Login Register Cart 0
Generic placeholder image

CNS & Neurological Disorders - Drug Targets

Editor-in-Chief

ISSN (Print): 1871-5273
ISSN (Online): 1996-3181

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Mini-Review Article

Scopolamine, a Toxin-Induced Experimental Model, Used for Research in Alzheimer’s Disease

Author(s): Win Ning Chen and Keng Yoon Yeong*

Volume 19, Issue 2, 2020

Page: [85 - 93] Pages: 9

DOI: 10.2174/1871527319666200214104331

Price: $65

Abstract

Scopolamine as a drug is often used to treat motion sickness. Derivatives of scopolamine have also found applications as antispasmodic drugs among others. In neuroscience-related research, it is often used to induce cognitive disorders in experimental models as it readily permeates the bloodbrain barrier. In the context of Alzheimer’s disease, its effects include causing cholinergic dysfunction and increasing amyloid-β deposition, both of which are hallmarks of the disease. Hence, the application of scopolamine in Alzheimer’s disease research is proven pivotal but seldom discussed. In this review, the relationship between scopolamine and Alzheimer’s disease will be delineated through an overall effect of scopolamine administration and its specific mechanisms of action, discussing mainly its influences on cholinergic function and amyloid cascade. The validity of scopolamine as a model of cognitive impairment or neurotoxin model will also be discussed in terms of advantages and limitations with future insights.

Keywords: Muscarinic antagonist, acetylcholine, Alzheimer’s disease, cognitive dysfunction, amyloid-beta plaque, scopolamine.

« Previous
Graphical Abstract

[1]
Kohnen-Johannsen KL, Kayser O. Tropane alkaloids: chemistry, pharmacology, biosynthesis and production. Molecules 2019; 24(4): E796
[http://dx.doi.org/10.3390/molecules24040796] [PMID: 30813289]
[2]
Aparkes MW. An examination of central actions characteristic of scopolamine: comparison of central and peripheral activity in scopolamine, atropine and some synthetic basic esters. Psychopharmacology (Berl) 1965; 7(1): 1-19.
[http://dx.doi.org/10.1007/BF00404160] [PMID: 5830966]
[3]
Wildiers H, Dhaenekint C, Demeulenaere P, et al. Atropine, hyoscine butylbromide, or scopolamine are equally effective for the treatment of death rattle in terminal care. J Pain Symptom Manage 2009; 38(1): 124-33.
[http://dx.doi.org/10.1016/j.jpainsymman.2008.07.007] [PMID: 19361952]
[4]
Imai K, Ikenaga M, Kodama T, Kanemura S, Tamura K, Morita T. Sublingually administered scopolamine for nausea in terminally ill cancer patients. Support Care Cancer 2013; 21(10): 2777-81.
[http://dx.doi.org/10.1007/s00520-013-1846-z] [PMID: 23722950]
[5]
Antor MA, Uribe AA, Erminy-Falcon N, et al. The effect of transdermal scopolamine for the prevention of postoperative nausea and vomiting. Front Pharmacol 2014; 5: 55.
[http://dx.doi.org/10.3389/fphar.2014.00055] [PMID: 24782768]
[6]
Navarria A, Wohleb ES, Voleti B, et al. Rapid antidepressant actions of scopolamine: Role of medial prefrontal cortex and M1-subtype muscarinic acetylcholine receptors. Neurobiol Dis 2015; 82: 254-61.
[http://dx.doi.org/10.1016/j.nbd.2015.06.012] [PMID: 26102021]
[7]
Martin AE, Schober DA, Nikolayev A, et al. Further evaluation of mechanisms associated with the antidepressantlike signature of scopolamine in mice. CNS Neurol Disord Drug Targets 2017; 16(4): 492-500.
[http://dx.doi.org/10.2174/1871527316666170309142646] [PMID: 28294051]
[8]
Mueller-Lissner S, Tytgat GN, Paulo LG, et al. Placebo- and paracetamol-controlled study on the efficacy and tolerability of hyoscine butylbromide in the treatment of patients with recurrent crampy abdominal pain. Aliment Pharmacol Ther 2006; 23(12): 1741-8.
[http://dx.doi.org/10.1111/j.1365-2036.2006.02818.x] [PMID: 16817918]
[9]
Tytgat GN. Hyoscine butylbromide: a review of its use in the treatment of abdominal cramping and pain. Drugs 2007; 67(9): 1343-57.
[http://dx.doi.org/10.2165/00003495-200767090-00007] [PMID: 17547475]
[10]
Alvarez-Jimenez R, Groeneveld GJ, van Gerven JM, et al. Model-based exposure-response analysis to quantify age related differences in the response to scopolamine in healthy subjects. Br J Clin Pharmacol 2016; 82(4): 1011-21.
[http://dx.doi.org/10.1111/bcp.13031] [PMID: 27273555]
[11]
Ha ZY, Mathew S, Yeong KY. Butyrylcholinesterase: a multifaceted pharmacological target and tool. Curr Protein Pept Sci 2020; 21(1): 99-109.
[http://dx.doi.org/10.2174/1389203720666191107094949] [PMID: 31702488]
[12]
Jones CK, Byun N, Bubser M. Muscarinic and nicotinic acetylcholine receptor agonists and allosteric modulators for the treatment of schizophrenia. Neuropsychopharmacology 2012; 37(1): 16-42.
[http://dx.doi.org/10.1038/npp.2011.199] [PMID: 21956443]
[13]
Drachman DA, Leavitt J. Human memory and the cholinergic system. A relationship to aging? Arch Neurol 1974; 30(2): 113-21.
[http://dx.doi.org/10.1001/archneur.1974.00490320001001] [PMID: 4359364]
[14]
Berger BD, Stein L. An analysis of the learning deficits produced by scopolamine. Psychopharmacology (Berl) 1969; 14(4): 271-83.
[http://dx.doi.org/10.1007/BF02190112] [PMID: 5389067]
[15]
Bajo R, Pusil S, López ME, et al. Scopolamine effects on functional brain connectivity: a pharmacological model of Alzheimer’s disease. Sci Rep 2015; 5: 9748.
[http://dx.doi.org/10.1038/srep09748] [PMID: 26130273]
[16]
Ghoneim MM, Mewaldt SP. Studies on human memory: the interactions of diazepam, scopolamine, and physostigmine. Psychopharmacology (Berl) 1977; 52(1): 1-6.
[http://dx.doi.org/10.1007/BF00426592] [PMID: 403551]
[17]
Snyder PJ, Bednar MM, Cromer JR, Maruff P. Reversal of scopolamine-induced deficits with a single dose of donepezil, an acetylcholinesterase inhibitor. Alzheimers Dement 2005; 1(2): 126-35.
[http://dx.doi.org/10.1016/j.jalz.2005.09.004] [PMID: 19595845]
[18]
Manuel I, Lombardero L, LaFerla FM, Giménez-Llort L, Rodríguez-Puertas R. Activity of muscarinic, galanin and cannabinoid receptors in the prodromal and advanced stages in the triple transgenic mice model of Alzheimer’s disease. Neuroscience 2016; 329: 284-93.
[http://dx.doi.org/10.1016/j.neuroscience.2016.05.012] [PMID: 27223629]
[19]
Atri A, Sherman S, Norman KA, et al. Blockade of central cholinergic receptors impairs new learning and increases proactive interference in a word paired-associate memory task. Behav Neurosci 2004; 118(1): 223-36.
[http://dx.doi.org/10.1037/0735-7044.118.1.223] [PMID: 14979800]
[20]
Hasanein P, Mahtaj AK. Ameliorative effect of rosmarinic acid on scopolamine-induced memory impairment in rats. Neurosci Lett 2015; 585: 23-7.
[http://dx.doi.org/10.1016/j.neulet.2014.11.027] [PMID: 25445372]
[21]
Hasselmo ME, McGaughy J. High acetylcholine levels set circuit dynamics for attention and encoding and low acetylcholine levels set dynamics for consolidation. Prog Brain Res 2004; 145: 207-31.
[http://dx.doi.org/10.1016/S0079-6123(03)45015-2] [PMID: 14650918]
[22]
Blokland A, Honig W, Raaijmakers WG. Effects of intra-hippocampal scopolamine injections in a repeated spatial acquisition task in the rat. Psychopharmacology (Berl) 1992; 109(3): 373-6.
[http://dx.doi.org/10.1007/BF02245886] [PMID: 1365638]
[23]
Elvander E, Schött PA, Sandin J, et al. Intraseptal muscarinic ligands and galanin: influence on hippocampal acetylcholine and cognition. Neuroscience 2004; 126(3): 541-57.
[http://dx.doi.org/10.1016/j.neuroscience.2004.03.058] [PMID: 15183504]
[24]
Peng XQ, Ke J. [Effects of 3 henbane drugs on acute forebrain ischemia and reperfusion injury in rats]. Zhongguo Yao Li Xue Bao 1992; 13(4): 357-8.
[PMID: 1456060]
[25]
Muramatsu I, Yoshiki H, Uwada J, et al. Pharmacological evidence of specific acetylcholine transport in rat cerebral cortex and other brain regions. J Neurochem 2016; 139(4): 566-75.
[http://dx.doi.org/10.1111/jnc.13843] [PMID: 27627023]
[26]
Toide K. Effects of scopolamine on extracellular acetylcholine and choline levels and on spontaneous motor activity in freely moving rats measured by brain dialysis. Pharmacol Biochem Behav 1989; 33(1): 109-13.
[http://dx.doi.org/10.1016/0091-3057(89)90438-3] [PMID: 2550972]
[27]
Szerb JC, Hadházy P, Dudar JD. Release of [3H]acetylcholine from rat hippocampal slices: effect of septal lesion and of graded concentrations of muscarnic agonists and antagonists. Brain Res 1977; 128(2): 285-91.
[http://dx.doi.org/10.1016/0006-8993(77)90995-7] [PMID: 871915]
[28]
Nordström O, Bartfai T. Muscarinic autoreceptor regulates acetylcholine release in rat hippocampus: in vitro evidence. Acta Physiol Scand 1980; 108(4): 347-53.
[http://dx.doi.org/10.1111/j.1748-1716.1980.tb06543.x] [PMID: 7415847]
[29]
Pfister M, Boix F, Huston JP, Schwarting RK. Different effects of scopolamine on extracellular acetylcholine levels in neostriatum and nucleus accumbens measured in vivo: possible interaction with aversive stimulation. J Neural Transm (Vienna) 1994; 97(1): 13-25.
[http://dx.doi.org/10.1007/BF01277959] [PMID: 7888146]
[30]
Riedel G, Kang SH, Choi DY, Platt B. Scopolamine-induced deficits in social memory in mice: reversal by donepezil. Behav Brain Res 2009; 204(1): 217-25.
[http://dx.doi.org/10.1016/j.bbr.2009.06.012] [PMID: 19527754]
[31]
Perry EK, Gibson PH, Blessed G, Perry RH, Tomlinson BE. Neurotransmitter enzyme abnormalities in senile dementia. Choline acetyltransferase and glutamic acid decarboxylase activities in necropsy brain tissue. J Neurol Sci 1977; 34(2): 247-65.
[http://dx.doi.org/10.1016/0022-510X(77)90073-9] [PMID: 144789]
[32]
Gutierres JM, Carvalho FB, Schetinger MR, et al. Neuroprotective effect of anthocyanins on acetylcholinesterase activity and attenuation of scopolamine-induced amnesia in rats. Int J Dev Neurosci 2014; 33: 88-97.
[http://dx.doi.org/10.1016/j.ijdevneu.2013.12.006] [PMID: 24374256]
[33]
Mohapel P, Leanza G, Kokaia M, Lindvall O. Forebrain acetylcholine regulates adult hippocampal neurogenesis and learning. Neurobiol Aging 2005; 26(6): 939-46.
[http://dx.doi.org/10.1016/j.neurobiolaging.2004.07.015] [PMID: 15718053]
[34]
Ray RS, Rai S, Katyal A. Cholinergic receptor blockade by scopolamine and mecamylamine exacerbates global cerebral ischemia induced memory dysfunction in C57BL/6J mice. Nitric Oxide 2014; 43: 62-73.
[http://dx.doi.org/10.1016/j.niox.2014.08.009] [PMID: 25168578]
[35]
Hulme EC, Birdsall NJ, Burgen AS, Mehta P. The binding of antagonists to brain muscarinic receptors. Mol Pharmacol 1978; 14(5): 737-50.
[PMID: 714022]
[36]
Kellar KJ, Martino AM, Hall DP Jr, Schwartz RD, Taylor RL. High-affinity binding of [3H]acetylcholine to muscarinic cholinergic receptors. J Neurosci 1985; 5(6): 1577-82.
[http://dx.doi.org/10.1523/JNEUROSCI.05-06-01577.1985] [PMID: 4009247]
[37]
Schmeller T, Sporer F, Sauerwein M, Wink M. Binding of tropane alkaloids to nicotinic and muscarinic acetylcholine receptors. Pharmazie 1995; 50(7): 493-5.
[PMID: 7675895]
[38]
Caulfield MP. Muscarinic receptors--characterization, coupling and function. Pharmacol Ther 1993; 58(3): 319-79.
[http://dx.doi.org/10.1016/0163-7258(93)90027-B] [PMID: 7504306]
[39]
Falsafi SK, Deli A, Höger H, Pollak A, Lubec G. Scopolamine administration modulates muscarinic, nicotinic and NMDA receptor systems. PLoS One 2012; 7(2): e32082
[http://dx.doi.org/10.1371/journal.pone.0032082] [PMID: 22384146]
[40]
Seeman P, Seeman N. Alzheimer’s disease: β-amyloid plaque formation in human brain. Synapse 2011; 65(12): 1289-97.
[http://dx.doi.org/10.1002/syn.20957] [PMID: 21633975]
[41]
Simons M, Keller P, De Strooper B, Beyreuther K, Dotti CG, Simons K. Cholesterol depletion inhibits the generation of beta-amyloid in hippocampal neurons. Proc Natl Acad Sci USA 1998; 95(11): 6460-4.
[http://dx.doi.org/10.1073/pnas.95.11.6460] [PMID: 9600988]
[42]
Ahmad SS, Khan S, Kamal MA, Wasi U. The structure and function of alpha, beta and gamma-Secretase as therapeutic target enzymes into the development of Alzheimer’s disease: a review. CNS Neurol Disord Drug Targets 2019; 18(9): 657-67.
[http://dx.doi.org/10.2174/1871527318666191011145941] [PMID: 31608840]
[43]
Singh A, Hasan A, Tiwari S, Pandey LM. Therapeutic advancement in Alzheimer disease: new hopes on the horizon? CNS Neurol Disord Drug Targets 2018; 17(8): 571-89.
[http://dx.doi.org/10.2174/1871527317666180627122448] [PMID: 29952273]
[44]
Liskowsky W, Schliebs R. Muscarinic acetylcholine receptor inhibition in transgenic Alzheimer-like Tg2576 mice by scopolamine favours the amyloidogenic route of processing of amyloid precursor protein. Int J Dev Neurosci 2006; 24(2-3): 149-56.
[http://dx.doi.org/10.1016/j.ijdevneu.2005.11.010] [PMID: 16423497]
[45]
Bihaqi SW, Singh AP, Tiwari M. Supplementation of Convolvulus pluricaulis attenuates scopolamine-induced increased tau and amyloid precursor protein (AβPP) expression in rat brain. Indian J Pharmacol 2012; 44(5): 593-8.
[http://dx.doi.org/10.4103/0253-7613.100383] [PMID: 23112420]
[46]
Patrick GN, Zukerberg L, Nikolic M, de la Monte S, Dikkes P, Tsai LH. Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration. Nature 1999; 402(6762): 615-22.
[http://dx.doi.org/10.1038/45159] [PMID: 10604467]
[47]
Saikia B, Barua CC, Sarma J, et al. Zanthoxylum alatum ameliorates scopolamine-induced amnesia in rats: Behavioral, biochemical, and molecular evidence. Indian J Pharmacol 2018; 50(1): 30-8.
[http://dx.doi.org/10.4103/ijp.IJP_417_17] [PMID: 29861525]
[48]
Jiang XW, Lu HY, Xu Z, et al. In Silico analyses for key genes and molecular genetic mechanism in epilepsy and Alzheimer’s disease. CNS Neurol Disord Drug Targets 2018; 17(8): 608-17.
[http://dx.doi.org/10.2174/1871527317666180724150839] [PMID: 30047339]
[49]
Sharma S, Sarathlal KC, Taliyan R. Epigenetics in neurodegenerative diseases: the role of histone deacetylases. CNS Neurol Disord Drug Targets 2019; 18(1): 11-8.
[http://dx.doi.org/10.2174/1871527317666181004155136] [PMID: 30289079]
[50]
Rossor M, Iversen LL. Non-cholinergic neurotransmitter abnormalities in Alzheimer’s disease. Br Med Bull 1986; 42(1): 70-4.
[http://dx.doi.org/10.1093/oxfordjournals.bmb.a072101] [PMID: 2869818]
[51]
Aizenstein HJ, Nebes RD, Saxton JA, et al. Frequent amyloid deposition without significant cognitive impairment among the elderly. Arch Neurol 2008; 65(11): 1509-17.
[http://dx.doi.org/10.1001/archneur.65.11.1509] [PMID: 19001171]
[52]
Ahmed M, Davis J, Aucoin D, et al. Structural conversion of neurotoxic amyloid-beta(1-42) oligomers to fibrils. Nat Struct Mol Biol 2010; 17(5): 561-7.
[http://dx.doi.org/10.1038/nsmb.1799] [PMID: 20383142]
[53]
Ricciarelli R, Fedele E. The amyloid cascade hypothesis in Alzheimer’s disease: it’s time to change our mind. Curr Neuropharmacol 2017; 15(6): 926-35.
[http://dx.doi.org/10.2174/1570159X15666170116143743] [PMID: 28093977]
[54]
Egan MF, Mukai Y, Voss T, et al. Further analyses of the safety of verubecestat in the phase 3 EPOCH trial of mild-to-moderate Alzheimer’s disease. Alzheimers Res Ther 2019; 11(1): 68.
[http://dx.doi.org/10.1186/s13195-019-0520-1] [PMID: 31387606]
[55]
Egan MF, Kost J, Tariot PN, et al. Randomized trial of verubecestat for mild-to-moderate Alzheimer’s disease. N Engl J Med 2018; 378(18): 1691-703.
[http://dx.doi.org/10.1056/NEJMoa1706441] [PMID: 29719179]
[56]
Andrew RJ, Kellett KA, Thinakaran G, Hooper NM. A Greek tragedy: the growing complexity of Alzheimer amyloid precursor protein proteolysis. J Biol Chem 2016; 291(37): 19235-44.
[http://dx.doi.org/10.1074/jbc.R116.746032] [PMID: 27474742]
[57]
More SV, Kumar H, Cho DY, Yun YS, Choi DK. Toxin-induced experimental models of learning and memory impairment. Int J Mol Sci 2016; 17(9): E1447
[http://dx.doi.org/10.3390/ijms17091447] [PMID: 27598124]
[58]
Lenz RA, Baker JD, Locke C, et al. The scopolamine model as a pharmacodynamic marker in early drug development. Psychopharmacology (Berl) 2012; 220(1): 97-107.
[http://dx.doi.org/10.1007/s00213-011-2456-4] [PMID: 21901320]
[59]
Gupta S, Singhal NK, Ganesh S, Sandhir R. Extending arms of insulin resistance from diabetes to Alzheimer’s disease: identification of potential therapeutic targets. CNS Neurol Disord Drug Targets 2019; 18(3): 172-84.
[http://dx.doi.org/10.2174/1871527317666181114163515] [PMID: 30430949]
[60]
Ali F, Siddique YH. Bioavailability and pharmaco-therapeutic potential of luteolin in overcoming Alzheimer’s disease. CNS Neurol Disord Drug Targets 2019; 18(5): 352-65.
[http://dx.doi.org/10.2174/1871527318666190319141835] [PMID: 30892166]
[61]
Reeta , Baek SC, Lee JP, et al. Ethyl acetohydroxamate incorporated chalcones: unveiling a novel class of chalcones for multitarget monoamine oxidase-B inhibitors against Alzheimer's disease. CNS Neurol Disord Drug Targets 2019; 18(8): 643-54.
[62]
Malikowska-Racia N, Podkowa A, Sałat K. Phencyclidine and scopolamine for modeling amnesia in rodents: direct comparison with the use of barnes maze test and contextual fear conditioning test in mice. Neurotox Res 2018; 34(3): 431-41.
[http://dx.doi.org/10.1007/s12640-018-9901-7] [PMID: 29680979]
[63]
Newcomer JW, Farber NB, Jevtovic-Todorovic V, et al. Ketamine-induced NMDA receptor hypofunction as a model of memory impairment and psychosis. Neuropsychopharmacology 1999; 20(2): 106-18.
[http://dx.doi.org/10.1016/S0893-133X(98)00067-0] [PMID: 9885791]
[64]
Brimijoin S, Chen VP, Pang YP, Geng L, Gao Y. Physiological roles for butyrylcholinesterase: a BChE-ghrelin axis. Chem Biol Interact 2016; 259(Pt B): 271-5.
[http://dx.doi.org/10.1016/j.cbi.2016.02.013]
[65]
Greig NH, Lahiri DK, Sambamurti K. Butyrylcholinesterase: an important new target in Alzheimer’s disease therapy. Int Psychogeriatr 2002; 14(Suppl. 1): 77-91.
[http://dx.doi.org/10.1017/S1041610203008676] [PMID: 12636181]
[66]
Lian W, Fang J, Xu L, et al. DL0410 ameliorates memory and cognitive impairments induced by scopolamine via increasing cholinergic neurotransmission in mice. Molecules 2017; 22(3): E410
[http://dx.doi.org/10.3390/molecules22030410] [PMID: 28272324]

Rights & Permissions Print Cite
Article Metrics
154
5
© 2024 Bentham Science Publishers | Privacy Policy