Abstract
Scopolamine- induced memory loss is used to study new drug discovery in Alzheimer’s disease (AD) pathogenesis. This study was aimed at evaluating the role of an antioxidant supplement alpha-lipoic acid (AHA), in ameliorating the oxidative damaging effects of scopolamine on cognition, memory, and the neurohistology of the cerebello-hippocampal cortex. Twenty adult male Wistar rats used were categorized into four (4) groups (n = 5): Group A- Control, Group B- 200 mg/kg of AHA, Group C- Scopolamine (memory-impaired model), and Group D- Neurodegenerative repair model (Scopolamine + AHA). The treatment lasted for fourteen (14) days. Y-maze and hang-wire (limb use test) were used as behavioural index to assess memory and motor function while brain tissues were processed for histology (H and E stain), histochemistry using Cresyl Fast violet stain for Nissl bodies, and immunohistochemistry of astrocytes using glial fibrillary acidic protein (GFAP). Results showed that scopolamine led to a decline in brain weight, impaired memory and motor function, induced oxidative tissue damage cumulating in loss of neuronal cells, chromatolysis, the proliferation of reactive astrocytes (neuroinflammation biomarker) in the cerebello-hippocampal cortex; but upon administration of AHA these neuropathological characterizations were inhibited and reversed by AHA demonstrating its antioxidant and neuro- repair potential. In conclusion, AHA is a useful therapeutic agent against scopolamine-induced cognitive and memory deficit because it has the ability to ameliorate oxidative tissue damage by attenuating reactive astrocytes proliferation and neuron chromatolysis thereby improving memory and motor function.
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References
Abeliovich A, Gitler AD (2016) Defect in trafficking bridge Parkinson's disease pathology and genetics. Nature. 539:207–216
Ahmad A, Ramasamy K, Jaafar SM, Majeed AB, Mani V (2014) Total isoflavones from soybean and tempeh reversed scopolamine-induced amnesia, improved cholinergic activities, and reduced neuroinflammation in brain. Food Chem Toxicol 65:120–128
Akinrinade ID, Memudu AE, Ogundele OM, Ajetunmobi OI (2015) Interplay of glia activation and oxidative stress formation in fluoride and Aluminium exposure. Pathophysiology. 22:39–48
Alleva R, Tomasetti M, Sartini D, Emanuelli M, Nasole E, di Donato F, Borghi B, Santarelli L, Neuzil J (2008) α-Lipoic acid modulates extracellular matrix and angiogenesis gene expression in non-healing wounds treated with hyperbaric oxygen therapy. Mol Med 14(3–4):175–183
Anand KS, Dhikav V (2012) Hippocampus in health & disease: an overview. Ann Indian Acad Neurol 15(4):239–246
Anya T, Allan CL, Valkanova V, Zsoldos E, Filippini N, Sexton C, Mahmood A, Fooks P, Singh-Manoux A, Mackay CE, Kivimäki M, Ebmeier KP. (2017). Moderate alcohol consumption as risk factor for adverse brain outcomes and cognitive decline: longitudinal cohort study. BMJ. 357
AVMA Guidelines for the euthanasia of animals (2013)
Awasthi M, Singh S, Tiwari S, Pandey VP, Dwivedi UN (2018) Computational approaches for therapeutic application of natural products in Alzheimer’s disease. In computational modeling of drugs against Alzheimer’s disease; Humana press: New York, NY, USA
Aydin E, Hritcu L, Dogan G, Hayta S, Bagci E (2016) The effects of inhaled Pimpinella peregrina essential oil on scopolamine-induced memory impairment, anxiety, and depression in laboratory rats. Mol Neurobiol 53:6557–6567
Bailey R (2017) Hippocampus and memory. Proc NatlAcadSci 94:14002–14008
Bancroft JD, Christopher LS, Kim S (2013) Bancroft's theory and practice of histological techniques Oxford] : Churchill Livingstone Elsevier: 7th ed
Bancroft JD, Gamble M (2005) Theory and practice of Histological techniques. 5th Edition London Churchill Livingstone: 374–375
Bestaven E, Kambrun C, Guehl D, Cazalets J, Guillaud E (2016) The influence of scopolamine on motor control and attentional processes. PeerJ. 4:e2008. https://doi.org/10.7717/peerj.2008
Boddum TP, Jensen V, Magloire et al (2016) Astrocytic GABA transporter activity modulates excitatory neurotransmission. Nature Communications. 7: Article ID 13572
Brhane TA, Abadi KG, Birhanetensay MA (2018) Reactive astrocytes as drug target in Alzheimer’s disease. Biomed Res Int 2018:10. https://doi.org/10.1155/2018/4160247
Broks P, Preston GC, Traub M, Poppleton P, Ward C, Stahl SM (1988) Modelling dementia: effects of. Scopolamine on Memory and attention Neuropschologia 26(5):685–700
Budzynska, B., Boguszewska-Czubara, A., Kruk-Slomka, M., Skalicka-Wozniak., K., Michalak, A., Musik, I., Biala, G. 2015. Effects of Imperatorin on scopolamine –induced cognitive impairment and oxidative stress in mic. Pschopharmacology. 232(5), 931–942
Canter RG, Penney J, Tsai LH (2016) The road to restoring neural circuits for the treatment of Alzheimer's disease. Nature 539:187–196
Carbone, L.,Carbone, E.T., Yi,E.M, Bauer,D.B., Lindstrom, K.A., Parker, J.M, Austin, J.A., Seo, Y., Gandhi, A.D., Wilkerson, J.D. 2012. Assessing cervical dislocation as a humane euthanasia method in mice. JAmAssoc Lab Anim Sci 51 (3): 352–356
Chang Y, Chang NW, Tsai NW, et al (2014) The roles of biomarkers of oxidative stress and antioxidant in Alzheimer’s disease: a systematic review. BioMed Research International, Article ID 182303, 14 pages
Chen KC, Baxter MG, Rodefer JS (2004) Central blockade of muscarinic cholinergic receptors disrupts affective and attentional set-shifting. Neurosci. 20:1081–1088
Chen Q, Chen X, Fu Z, Vbais S, Hou X (2019) Antiemnesic effects of Leea Indica extract on scopolamine –induced amnesia of Alzheimer’s type in rat. Int.J.Pharmacol 15:116–123
Cheng XR, Zhou XY, Zhang YX (2014) The behavioral, pathological and therapeutic features of the senescence-accelerated mouse prone 8 strain as an Alzheimer’s disease animal model. Ageing Res Rev 13:13–37
Craggs L, Kalaria RN (2011) Revisiting dietary antioxidants, neurodegeneration and dementia. Neuroreport 22:1–3
Cremer DR, Rabeler R, Roberts A, Lynch B (2006) Long-term safety of alpha-lipoic acid (ALA) consumption: a 2-year study. Regul Toxicol Pharmacol 46(3):193–201
Dresden D (2016) Hippocampus: what is its function? Neurosci. 16:3534–3540
Dudek M, Bednarski M, Bilska A (2008) The role of lipoic acid in the prevention of nitroglycerin tolerance. Eur J Pharmacol 591(1–3):203–210
Ericson J (2013) Common prescription drugs that may cause memory loss: examples and alternatives. J Exp PsycholGen 122(4):411.428
Evans JL, Goldfine ID (2000) Alpha lipoic acid: an antioxidant that improves insulin sensitivity in type II diabetes. Diabetes technology and therapeutics 19:227–250
Eysenck MW (2012) Fundamentals of cognition. New York: Psychology Press 17(12):698–701
Feng Y, Wang X (2012) Antioxidant therapies for Alzheimer’s disease. Oxidative Med Cell Longev 472932
Finsterwald C, Magistretti PJ, Lengacher S (2015) Astrocytes: new targets for the treatment of neurodegenerative diseases. Curr Pharm Des 21(25):3570–3581
Flood JF, Cherkin A (1986) Scopolamine effects on memory retention in mice: A model of dementia? Behavioural and Neural Biology 45(2):169–184
Fransisco JC (2015) Adverse neurological effects caused by the ingestion of plants, seeds, and fruits. Nutraceuticals and dietary supplements in neurological and brain disease, 215-219
Galeshkalami NS, Abdollahi M, Najafi R et al (2019) Alpha-lipoic acid and coenzyme Q10 combination ameliorates experimental diabetic neuropathy by modulating oxidative stress and apoptosis. Life Sci 216(18):101–110
Gentile MT, D’Amato LC (2018) Introductory Chapter: The Importance of Astrocytes in the Research of CNS Diseases, Astrocyte - Physiology and Pathology, Maria Teresa Gentile and Luca Colucci D’Amato, IntechOpen, https://doi.org/10.5772/intechopen.74710. Available from: https://www.intechopen.com/books/astrocyte-physiology-and-pathology/introductory-chapter-the-importance-of-astrocytes-in-the-research-of-cns-diseases
Gomez-Pinilla F, Nguyen TT (2012) Natural mood foods: the actions of polyphenols against psychiatric and cognitive disorders. Nutr Neurosci 15:127–133
Goverdhan P, Sravanthi A, Mamatha T (2012) Neuroprotective effects of meloxicam and selegiline in scopolamine-induced cognitive impairment and oxidative stress. Int J Alzheimers Dis 2012:1–8. https://doi.org/10.1155/2012/974013
Haass C, Selkoe DJ (2007) Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid beta-peptide. Nat Rev Mol Cell Biol 8(2):101–112
Hala F, Zaki MA, Abd-El-Fattah A, Attia S (2013) Naringerin protects against scopolamine- dementia in rats. Bulletin of Faculty of Pharmacy 52:15–25
Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science. 297(5580):353–356
Harvey BS, Musgrave IF, Ohlsson KS, Fransson A, Smid SD (2011) The green tea polyphenol (−)-epigallocatechin-3-gallate inhibits amyloid-β evoked fibril formation and neuronal cell death in vitro. Food Chem 129:1729–1736
Hasanein P, Mahtaj AK (2015) Ameliorative effect of rosmarinic acid on scopolamine-induced memory impairment in rats. Neuro- science letters 585:23–27
Heemels MT (2016) Neurodegenerative diseases. Nature 539:179
Hoffman E, Winder SJ (2016) A Modified Wire Hanging Apparatus for Small Animal Muscle Function Testing PLOS Currents Muscular Dystrophy Edition 1. doi: https://doi.org/10.1371/currents.md.1e2bec4e78697b7b0ff80ea25a1d38be
Holmquist L, Stuchbury G, Berbaum K (2007) Lipoic acid as a novel treatment for Alzheimer's disease and related dementias. Pharmacol Ther 113(1):154–164
Huang WJ, Zhang X, Chen WW (2016) Role of oxidative stress in Alzheimer’s disease. Biomed Rep 4:519–522
Hughes RN (2004) The value of spontaneous alternation behavior (SAB) as a test of retention in pharmacological investigations of memory. Neurosci Biobehav Rev 28:497–450
Ionita R, Postu PA, Beppe GJ, Mihasan M, Petre BA, Hancianu M, Cioanca O, Hritcu L (2017) Cognitive-enhancing and antioxidant activities of the aqueous extract from Markhamia tomentosa (Benth.) K. Schum. Stem bark in a rat model of scopolamine. Behav brain Funct 13(5). https://doi.org/10.1186/s12993-017-0123-6
Ishida Y, Ohara T, Okuno Y (2007) Alpha-lipoic acid and insulin autoimmune syndrome. Diabetes Care 30(9):2240–2251
Jahanshahi M, Nickmahzar EG, Babakordi F (2013) The effect of Ginkgo biloba extract on scopolamine-induced apoptosis in the hippocampus of rats. Anat Sci Int 88:217–222
Jang YJ, Kim J, Shim J, Kim CY, Jang JH, Lee KW (2013) Decaffeinated coffee prevents scopolamine-induced memory impairment in rats. Behav Brain Res 245:113–119
Jin-Ting He, Xiao-Yan LI, Le Yang, Xin Zhao (2020) Astroglial connexins and cognition: memory formation or deterioration?. Biosci Rep 40(1):BSR20193510. https://doi.org/10.1042/BSR20193510
Jomova K, Vondrakova D, Lawson M, Valko M (2010) Metals, oxidative stress and neurodegenerative disorders. Mol Cell Biochem 345(1):91–104
KaddourTaïr OK, Oussama A, Nouria H, Iméne B, Abdelkader A (2016) Aluminum-induced acute neurotoxicity in rats: treatment with aqueous extract of Arthrophytum (Hammada scoparia). Journal of Acute Disease 5(6):470–482
Karim NS, Khan I, Abdelhalim A, Abdel-Halim H, Hanrahan JR (2017) Molecular docking and antiamnesic effects of nepitrin isolated from Rosmarinus officinalis on scopolamine-induced memory impairment in mice. Biomed Pharmacother 96:700–709
Khan S, Shad KF, Shad F (2015) Neuroprotective Effect of Curcumin and Vitamin D3 on Scopolamine Hydro-Bromide Treated Rat Model of Alzheimer’s Disease .EC Neurology 24: 155–161
Kuijpers M, Haucke V (2018) Presynaptic endocytic factors in autophagy and neurodegeneration. Curr Opin Neurobiol 48:153–159
Kulkarni KS, Kasture SB, Mengi SA (2010) Efficacy study of Prunus amygdalus (almond) nuts in scopolamine-induced amnesia in rats. Indian J Pharmacol. 42:168–173
Kwon SH, Lee HK, Kim JA, Hong SI, Kim HC, Jo TH (2010) Neuroprotective effects of chlorogenic acid on scopolamine-induced amnesia via anti-acetylcholinesterase and anti-oxidative activities in mice. Eur J Pharmacol 649:210–217
Kwon SH, Ma SX, Jo HJ, Lee SY, Jang CG (2013) Inhibitory effect of Eucommia ulmoides Oliv. Bark on scopolamine-induced learning and memory deficits in mice. Biomol Ther (Seoul) 21:462–469
Magalingam KB, Radhakrishnan A Ping NS, Haleagrahara N (2018) Current concepts of neurodegenerative mechanisms in Alzheimer's disease. BioMed Research international. Article ID 3740461
Mahboob A, Farhat SM, Iqbal G, Babar MM, Zaidi NU, Nabavi SM et al (2016) Alpha-lipoic acid-mediated activation of muscarinic receptors improves hippocampus- and amygdala-dependent memory. Brain Res Bull 122:19–28
Maina MB, Garba SH, Jacks TW (2008) Histological evaluation of the rats testis following administration of a herbal tea mixture. J Pharmacol Toxicol 3:464–470
Makhaeva GF, Lushchekina SV, Boltneva NP, Sokolov VB, Grigoriev VV, Serebryakova OG, Vikhareva EA, Aksinenko AY, Barreto GE, Aliev G, Bachurin SO (2015) Conjugates of γ-Carbolines and phenothiazine as new selective inhibitors of butyrylcholinesterase and blockers of NMDA receptors for Alzheimer disease. Sci Rep 5:13164
Memudu AE, Pantong S, Osahon RI (2020) Histomorphological evaluations on the frontal cortex extrapyramidal cell layer following administration of N-acetyl cysteine in aluminum induced neurodegeneration rat model. Metab Brain Dis 35:829–839. https://doi.org/10.1007/s11011-020-00556-9
Mesher AL (2013) Junqueira’s basic histology: text and atlas. 13thedition. McGraw Hill companies Inc: 174-175
Molz P, Schröder N (2017) Potential therapeutic effects of lipoic acid on memory deficits related to aging and neurodegeneration. Front Pharmacol 8:849. https://doi.org/10.3389/fphar.2017.00849
Morris MC, Evans DA, Bienias JL, Tangney CC, Bennett DA, Aggarwal N (2002) Dietary intake of antioxidant nutrients and the risk of incident Alzheimer disease in a biracial community study. JAMA. 287:3230–3237
National Institutes of Mental Health (2002) Methods and welfare considerations in behavioral research with animals: Report of a National Institutes of Health Workshop. Morrison, A.R., Evans, H. L., Ator, N. A.and Nakamura, R. K. (Eds.). NIH Publications No. 02–5083. Washington, DC: US Government Printing Office
National Research Council (2003) Guidelines for the care and use of mammals in neuroscience and behavioral research. The National Academies Press, Washington, DC
National Research Council (2011) Guide for the care and use of laboratory animals, 8th edn. The National Academies Press, Washington, DC
Navarria A, Wohleb ES, Voleti B, Ota KT, Dutheil S, Lepack AE, Dwyer JM, Fuchikami M, Becker A, Drago F, Duman RS (2015) Rapid antidepressant actions of scopolamine: Role of medial prefrontal cortex and M1-subtype muscarinic acetylcholine receptors. Neurobiol Dis 82:254–261. https://doi.org/10.1016/j.nbd.2015.06.012
Paxinos G, Watson C, (2007) The rat brain in stereotaxic coordinates. New York: New York: Academic
Phelps JR (2014) Memory, learning, and emotion: the hippocampus. J Neural Transm 111(2):127–139
Pohanka M (2014) Alzheimer’s disease and oxidative stress: a review. Curr Med Chem 21(3):356–364
Quesada I, de Paola M, Torres-Palazzolo C, Camargo A, Ferder L, Manucha W, Castro C (2020) Effect of Garlic’s active constituents in inflammation, obesity and cardiovascular disease. Current Hypertension Reports.22
Ramakrishna N, Vinod KS, Sautana J, Santosh KP, Anil G (2015) What suits best for organ weight analysis: review of relationship between organ weight for rodent toxicity studies. Inter J of Pharm Sci Res 1:90–96
Raza SS, Khan MM, Ahmad A, Ashafaq M, Islam F, Wagner AP (2013) Neuroptoective effect of alpha lipoic acid is mediate through suppression of NF-kb signalling pathway in experimental stroke. Neuroscience 230:157–171
Reiss AB, Arain HA, Stecker MM, Siegart NM, Kasselman LJ (2018) Amyloid toxicity in Alzheimer’s disease. Rev Neurosci 29(6):6201813–6201627
Reitz C, Brayne C, Mayeux R (2011) Epidemiology of Alzheimer disease. Nat Rev Neurol 7:137–152
Robertson S (2017) What is hippocampus. Neuroscience. 97:253–266
Sanabria-Castro A, Alvarado-Echeverría I, Monge-Bonilla C (2017) Molecular pathogenesis of Alzheimer’s disease: an update. Ann Neurosci 24:46–54
Saraf MK, Prabhakar S, Khanduja KL, Anand A (2011) Bacopa monniera attenuates scopolamine-induced impairment of spatial memory in mice. Evidence-Based Complement Altern Med 2011:1–10. https://doi.org/10.1093/ecam/neq038
Schwabe L, Wolf OT (2010) Learning under stress impairs memory formation. Neurobiol Learn Mem 93(2):183–188
Silverstein JH (2014) Influence of anesthetics on Alzheimer’s disease: biophysical, animal model, and clinical reports. J Alzheimers Dis 40(4):839–848
Simmons JE, Yang RS, Berman E (1995) Evaluation of the nephrotoxicity of complex mixtures containing organics and metals: advantages and disadvantages of the use of real-world complex mixtures. Environ Health Perspect 103(Suppl 1):67–71
Singh AP, Bihaqi SW, Tiwari M (2012) Supplementation of Convolvulus pluricaulis attenuates scopolamine-induced increased tau and amyloid precursor protein (AßPP) expression in rat brain. Indian J Pharmacol 44:593–598
Singh I (2014) Textbook of human Neuroanatomy: fundamental and clinical. 9th edition. Jaypee Brothers medical publisher: 147-158
Staehelin HB (2008) Neuronal protection by bioactive nutrients. Int J Vitam Nutr Res 78:282–285
Taylor JP, Brown RH, Cleveland DW (2016) Decoding ALS: from genes to mechanism. Nature. 539:197–206
Terry AV (2006) Muscarinic receptor antagonists in rats. Neuroscience 131:43–54
Tzvetanova ER, Georgieva AP, Alexandrova AV, et al. (2018) Antioxidant mechanisms in neuroprotective action of lipoic acid on learning and memory of rats with experimental dementia. 50: 52–57
Vaisman N, Pelled D (2009) n-3 phosphatidylserine attenuated scopolamine-induced amnesia in middle-aged rats. Prog Neuropsychopharmacol Biol Psychiatry 33:952–959
van Putten M (2014) The use of hanging wire tests to monitor muscle strength and condition over time. TREAT-NMD SOP DMD_M.2.1.004:http://www.treat-nmd.eu/research/preclinical/dmd-sops/
van Zutphen LFM, Baumans V, Benyen AC (1993) In Principles of Laboratory Animal Science. (Eds L.F.M van Zutphen, V. Baumans and a.C Beyen), Amsterdam, Elsevier. Pp. 389
Vijayan V, Verstreken P (2017) Autophagy in the presynaptic compartment in health and disease. J. Cell Biol 216:895–1906
Wegerer J (2014) Nutrition and Dementia: Foods That May Induce Memory Loss & Increase Alzheimer’s 24(4):479–489
Wyss-CoraY T (2016) Ageing, neurodegeneration and brain rejuvenation. Nature 539:180–186
Xu X, Guolin W, Wenqian Z, Wenwen B, Tiaotiao L, Xin T (2012) Effect of propofol on local field potential in rat prefrontal cortex during working memory task. World Journal of Neuroscience 2:166–171
Yang C, Li L, Yang L, Lǚ H, Wang S, Sun G (2018) Anti-obesity and Hypolipidemic effects of garlic oil and onion oil in rats fed a high-fat diet. Nutr Metab (Lond) 15:43. https://doi.org/10.1186/s12986-018-0275-x
Zhang J, Wang J, Gui-Sheng Z, Ya-Jie T, Tao H, Chen J, Pu Z, Ma Y, She W, Yang A, Zhu Y, Liu MP, Zhu Z, Shi Q, Tang Y, Duan Y (2019) Studies of the anti-amnesic effects and mechanisms of single and combined use of donepezil and Ginkgo Ketoester tablet on scopolamine-induced memory impairment in mice. Oxid Med Cell Longev 2019:16. https://doi.org/10.1155/2019/8636835
Acknowledgments
The authors appreciate the Anatomy Department of Bingham University, Karu Nasarawa State Nigeria for providing adequate facility to experiment and Mr. Jonathan Madukwe a Histopathology scientist (Histopathology Department, National Hospital, Abuja, Nigeria) for his technical assistance in histological and immunohistochemical analysis of this study.
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Adejoke Elizabeth Memudu: Conceptualization, Methodology, data interpretation, Writing- Reviewing and Editing, formal analysis, supervision, Data curation.
Abosede Esther Adewumi: Writing- Reviewing and Editing, formal analysis, resources, data interpretation.
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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed according to the standard recommendations in the Guide for the Care and Use of Laboratory Animals, and Animal Care and Use in Mental Health; of the National Institutes of Health (NIH, 2011) and the experi-mental protocols approved by the Departmental Research, Animal Care and Use Ethics Committee. The behavioral procedures were carried out in behavioural room equipped with a facility for the test done and the experimental animals were handled in compliance with “Methods and welfare considerations in behavioral research with animals” (National Institutes of Mental Health (2002), and Guidelines for the care and use of mammals in neuroscience and behavioral research (National Research Council 2003).
This research follows standard guidelines involving the use animals of animals as approved by the Anatomy department research ethics committee.
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Memudu, A.E., Adewumi, A.E. Alpha lipoic acid ameliorates scopolamine induced memory deficit and neurodegeneration in the cerebello-hippocampal cortex. Metab Brain Dis 36, 1729–1745 (2021). https://doi.org/10.1007/s11011-021-00720-9
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DOI: https://doi.org/10.1007/s11011-021-00720-9