity and oxidative stress markers. Histological analysis revealed severe damaging effects of scopolamine on the structure of cerebral cortex and hippocampus. Administration of compounds 7k and 7l at 5 mg/kg significantly reversed scopolamine-induced behavioural, biochemical, neurochemical and histological changes in a manner comparable to standard donepezil. Together the present findings and previous studies indicate that compounds 7k and 7l have neuroprotective and cognition-enhancing effects, which makes them a promising multi-target candidate for addressing the complex nature of AD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  • Anandatheerthavarada HK, Biswas G, Robin M-A, Avadhani NG (2003) Mitochondrial targeting and a novel transmembrane arrest of Alzheimer’s amyloid precursor protein impairs mitochondrial function in neuronal cells. J Cell Biol 161(1):41–54

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bartus RT (2000) On neurodegenerative diseases, models, and treatment strategies: lessons learned and lessons forgotten a generation following the cholinergic hypothesis. Exp Neurol 163(2):495–529

    Article  CAS  PubMed  Google Scholar 

  • Behl C, Davis J, Cole GM, Schubert D (1992) Vitamin E protects nerve cells from amyloid β protein toxicity. Biochem Biophys Res Commun 186(2):944–950

    Article  CAS  PubMed  Google Scholar 

  • Bihaqi SW, Singh AP, Tiwari M (2012) Supplementation of Convolvulus pluricaulis attenuates scopolamine-induced increased tau and Amyloid precursor protein (AβPP) expression in rat brain. Indian J Pharmacol 44(5):593

    Article  PubMed  PubMed Central  Google Scholar 

  • Blake M, Krawczyk M, Baratti Boccia M (2014) Neuropharmacology of memory consolidation and reconsolidation: insights on central cholinergic mechanisms. J Physiol Paris 108(4):286–291

    Article  CAS  PubMed  Google Scholar 

  • Blokland A, Schreiber R, Prickaerts J (2006) Improving memory: a role for phosphodiesterases. Curr Pharm Des 12(20):2511–2523

    Article  CAS  PubMed  Google Scholar 

  • Boldogh I, Kruzel ML, Colostrinin TM (2008) An oxidative stress modulator for prevention and treatment of age-related disorders. J Alzheimer’s Dis 13:303–321

    CAS  Google Scholar 

  • Bores GM, Huger FP, Petko W, Mutlib AE, Camacho F, Rush DK, Selk DE, Wolf V, Kosley R, Davis L (1996) Pharmacological evaluation of novel Alzheimer’s disease therapeutics: acetylcholinesterase inhibitors related to galanthamine. J Pharmacol Exp Ther 277(2):728–738

    CAS  PubMed  Google Scholar 

  • Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72(1):248–254

    Article  CAS  PubMed  Google Scholar 

  • Buckingham SD, Jones AK, Brown LA, Sattelle DB (2009) Nicotinic acetylcholine receptor signalling: roles in Alzheimer’s disease and amyloid neuroprotection. Pharmacol Rev 61(1):39–61

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Canal CE, Chang Q, Gold PE (2007) Amnesia produced by altered release of neurotransmitters after intraamygdala injections of a protein synthesis inhibitor. Proc Natl Acad Sci 104(30):12500–12505

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Castellano C, Cabib S, Puglisi-Allegra S (1996) Psychopharmacology of memory modulation: evidence for multiple interaction among neurotransmitters and hormones. Behav Brain Res 77(1):1–21

    Article  CAS  PubMed  Google Scholar 

  • Cavalli A, Bolognesi ML, Minarini A, Rosini M, Tumiatti V, Recanatini M, Melchiorre C (2008) Multi-target-directed ligands to combat neurodegenerative diseases. J Med Chem 51(3):347–372

    Article  CAS  PubMed  Google Scholar 

  • Cecchi C, Fiorillo C, Baglioni S, Pensalfini A, Bagnoli S, Nacmias B, Sorbi S, Nosi D, Relini A, Liguri G (2007) Increased susceptibility to amyloid toxicity in familial Alzheimer’s fibroblasts. Neurobiol Aging 28(6):863–876

    Article  CAS  PubMed  Google Scholar 

  • Chen J, Long Y, Han M, Wang T, Chen Q, Wang R (2008) Water-soluble derivative of propolis mitigates scopolamine-induced learning and memory impairment in mice. Pharmacol Biochem Behav 90(3):441–446

    Article  CAS  PubMed  Google Scholar 

  • Choi DY, Lee YJ, Lee SY, Lee YM, Lee HH, Choi IS, Oh KW, Han SB, Nam SY, Hong JT, (2012) Attenuation of scopolamine-induced cognitive dysfunction by obovatol. Arch Pharm Res 35(7):1279–1286

    Article  CAS  PubMed  Google Scholar 

  • Chyan Y-J, Poeggeler B, Omar RA, Chain DG, Frangione B, Ghiso J, Pappolla MA (1999) Potent neuroprotective properties against the Alzheimer β-amyloid by an endogenous melatonin-related indole structure, indole-3-propionic acid. J Biol Chem 274(31):21937–21942

    Article  CAS  PubMed  Google Scholar 

  • Cummings JL, Doody R, Clark C (2007) Disease-modifying therapies for Alzheimer disease challenges to early intervention. Neurology 69(16):1622–1634

    Article  PubMed  Google Scholar 

  • Dringen R, Gutterer JM, Hirrlinger J (2000) Glutathione metabolism in brain. Eur J Biochem 267(16):4912–4916

    Article  CAS  PubMed  Google Scholar 

  • Ellman GL, Courtney KD, Andres V, Featherstone RM (1961) A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 7(2):88–95

    Article  CAS  PubMed  Google Scholar 

  • Flohé L, Günzler WA (1984) Assays of glutathione peroxidase. Methods Enzymol 105(1):14–120

    Google Scholar 

  • Fukui K, Omoi NO, Hayasaka T, Shinnkai T, Suzuki S, Abe K, Urano S (2002) Cognitive impairment of rats caused by oxidative stress and aging, and its prevention by vitamin E. Ann NY Acad Sci 959(1):275–284

    Article  CAS  PubMed  Google Scholar 

  • Giacobini E (1998) Cholinergic foundations of Alzheimer’s disease therapy. J Physiol Paris 92(3):283–287

    Article  CAS  PubMed  Google Scholar 

  • Giacobini E (2002) Long-term stabilizing effect of cholinesterase inhibitors in the therapy of Alzheimer’disease. J Neural Transm Suppl 62:181–187

    Article  CAS  PubMed  Google Scholar 

  • Giridharan VV, Thandavarayan RA, Konishi T (2011) Amelioration of scopolamine induced cognitive dysfunction and oxidative stress by Inonotus obliquus–a medicinal mushroom. Food Funct 2(6):320–327

    Article  CAS  PubMed  Google Scholar 

  • Gupta VB, Indi SS, Rao KSJ (2009) Garlic extract exhibits antiamyloidogenic activity on amyloid‐beta fibrillogenesis: relevance to Alzheimer's disease. Phytother Res 23(1):111–115

    Article  PubMed  Google Scholar 

  • Hensley K, Hall N, Subramaniam R, Cole P, Harris M, Aksenov M, Aksenova M, Gabbita SP, Wu JF, Carney JM (1995) Brain regional correspondence between Alzheimer’s disease histopathology and biomarkers of protein oxidation. J Neurochem 65(5):2146–2156

    Article  CAS  PubMed  Google Scholar 

  • Huber SJ, Shulman HG, Paulson GW, Shuttleworth EC (1989) Dose-dependent memory impairment in Parkinson’s disease. Neurology 39(3):438

    Article  CAS  PubMed  Google Scholar 

  • Iversen SD (1998) The pharmacology of memory. Comptes Rendus de l’Académie des Sciences-Series III-Sciences de la Vie 321(2):209–215

    Article  CAS  Google Scholar 

  • Jollow D, Mitchell J, Zampaglione NA, Gillette J (1974) Bromobenzene-induced liver necrosis. Protective role of glutathione and evidence for 3,4-bromobenzene oxide as the hepatotoxic metabolite. Pharmacology 11(3):151–169

    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 

  • Leuner K, Müller WE, Reichert AS (2012) From mitochondrial dysfunction to amyloid beta formation: novel insights into the pathogenesis of Alzheimer’s disease. Mol Neurobiol 46(1):186–193

    Article  CAS  PubMed  Google Scholar 

  • Levine RL, Garland D, Oliver CN, Amici A, Climent I, Lenz A-G, Ahn B-W, Shaltiel S, Stadtman ER (1990) Determination of carbonyl content in oxidatively modified proteins. Methods Enzymol 186:464–478

    Article  CAS  PubMed  Google Scholar 

  • Li S-Y, Wang X-B, Xie S-S, Jiang N, Wang KD, Yao H-Q, Sun H-B, Kong L-Y (2013) Multifunctional tacrine–flavonoid hybrids with cholinergic, β-amyloid-reducing, and metal chelating properties for the treatment of Alzheimer’s disease. Eur J Med Chem 69:632–646

    Article  CAS  PubMed  Google Scholar 

  • Liang K, McGaugh JL, Yao H-Y (1990) Involvement of amygdala pathways in the influence of post-training intra-amygdala norepinephrine and peripheral epinephrine on memory storage. Brain Res 508(2):225–233

    Article  CAS  PubMed  Google Scholar 

  • Liu T, Xia Z, Zhang W-W, Xu J-R, Ge X-X, Li J, Cui Y, Qiu Z-B, Xu J, Xie Q (2013) Bis (9)-(−)-nor-meptazinol as a novel dual-binding AChEI potently ameliorates scopolamine-induced cognitive deficits in mice. Pharmacol Biochem Behav 104:138–143

    Article  CAS  PubMed  Google Scholar 

  • Loizzo MR, Tundis R, Menichini F, Menichini F (2008) Natural products and their derivatives as cholinesterase inhibitors in the treatment of neurodegenerative disorders: an update. Curr Med Chem 15(12):1209-1228

    Article  CAS  PubMed  Google Scholar 

  • Loo DT, Copani A, Pike CJ, Whittemore ER, Walencewicz AJ, Cotman CW (1993) Apoptosis is induced by beta-amyloid in cultured central nervous system neurons. Proc Natl Acad Sci 90(17):7951–7955

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Manral A, Saini V, Meena P, Tiwari M (2015) Multifunctional novel diallyl disulfide (DADS) derivatives with β-amyloid-reducing, cholinergic, antioxidant and metal chelating properties for the treatment of Alzheimer’s disease. Bioorg Med Chem 23(19):6389–6403

    Article  CAS  PubMed  Google Scholar 

  • Meister A (1988) Glutathione metabolism and its selective modification. J Biol Chem 263(33):17205–17208

    CAS  PubMed  Google Scholar 

  • Melo JB, Agostinho P, Oliveira CR (2003) Involvement of oxidative stress in the enhancement of acetylcholinesterase activity induced by amyloid beta-peptide. Neurosci Res 45(1):117–127

    Article  CAS  PubMed  Google Scholar 

  • Morgan D, Munireddy S, Alamed J, DeLeon J, Diamond DM, Bickford P, Hutton M, Lewis J, McGowan E, Gordon MN (2008) Apparent behavioral benefits of tau overexpression in P301L tau transgenic mice. J Alzheimer’s Dis JAD 15(4):605

    CAS  PubMed  Google Scholar 

  • Morice E, Billard J-M, Denis C, Mathieu F, Betancur C, Epelbaum J, Giros B, Nosten-Bertrand M (2007) Parallel loss of hippocampal LTD and cognitive flexibility in a genetic model of hyperdopaminergia. Neuropsychopharmacology 32(10):2108–2116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nalini K, Karanth K, Rao A, Aroor A (1992) Effects of piracetam on retention and biogenic amine turnover in albino rats. Pharmacol Biochem Behav 42(4):859–864

    Article  CAS  PubMed  Google Scholar 

  • Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95(2):351–358

    Article  CAS  PubMed  Google Scholar 

  • Pachauri SD, Tota S, Khandelwal K, Verma P, Nath C, Hanif K, Shukla R, Saxena J, Dwivedi AK (2012) Protective effect of fruits of Morinda citrifolia L. on scopolamine induced memory impairment in mice: a behavioral, biochemical and cerebral blood flow study. J Ethnopharmacol 139(1):34–41

    Article  PubMed  Google Scholar 

  • Park CH, Lee YJ, Lee SH, Choi SH, Kim HS, Jeong SJ, Kim SS, Suh YH (2000) Dehydroevodiamine· HCl prevents impairment of learning and memory and neuronal loss in rat models of cognitive disturbance. J Neurochem 74(1):244–253

    Article  CAS  PubMed  Google Scholar 

  • Pepeu G, Giovannini MG, Bracco L (2013) Effect of cholinesterase inhibitors on attention. Chem Biol Interact 203(1):361–364

    Article  CAS  PubMed  Google Scholar 

  • Pollack SJ, Sadlerl IJ, Hawtin SR, Tailor VJ, Shearman MS (1995) Sulfated glycosammnoglycans and dyes attenuate the neurotoxic effects of β-amyloid in rat PC12 cells. Neurosci Lett 184:113–116

    Article  CAS  PubMed  Google Scholar 

  • Rai SK, Sharma M, Tiwari M (2009) Inhibitory effect of novel diallyldisulfide analogs on HMG-CoA reductase expression in hypercholesterolemic rats: CREB as a potential upstream target. Life Sci 85(5):211–219

    Article  CAS  PubMed  Google Scholar 

  • Schlumpf M, Lichtensteiger W, Langemann H, Waser PG, Hefti F (1974) A fluorometric micromethod for the simultaneous determination of serotonin, noradrenaline and dopamine in milligram amounts of brain tissue. Biochem Pharmacol 23(17):2437–2446

    Article  CAS  PubMed  Google Scholar 

  • Selkoe DJ (2001) Clearing the brain's amyloid cobwebs. Neuron 32(2):177–180

    Article  CAS  PubMed  Google Scholar 

  • Serrano-Pozo A, Frosch MP, Masliah E, Hyman BT (2011) Neuropathological alterations in Alzheimer disease. Cold Spring Harbor Perspect Med 1(1):a006189

    Article  Google Scholar 

  • Sharma M, Tiwari M, Chandra R (2004) Bis [3-(4′-substituted phenyl)prop-2-ene] disulfides as a new class of antihyperlipidemic compounds. Bioorg Med Chem Lett 14(21):5347–5350

    Article  CAS  PubMed  Google Scholar 

  • Sharma DK, Manral A, Saini V, Singh A, Srinivasan B, Tiwari M (2012) Novel diallyldisulfide analogs ameliorate cardiovascular remodeling in rats with L-NAME-induced hypertension. Eur J Pharmacol 691(1):198–208

    Article  PubMed  Google Scholar 

  • Smith IK, Vierheller TL, Thorne CA (1988) Assay of glutathione reductase in crude tissue homogenates using 5,5′-dithiobis (2-nitrobenzoic acid). Anal Biochem 175(2):408–413

    Article  CAS  PubMed  Google Scholar 

  • Steele T, Hodges D, Levesque T, Locke K, Sandage B (1996) The D1 agonist dihydrexidine releases acetylcholine and improves cognition in rats. Ann NY Acad Sci 777(1):427–430

    Article  CAS  PubMed  Google Scholar 

  • Stone WS, Croul CE, Gold PE (1988) Attenuation of scopolamine-induced amnesia in mice. Psychopharmacology 96(3):417–420

    Article  CAS  PubMed  Google Scholar 

  • Sugaya K, Giacobini E, Chiappinelli V (1990) Nicotinic acetylcholine receptor subtypes in human frontal cortex: changes in Alzheimer’s disease. J Neurosci Res 27(3):349–359

    Article  CAS  PubMed  Google Scholar 

  • The Organisation of Economic Co-operation and Development (OECD) The OECD Guideline for Testing of Chemical (2001) 407 repeated dose oral toxicity-rodent: 28-day or 14-day study. OECD, Paris, pp 1–7

  • Tuppo EE, Arias HR (2005) The role of inflammation in Alzheimer’s disease. Int J Biochem Cell Biol 37(2):289–305

    Article  CAS  PubMed  Google Scholar 

  • Vasudevan M, Parle M (2006) Pharmacological actions of Thespesia populnea relevant to Alzheimer’s disease. Phytomedicine 13(9):677–687

    Article  CAS  PubMed  Google Scholar 

  • Vizi ES, Harsing LG, Zimanvi I, Gaal G (1985) Release and turnover of noradrenaline in isolated median eminence: lack of negative feedback modulation. Neurosci 16(4):907–916

    Article  CAS  Google Scholar 

  • Walton NM, Shin R, Tajinda K, Heusner CL, Kogan JH, Miyake S, Chen Q, Tamura K, Matsumoto M (2012) Adult neurogenesis transiently generates oxidative stress. PLoS One 7(4):e35264

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang R-G, Zhu X-Z (2003) Subtoxic concentration of manganese synergistically potentiates 1-methyl-4-phenylpyridinium-induced neurotoxicity in PC12 cells. Brain Res 961(1):131–138

    Article  CAS  PubMed  Google Scholar 

  • Wang X, Wang Z-H, Wu Y-Y, Tang H, Tan L, Wang X, Gao X-Y, Xiong Y-S, Liu D, Wang J-Z (2013) Melatonin attenuates scopolamine-induced memory/synaptic disorder by rescuing EPACs/miR-124/Egr1 pathway. Mol Neurobiol 47(1):373–381

    Article  CAS  PubMed  Google Scholar 

  • Weinstock M (1995) The pharmacotherapy of Alzheimer’s disease based on the cholinergic hypothesis: an update. Neurodegeneration 4(4):349–356

    Article  CAS  PubMed  Google Scholar 

  • Xia Y, Cheng S, He J, Liu X, Tang Y, Yuan H, He L, Lu T, Tu B, Wang Y (2011) Effects of subchronic exposure to benzo [a] pyrene (B [a] P) on learning and memory, and neurotransmitters in male Sprague–Dawley rat. Neurotoxicology 32(2):188–198

    Article  CAS  PubMed  Google Scholar 

  • Yang J, Liu X, Bhalla K, Kim CN, Ibrado AM, Cai J, Peng TI, Jones DP, Wang X (1997) Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked. Sci 275(5303): 1129–1132

    Article  CAS  Google Scholar 

  • Yu BP, Yang R (1996) Critical evaluation of the free radical theory of aging. Ann Ny Acad Sci 786(1):1–11

    Article  CAS  PubMed  Google Scholar 

  • Zhou W, Fukumoto S, Yokogoshi H (2009) Components of lemon essential oil attenuate dementia induced by scopolamine. Nutr Neurosci 12(2):57–64

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

The authors wish to gratefully acknowledge scientific contributions from Prof. Vani Brahmachari. Financial assistance from the University of Delhi is acknowledged. The authors gratefully acknowledge Dr. Dipti Prasad, DIPAS, New Delhi, for providing necessary facilities to conduct behavioural experiments. Apra Manral wishes to acknowledge the Senior Research Fellowship awarded by the University Grants Commission—Govt. of India. The facilities provided by ACBR and the University of Delhi are gratefully acknowledged.

Author information

Authors and Affiliations

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

    Apra Manral, Poonam Meena, Vikas Saini, Shruti Shalini & Manisha Tiwari

  2. Department of Histopathology, National Institute of Pathology, Indian Council of Medical Research, New Delhi, India

    Fouzia Siraj

Authors
  1. Apra Manral
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Poonam Meena
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Vikas Saini
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Fouzia Siraj
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shruti Shalini
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Manisha Tiwari
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Manisha Tiwari.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Manral, A., Meena, P., Saini, V. et al. DADS Analogues Ameliorated the Cognitive Impairments of Alzheimer-Like Rat Model Induced by Scopolamine. Neurotox Res 30, 407–426 (2016). https://doi.org/10.1007/s12640-016-9625-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12640-016-9625-5

Keywords

Search

Navigation