International Journal of Preventive Medicine Research
Articles Information
International Journal of Preventive Medicine Research, Vol.1, No.2, Jun. 2015, Pub. Date: Jun. 2, 2015
Neuroprotective Effect of Ellagic Acid Against Chronically Scopolamine Induced Alzheimer's Type Memory and Cognitive Dysfunctions: Possible Behavioural and Biochemical Evidences
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[01] Ramandeep Kaur, Department of Pharmacology, Rajendra Institute of Tech & Sciences, Sirsa, Haryana, India.
[02] Shaba Parveen, Department of Pharmacology, Rajendra Institute of Tech & Sciences, Sirsa, Haryana, India.
[03] Sidharth Mehan, Department of Pharmacology, Rajendra Institute of Tech & Sciences, Sirsa, Haryana, India.
[04] Deepa Khanna, Department of Pharmacology, Rajendra Institute of Tech & Sciences, Sirsa, Haryana, India.
[05] Sanjeev Kalra, Department of Pharmacology, Rajendra Institute of Tech & Sciences, Sirsa, Haryana, India.
Adjudge the neuroprotective ability of Ellagic acid (EA) as a constructive herbal drug to impede cholinergic dysfunctions and oxidative stress in Alzheimer’s disease (AD) in chronically administered scopolamine induced Alzheimer’s type dementia in rats. Alzheimer’s type dementia was induced by chronically administered intraperitoneal injection of scopolamine (0.7 mg/kg) to rats for period of 7 days. EA (25 mg/kg and 50 mg/kg) and Donepezil (0.5 mg/kg) were administrated to rats orally daily for a period of 13 days. Memory-related behavioral parameters were evaluated using the elevated plus maze (EPM) for 2 days and morris water maze (MWM) for 5 days. At the end of protocol schedulei.e day 14, biochemical parameters were estimated like AChE, MDA, GSH, catalase and SOD to evaluate the neuroprotective action of EA via AChE inhibition and antioxidant activity. Chronically injected scopolamine treatment increased the transfer latency in EPM, escape latency time and shortened time spent in the target quadrant in MWM; these effects were reversed by EA. Scopolamine-mediated changes in malondialdehyde (MDA) and AChE activity were significantly attenuated by EA in rats. Recovery of antioxidant capacities, including reduced glutathione (GSH) content, and the activities of SOD and catalase was also evident in EA treated rats. The present findings sufficiently encourage that EA has a major role in the neuroprotection in chronically injected Scopolamine induced Alzheimer type dementia. The EA can be used as an effectual herbal treatment to prevent cholinergic dysfunctions and oxidative stress associated with Alzheimer type dementia.
Neuroinflammation, Oxidative Stress, Acetylcholinesterase, Polyphenols, Ellagic Acid
[01] Chong ZZ, Li F, Maiese K. Stress in the brain: novel cellular mechanisms of injury linked to Alzheimer’s disease. Brain Res Rev. 2005; 49:1-21.
[02] Walsh DM, Klyubin I, Shankar GM, Townsend M, Fadeeva JV, Betts V, et al. The role of cell-derived oligomers of Abeta in Alzheimer's disease and avenues for therapeutic intervention. Biochem Soc Trans. 2005; 33(Pt 5):1087-90.
[03] Jellinger KA. Alzheimer 100-highlights in the history of Alzheimer research. J Neural Transm. 2006; 113:1603-23.
[04] Muthaiyah B, Essa MM, Chauhan V, Chauhan, A. Protective Effects of Walnut Extract Against Amyloid Beta Peptide-Induced Cell Death and Oxidative Stress in PC12 Cells. Neurochem Res. 2011; 36: 2096-103.
[05] Anand R, Gill KD, Mahdi AA. Therapeutics of Alzheimer's disease: Past, present and future. Neuropharmacology. 2014; 76 Pt:A 27-50.
[06] Alzheimer’s Association. Alzheimer’s disease Facts and Figures, Alzheimer’s & Dementia. 2014; 10:16.
[07] Anderson DC. Alzheimer’s disease Biomarkers: More Than Molecular Diagnostics. Drug Develop Res. 2013; 74:92–111.
[08] Blennow K, Zetterberg H, Fagan AM. Fluid biomarkers in Alzheimer disease. Cold Spring Harb Perspect Med. 2012; 2: a006221.
[09] Mehan S, Meena H, Sharma D, Sankhla R. JNK: a stress-activated protein kinase therapeutic strategies and involvement in Alzheimer's and various neurodegenerative abnormalities. J Mol Neurosci. 2011; 43: 376-90.
[10] Kihara T, Shimohama S. Alzheimer's disease and acetylcholine receptors. Acta Neurobiol Exp. 2004; 64:99-105.
[11] Verdile G, Fuller S, Atwood CS, Laws SM, Gandy SE, Martin RN. The role of beta amyloid in alzheimers disease: still a cause of everything or the only one who got caught? Pharmaclo Res. 2004; 50:397-409.
[12] Anandatheerthavarada HK, Biswas G, Robin MA, Avadhani NG. Mitochondrial targeting and a novel transmembrane arrest of Alzheimer’s amyloid precursor protein impairs mitochondrial function in neuronal cells. J Cell Biol. 2003; 161: 41-53.
[13] Marcus DL, Thomas C, Rodriguez C, Simberkoff K, Tsai JS, Strafaci JA, et al. Increased peroxidation and reduced antioxidant enzyme activity in Alzheimer’s disease. Exp Neurol. 1998; 150:40-4.
[14] Nunomura A, Perry G, Aliev G, Hirai K, Takeda A, Balraj EK, et al. Oxidative damage is the earliest event in Alzheimer’s disease. J Neuropathol Exp Neurol. 2001; 60: 759-67.
[15] Sarkar PK. Degeneration and death of neurons in adult neurodegenerative diseases. Curr Sci. 2005; 89:746-73.
[16] Heneka MT, O’Banion MK. Inflammatory processes in Alzheimer’s disease. J Neuroimmunol. 2007; 184: 69-91
[17] Galasko D, Montine TJ. Biomarkers of oxidative damage and inflammation in Alzheimer's disease. Biomark Med. 2010; 4: 27-36.
[18] Engelhart MJ, Geerlings MI, Ruitenberg A, van Swieten JC, Hofman A, Witteman JC, et al. Dietary intake of antioxidants and risk of Alzheimer disease. JAMA. 2002; 287:3223-9.
[19] Morris MC, Evans DA, Bienias JL, Tangney CC, Bennett DA, Aggarwal N, et al. Dietary Intake of Antioxidant Nutrients and the Risk of Incident Alzheimer Disease in a Biracial C-ommunity Study. JAMA. 2002; 287:3230-7.
[20] Dai Q, Borenstein AR, Wu Y, Jackson JC, Larson EB. Fruit and vegetable juices and Alzheimer's disease: the Kame Project. Am J Med. 2006; 119:751-9.
[21] Mancuso C, Bates TE, Butterfield DA, Calafato S, Cornelius C, De Lorenzo A, et al. Natural antioxidants in Alzheimer's disease. Expert Opin Investig Drugs. 2007; 16:1921-31.
[22] Staehelin HB. Neuronal protection by bioactive nutrients. Int J Vitam Nutr Res. 2008; 78: 282-5.
[23] Harvey BS, Musgrave IF, Ohlsson KS, Fransson A, Smid SD. The green tea polyphenol (-)-epigallocatechin-3-gallate inhibits amyloid-b evoked fibril formation and neuronal cell death in vitro. Food Chemistry. 2011; 129:1729-36
[24] Obulesu M, Rao DM. Effect of plant extracts on Alzheimer's disease: An insight into therapeutic avenues. J Neurosci Rural Pract. 2011; 2: 56-61
[25] Bastianetto S, Ramassamy C, Doré S, Christen Y, Poirier J, Quirion R. The Ginkgo biloba extract (EGb761) protects hippocampal neurons against cell death induced by beta-amyloid. Eur J Neurosci. 2000; 12:1882-90.
[26] Choi YT, Jung CH, Lee SR, Bae JH, Baek WK, Suh MH, et al. The green tea polyphenol (-)-epigallocatechin gallate attenuates beta-amyloid-induced neurotoxicity in cultured hippocampal neurons. Life Sci. 2001; 70:603-14.
[27] Li MH, Jang JH, Sun B, Surh YJ. Protective effects of oligomers of grape seed polyphenols against beta-amyloid-induced oxidative cell death. Ann N Y Acad Sci. 2004; 1030:317-29.
[28] Mishra S, Palanivelu K. The effect of curcumin (turmeric) on Alzheimer's disease: An overview. Ann Indian Acad Neurol. 2008; 11:13-9.
[29] Craggs L, Kalaria RN. Revisiting dietary antioxidants, neurodegeneration and dementia. Neuroreport. 2011; 22:1-3.
[30] Choi DY, Lee YJ, Lee SY, Lee YM, Lee HH, Choi IS, et al. Attenuation of scopolamine-induced cognitive dysfunction by obovatol. Arch Pharm Res. 2012; 35:1279-86.
[31] Lim GP, Chu T, Yang F, Beech W, Frautschy SA, Cole GM. The curry spice curcumin reduces oxidative damage and amyloid pathology in an Alzheimer transgenic mouse. J Neurosci. 2001; 21:8370-7.
[32] Thomas P, Wang YJ, Zhong JH, Kosaraju S, O'Callaghan NJ, Zhou XF, Fenech M. Grape seed polyphenols and curcumin reduce genomic instability events in a transgenic mouse model for Alzheimer's disease. Mutat Res. 2009; 661:25-34.
[33] Fernández-Fernández L, Comes G, Bolea I, Valente T, Ruiz J, Murtra P, et al. LMN diet, rich in polyphenols and polyunsaturated fatty acids, improves mouse cognitive decline associated withaging and Alzheimer's disease. Behav Brain Res. 2012; 228:261-71.
[34] Gomez-Pinilla F, Nguyen TT. Natural mood foods:the actions of polyphenols against psychiatric and cognitive disorders. Nutr Neurosci. 2012; 15:127-33
[35] Anhe FF, Desjardins Y, Pilon G, Dudonne S, Genovese M, Lajolo FM, et al. Polyphenols and type 2 diabetes: A prospective review. PharmaNutrition. 2013; 1:105–114.
[36] Hakkinen S, Heinonen M, Karenlampi Mykkanen H, Ruuskanen J, Torronen R. Screening of selected favonoids and phenolic acids in 19 berries. Food Res Int. 1999; 32: 345-53.
[37] Gil MI, Tomas-Barberan FA, Hess-Pierce B, Holcroft DM, Kader AA. Antioxidant Activity of Pomegranate Juice and Its Relationship with Phenolic Composition and Processing. J Agric Food Chem. 2000; 48:4581-89.
[38] Hartman RE, Shah A, Fagan AM, Schwetye KE, Parsadanian M, Schulman RN, et al. Pomegranate juice decreases amyloid load and improves behavior in a mouse model of Alzheimer's disease. Neurobiol Dis. 2006; 24:506-15.
[39] Nantitanon W, Yotsawimonwat S, Okonogi S. Factors influencing antioxidant activities and total phenolic content of guava leaf extract. LWT - Food Sci Technol. 2010; 43:1095-1103.
[40] Landete JM. Ellagitannins, ellagic acid and their derived metabolites: A review about source metabolism, functions and health. Food Res Int. 2011; 44:1150–60.
[41] Singh K, Khanna AK, Chander R. Hepatoprotective activity of ellagic acid against carbon tetrachloride induced hepatotoxicity in rats. Indian J Exp Biol. 1999; 37: 1025-6.
[42] Ateşşahín A, Ceríbaşi AO, Yuce A, Bulmus O, Cikim G. Role of Ellagic Acid against Cisplatin-Induced Nephrotoxicity and Oxidative Stress in Rats. Basic Clin Pharmacol Toxicol. 2007; 100:121-6.
[43] Yüce A, Ateşşahin A, Ceribaşi AO, Aksakal M. Ellagic Acid Prevents Cisplatin-Induced Oxidative Stress in Liver and Heart Tissue of Rats. Basic Clin Pharmacol Toxicol. 2007; 101:345-9.
[44] Chao PC, Hsu CC, Yin MC. Anti-inflammatory and anti-coagulatory activities of caffeic acid and ellagic acid in cardiac tissue of diabetic mice. Nutr Metab (Lond). 2009; 6:33.
[45] Özkaya A, Celik S, Yüce A, Şahin Z, Yilmaz O. The Effects of Ellagic Acid on Some Biochemical Parameters in the Liver of Rats Against Oxidative Stress Induced by Aluminum. Kafkas Univ Vet Fak DerG. 2010; 16:263-268.
[46] Türk G, Sönmez M, Çeribaş AO, Yüce A, Ateşşahin A. Attenuation of cyclosporine A-induced testicular and spermatozoal damages associated with oxidative stress by ellagic acid. Int Immunopharmacol. 2010; 10:177–182
[47] Papoutsi Z, Kassi E, Chinou I, Halabalaki M, Skaltsounis LA, Moutsatsou P. Walnut extract (Juglans regia L.) and its component ellagic acid exhibit anti-inflammatory activity in human aorta endothelial cells and osteoblastic activity in the cell line KS483. Z. Br J Nutr. 2008; 99:715-22.
[48] Bae JY, Choi JS, Kang SW, Lee YJ, Park J, Kang YH. Dietary compound ellagic acid alleviates skin wrinkle and inflammation induced by UV-B irradiation. Exp Dermatol. 2010; 19: e182-90.
[49] Umesalma S, Sudhandiran G. Differential Inhibitory Effects of the Polyphenol Ellagic Acid on Inflammatory Mediators NF-jB, iNOS, COX-2, TNF-a, and IL-6 in 1,2-Dimethylhydrazine-Induced Rat Colon Carcinogenesis. Basic Clin Pharmacol Toxicol. 2010; 107:650-5.
[50] Rosillo MA, Sánchez-Hidalgo M, Cárdeno A, Aparicio-Soto M, Sánchez-Fidalgo S, Villegas I, et al. Dietary supplementation of an ellagic acid-enriched pomegranate extract attenuates chronic colonic inflammation in rats. Pharmacol Res. 2012; 66:235-42.
[51] Cornélio Favarin D, Martins Teixeira M, Lemos de Andrade E, de Freitas Alves C, Lazo Chica JE, Artério Sorgi C et al. Anti-Inflammatory Effects of Ellagic Acid on Acute Lung Injury Induced by Acid in Mice. Mediators Inflamm. 2013; 2013:164202.
[52] Malik A, Afaq S, Shahid M, Akhtar K, Assiri A. Influence of ellagic acid on prostate cancer cell proliferation: A caspase dependent Pathway. Asian Pac J Trop Med. 2011; 4:550-5.
[53] Srigopalram S, Ilavenil S, Jayraaj IA. Apoptosis associated inhibition of DEN-induced hepatocellular carcinogenesis by ellagic acid in experimental rats. Biomedicine & Preventive Nutrition. 2012; 2:1-8.
[54] Umesalma S, Sudhandiran G. Ellagic acid prevents rat colon carcinogenesis induced by 1, 2 dimethyl hydrazine through inhibition of AKT-phosphoinositide-3 kinase pathway. Eur J Pharmacol. 2011; 660:249-58.
[55] Qiu Z, Zhou B, Jin L, Yu H, Liu L, Liu Y et al. In vitro antioxidant and antiproliferative effects of ellagic acid and its colonic metabolite, urolithins, on human bladder cancer T24 cells. Food Chem Toxicol. 2013; 59:428-37.
[56] Zhao M, Tang SN, Marsh JL, Shankar S, Srivastava RK. Ellagic acid inhibits human pancreatic cancer growth in Balb c nude mice. Cancer Lett. 2013; 337:210-7.
[57] Malini P, Kanchana G, Rajadurai M. Antibiabetic efficacy of ellagic acid in streptozotoc induced diabetes mellitus in albino wistar rats. Asian J Pharm Clin Res. 2011; 4:124-8.
[58] You Q, Chen F, Wang X, Jiang Y, Lin S. Anti-diabetic activities of phenolic compounds in muscadine against alpha-glucosidase and pancreatic lipase. LWT - Food Sci Technol. 2012; 46:164-8.
[59] Akileshwari C, Raghu G, Muthenna P, Mueller NH, Suryanaryana P, Petrash JM et al. Bioflavonoid ellagic acid inhibits aldose reductase: Implications for prevention of diabetic complications. J Funct Foods. 2014; 6:374-83
[60] Kannan MM, Quine SD. Ellagic acid inhibits cardiac arrhythmias, hypertrophy and hyperlipidaemia during myocardial infarction in rats. Metabolism. 2013; 62:52-61.
[61] Rani UP, Kesavan R, Ganugula R, Avaneesh T, Kumar UP, Reddy GB et al. Ellagic acid inhibits PDGF-BB-induced vascular smooth muscle cell proliferation and prevents atheroma formation in streptozotocin-induced diabetic rats. J Nutr Biochem. 2013; 24:1830-9.
[62] Hassoun EA, Vodhanel J, Abushaban A. The modulatory effects of ellagic acid and vitamin E succinate on TCDD-induced oxidative stress in different brain regions of rats after subchronic exposure. J Biochem Mol Toxicol. 2004; 18:196-203.
[63] Pavlica S, Gebhardt R. Protective effects of ellagic and chlorogenic acids against oxidative stress in PC12 cells. Free Radic Res. 2005; 39:1377-90.
[64] Shukitt-Hale B, Lau FC, Carey AN, Galli RL, Spangler EL, Ingram DK, et al. Blueberry polyphenols attenuate kainic acidinduced decrements in cognition and alter inflammatory gene expression in rat hippocampus. Nutr Neurosci. 2008; 11:172-82.
[65] Tan HP, Wong DZ, Ling SK, Chuah CH, Kadir HA. Neuroprotective activity of galloylated cyanogenic glucosides and hydrolysable tannins isolated from leaves of Phyllagathis rotundifolia. Fitoterapia. 2012; 83:223-9.
[66] Uzar E, Alp H, Cevik MU, Fırat U, Evliyaoglu O, Tufek A et al. Ellagic acid attenuates oxidative stress on brain and sciatic nerve and improves histopathology of brain in streptozotocin-induced diabetic rats. Neurol Sci. 2012; 33:567-74.
[67] Gaire BP, Jamarkattel-Pandit N, Lee D, Song J, Kim JY, Park J et al. Terminalia chebulaextract protects OGD-R induced PC12 cell death and inhibits LPS induced microglia activation. Molecules. 2013; 18:3529-42.
[68] Rojanathammanee L, Puig KL, Combs CK. Pomegranate polyphenols and extract inhibit nuclear factor of activated t-cell activity and microglial activation in vitro and in a transgenic mouse model of Alzheimer disease. J Nutr. 2013; 143:597-605.
[69] Feng Y, Yang SG, Du XT, Zhang X, Sun XX, Zhao M et al. Ellagic acid promotes Aβ42 fibrillization and inhibits Aβ42-induced neurotoxicity. Biochem Biophys Res Commun. 2009; 390:1250-4.
[70] Wilson GN, Mickley GA, Matera KM. The efficacy of ellagic acid in attenuating neurophysiological and cognitive-behavioral symptoms associated with infusion of amyloid-beta (Aβ) peptide fragments in adult rats. The Baldwin-Wallace College Journal of Research and Creative Studies, Spring 2010; 3:15-30.
[71] Sheean P, Rout MK, Head RJ, Bennett LE. Modulation of in vitro activity of zymogenic and mature recombinant human β-secretase by dietary plants. FEBS J. 2012; 279:1291-1305.
[72] Messier C, Gagnon M. Glucose regulation and cognitive functions: relation to Alzheimer's disease and diabetes. Behav Brain Res. 1996; 75:1-11.
[73] Beal MF. Energetics in the pathogenesis of neurodegenerative diseases. Trends Neurosci. 2000; 23:298-304.
[74] Dhingra D, Parle M, Kulkarni SK. Effect of combination of insulin with dextrose, d(-) fructose and diet on learning and memory in mice. Indian J Pharmacol. 2003; 35:151-156.
[75] Mehan S, Arora R, Sehgal V, Sharma D, Sharma G. Dementia – A Complete Literature Review on Various Mechanisms Involves in Pathogenesis and an Intracerebroventricular Streptozotocin Induced Alzheimer’s Disease. Inflammatory Diseases – Immunopathology, Clinical and Pharmacological Bases. 2012; 4-19.
[76] Poulose N, Prasad CNV, Haridas PAN, Anilkumar G. Ellagic acid stimulates glucose transport in adipocytes and muscles through AMPK mediated pathway. J Diabetes Metab. 2011; 2:7
[77] Makino-Wakagi Y, Yoshimura Y, Uzawa Y, Zaima N, Moriyama T, Kawamura Y. Ellagic acid in pomegranate suppresses resistin secretion by a novel regulatory mechanism involving the degradation of intracellular resistin protein in adipocytes. Biochem Biophys Res Commun. 2012; 417:880-5
[78] Dhingra D, Chhillar R. Antidepressant-like activity of ellagic acid in unstressed and acute immobilization-induced stressed mice. Pharmacol Rep. 2012; 64:796-807.
[79] Girish C, Raj V, Arya J, Balakrishnan S. Involvement of the GABAergic system in the anxiolytic-like effect of the flavonoid ellagic acid in mice. Eur J Pharmacol. 2013; 710:49-58.
[80] Girish C, Raj V, Arya J, Balakrishnan S. Evidence for the involvement of the monoaminergic system, but not the opioid system in the antidepressant-like activity of ellagic acid in mice. Eur J Pharmacol. 2012; 682:118-25.
[81] Friedman JI, Adler DN, Davis KL. The role of norepinephrine in the pathophysiology of cognitive disorders: potential applications to the treatment of cognitive dysfunction in schizophrenia and Alzheimer's disease. Biol Psychiatry. 1999; 46:1243-52.
[82] Brambilla P, Perez J, Barale F, Schettini G, Soares JC. GABAergic dysfunction in mood disorders. Mol Psychiatry. 2003; 8:721-37.
[83] Tatton W, Chen D, Chalmers-Redman R, Wheeler L, Nixon R, Tatton N. Hypothesis for a common basis for neuroprotection in glaucoma and Alzheimer's disease: anti-apoptosis byalpha-2-adrenergic receptor activation. Surv Ophthalmol. 2003; 48:S25-37.
[84] Wenk GL, McGann K, Hauss-Wegrzyniak B, Rosi S. The toxicity of tumor necrosis factor-alpha upon cholinergic neurons within the nucleus basalis and the role of norepinephrine in the regulation of inflammation: implications for Alzheimer's disease. Neuroscience. 2003; 121:719-29.
[85] Choudary PV, Molnar M, Evans SJ, Tomita H, Li JZ, Vawter MP et al. Altered cortical glutamatergic and GABAergic signal transmission with glial involvement in depression. Proc Natl Acad Sci. 2005; 102:15653-8.
[86] Ciranna L. Serotonin as a modulator of glutamate- and GABA-mediated neurotransmission: implications in physiological functions and in pathology. Curr Neuropharmacol. 2006; 4:101-14.
[87] Madsen K, Neumann WJ, Holst K, Marner L, Haahr MT, Lehel Set al. Cerebral serotonin 4 receptors and amyloid-β in early Alzheimer's disease. J Alzheimers Dis. 2011; 26:457-66.
[88] Xu Y, Yan J, Zhou P, Li J, Gao H, Xia Yet al. Neurotransmitter receptors and cognitive dysfunction in Alzheimer's disease and Parkinson's disease. Prog Neurobiol. 2012; 97:1-13.
[89] Chalermpalanupap T, Kinkead B, Hu WT, Kummer MP, Hammerschmidt T, Heneka MT et al. Targeting norepinephrine in mild cognitive impairment and Alzheimer’s disease. Alzheimers Res Ther. 2013; 5:21.
[90] Yu JT, Wang ND, Ma T, Jiang H, Guan J, Tan L. Roles of β-adrenergic receptors in Alzheimer's disease: implications for novel therapeutics. Brain Res Bull. 2011; 84:111-7.
[91] Coutellier L. Ardestani PM, Shamloo M. β1-adrenergic receptor activation enhances memory in Alzheimer's disease model. Ann Clin Transl Neurol. 2014; 1:348-60.
[92] Bierhaus A, Schiekofer S, Schwaninger M, Andrassy M, Humpert PM, Chen Jet al. Diabetes-associated sustained activation of the transcription factor nuclear factor-kappa B. Diabetes. 2001; 50:2792-808.
[93] Cheng X, Wu J, Geng M, Xiong J. The role of synaptic activity in the regulation of amyloid beta levels in Alzheimer's disease. Neurobiol Aging. 2014; 35:1217-32.
[94] Spencer DG, La H. Effects of Anticholinergic Drugs on Learning and Memory. Drug Develop. Res. 1983; 3:489-502
[95] Chen KC, Baxter MG, Rodefer JS. Central blockade of muscarinic cholinergic receptors disrupts affective and attentional set-shifting. Eur J Neurosci. 2004; 20:1081-8.
[96] Wang D, Yu R, Lu YQ. Protective effect of Pregnenolone sulfate against scopolamine induced memory impairment in an experimental animal model. Med hypotheses res. 2005; 2:295-302.
[97] Terry AV Jr. Muscarinic Receptor Antagonists in Rats. In: Levin ED, Buccafusco JJ, editors. Animal Models of Cognitive Impairment. Boca Raton (FL): CRC Press. 2006.
[98] Lee YK, Yuk DY, Kim TI, Kim YH, Kim KT, Kim KH, et al. Protective effect of the ethanol extract of Magnolia officinalis and 4-O-methylhonokiol on scopolamine-induced memory impairment and the inhibition of acetylcholinesterase activity. J Nat Med. 2009; 63:274-82.
[99] Kwon SH, Lee HK, Kim JA, Hong SI, Kim HC, Jo TH, et al. Neuroprotective effects of chlorogenic acid on scopolamine-induced amnesia via anti-acetylcholinesterase andanti-oxidative activities in mice. Eur J Pharmacol. 2010; 649:210-7.
[100] Liem-Moolenaar M, de Boer P, Timmers M, Schoemaker RC, van Hasselt JG, Schmidt S et al. Pharmacokinetic-pharmacodynamic relationships of central nervous system effects of scopolamine in healthy subjects. Br J Clin Pharmacol. 2011; 71:886-98.
[101] Sahraei E, Soodi M, Jafarzadeh E, Karimivaghef Z. Investigation of the scopolamine effect on acetylcholinesterase activity. Res Pharmaceutic Sci. 2012; 7.
[102] Arafa NMS, Abdel-Rahman M, Mahmoud RAHA. Prophylactic Effect of Hypericum Perforatum L. extract in scopolamine rat model of cognitive dysfunction. TOPROCJ. 2013; 4:23-30.
[103] Kwon SH, Ma SX, Joo HJ, Lee SY, Jang CG. Inhibitory effects of Eucommia ulmoides Oliv. bark on scopolamine induced learning and memory deficits in mice. Biomol Ther (Seoul). 2013; 21:462-9.
[104] Tsukada H, Yamazaki S, Noda A, Inoue T, Matsuoka N, Kakiuchi T, et al. FK960 [N-(4-acetyl-1-piperazinyl)-p-fluorobenzamide monohydrate], a novel potential antidementia drug, restores the regional cerebral blood flow response abolished by scopolamine but not by HA-966: a positron emission tomography study with unanesthetized rhesus monkeys. Brain Res. 1999; 832:118-23.
[105] Tsukada H, Kakiuchi T, Ando I, Ouchi Y. Functional activation of cerebral blood flow abolished by scopolamine is reversed by cognitive enhancersassociated with cholinesterase inhibition:a positron emission tomography study in unanesthetized monkeys. J Pharmacol Exp Ther. 1997; 281:1408-14.
[106] Pachauri SD, Tota S, Khandelwal K, Verma PR, Nath C, Hanif K, et al. 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. 2012; 139:34-41.
[107] Tota S, Nath C, Najmi AK, Shukla R, Hanif K. Inhibition of central angiotensin converting enzyme ameliorates scopolamine induced memory impairment in mice: role of cholinergic neurotransmission, cerebral blood flow and brain energy metabolism. Behav Brain Res. 2012; 232:66-76.
[108] Hebbel RP, Shalev O, Foker W, Rank BH. Inhibition of erythrocyte Ca2+-ATPase by activated oxygen through thiol- and lipid-dependent mechanisms. Biochim Biophys Acta. 1986; 862: 8-16.
[109] El-Sherbiny DA, Khalifa AE, Attia AS, Eldenshary Eel-D. Hypericum perforatum extract demonstrates antioxidant properties against elevated rat brain oxidative status induced by amnestic dose of scopolamine. Pharmacol Biochem Behav. 2003; 76: 525-33.
[110] Fan Y, Hu J, Li J, Yang Z, Xin X, Wang J, Ding J, Geng M. Effect of acidic oligosaccharide sugar chain on scopolamine-induced memory impairment in rats and itsrelatedmechanisms. Neurosci Lett. 2005; 374: 222-6.
[111] Jeong EJ, Lee KY, Kim SH, Sung SH, Kim YC. Cognitive-enhancing and antioxidant activities of iridoid glycosides from Scrophularia buergeriana in scopolamine-treated mice. Eur J Pharmacol. 2008; 588:78-84.
[112] Hancianu M, Cioanca O, Mihasan M, Hritcu L. Neuroprotective effects of inhaled lavender oil on scopolamine-induced dementia via anti-oxidative activities in rats. Phytomedicine. 2013; 20:446-52.
[113] Jain NK, Patil CS, Kulkarni SK, Singh A. Modulatory role of cyclooxygenase inhibitors in aging- and scopolamine or lipopolysaccharide-induced cognitivedysfunction in mice. Behav Brain Res. 2002; 133:369-76.
[114] Kim S, Kim DH, Choi JJ, Gu J, Lee CH, Park SJ, et al. Forsythiaside, a Constituent of the Fruits of Forsythia suspense,Ameliorates Scopolamine-Induced Memory Impairment in mice. Biomolecules & Therapeutics. 2009; 17:249-255
[115] Lee B, Shim I, Lee H, Hahm DH. Rehmannia glutinosa ameliorates scopolamine-induced learning and memory impairment in rats. J Microbiol Biotechnol. 2011; 21:874-83.
[116] Lee B, Sur B, Shim I, Lee H, Hahm DH. Phellodendron amurense and Its Major Alkaloid Compound, Berberine Ameliorates Scopolamine-Induced Neuronal Impairment and Memory Dysfunction in Rats. Korean J Physiol Pharmacol. 2012; 16:79-89.
[117] Jang YJ, Kim J, Shim J, Kim CY, Jang JH, Lee KW et al. Decaffeinated coffee prevents scopolamine-induced memory impairment in rats. Behav Brain Res. 2013; 245:113-9.
[118] Ahmad A, Ramasamy K, Jaafar SM, Majeed AB, Mani V. Total isoflavones from soybean and tempeh reversed scopolamine-induced amnesia, improved cholinergic activities and reduced neuroinflammation in brain. Food Chem Toxicol. 2014; 65:120-8.
[119] Abd-El-Fattah MA, Abdelakader NF, Zaki HF. Pyrrolidine dithiocarbamate protects against scopolamine-induced cognitive impairment in rats. Eur J Pharmacol. 2014; 723: 330-8.
[120] Haroutunian V, Greig N, Pei XF, Utsuki T, Gluck R, Acevedo LD et al. Pharmacological modulation of Alzheimer’s b-amyloid precursor protein levels in the CSF of rats with forebrain cholinergic system lesions. Brain Res Mol Brain Res. 1997; 46:161-8
[121] LiskowskyW, 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. Devl Neuroscience. 2006; 24:149-56
[122] 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: 593-8
[123] Preston GC, Brazell C, Ward C, Broks P, Traub M, Stahl SM.The scopolamine model of dementia: determination of central cholinomimetic effects of physostigmine on cognition and biochemical markers in man.J Psychopharmacol. 1988; 2:67-79.
[124] Wesnes K, Anand R, Lorscheid T. Potential of moclobemide to improve cerebral insufficiency identified using a scopolamine model of aging and dementia. Acta Psychiatr Scand Suppl. 1990; 360:71-2.
[125] Molchan SE, Mellow AM, Lawlor BA, Weingartner HJ, Cohen RM, Cohen MRet al.TRH attenuates scopolamine-induced memory impairment in humans.Psychopharmacology (Berl). 1990; 100:84-9.
[126] Lines CR, Ambrose JH, Heald A, Traub M. A double-blind, placebo-controlled study of the effects of eptastigmine on scopolamine-induced cognitive deficits in healthy male subjects.Human Psychopharmacology: Clinical and Experimental. 1993; 8: 271-8.
[127] Gattu M, Boss KL, Terry AV Jr, Buccafusco JJ. Reversal of scopolamine-induced deficits in navigational memory performance by the seed oil of Celastrus paniculatus. Pharmacol Biochem Behav. 1997; 57:793-9.
[128] Buccafusco JJ. The Revival of Scopolamine Reversal for the Assessment of Cognition-Enhancing Drugs. Methods of Behavior Analysis in Neuroscience. 2nd edition. Boca Raton (FL): CRC Press, 2009.
[129] Rogers J, Lue LF. Microglial chemotaxis, activation, and phagocytosis of amyloid beta peptide as linked phenomena in Alzheimer’s disease. Neurology. 2001; 39:333-40.
[130] Sugimoto H, Yamanishi Y, Iimura Y, Kawakami Y. Donepezil hydrochloride (E2020) and other acetylcholinesterase inhibitors. Curr Med Chem. 2000; 7:303-39.
[131] Bartolini M, Bertucci C, Cavrini V, Andrisano V. beta-Amyloid aggregation induced by human acetylcholinesterase: inhibition studies. Biochem Pharmacol. 2003; 65:407-16.
[132] Kimura M, Akasofu S, Ogura H, Sawada K. Protective effect of Donepezil against Abeta (1-40) neurotoxicity in rat septal neurons. Brain Res. 2005a; 1047:72-84.
[133] Kimura M, Komatsu H, Ogura H, Sawada K. Comparison of donepezil and memantine for protective effect against amyloid-beta(1-42) toxicity in rat septal neurons. Neurosci Lett. 2005b; 391:17-21.
[134] Reale M, Iarlori C, Gambi F, Feliciani C, Isabella L, Gambi D. The acetylcholinesterase inhibitor, Donepezil, regulates a Th2 bias in Alzheimer's disease patients. Neuropharmacology. 2006; 50:606-13.
[135] Molino I, Colucci L, Fasanaro AM, Traini E, Amenta F. Efficacy of memantine, donepezil, or their association in moderate-severe Alzheimer's disease: a review of clinical trials. Scientific World J. 2013; 2013:925702.
[136] Yatabe Y, Hashimoto M, Kaneda K, Honda K, Ogawa Y, Yuuki S, et al. Efficacy of increasing donepezil in mild to moderate Alzheimer's disease patients who show a diminished response to 5 mg donepezil: a preliminary study. Psychogeriatrics. 2013; 13:88–93.
[137] Schwarz RD, Callahan MJ, Davis RE, Jaen JC, Tecle H. Development of M1 Subtype Selective Muscarinic Agonists for Alzheimer’s Disease: Translation of In Vitro Selectivity Into In Vivo Efficacy. Drug Develop Res. 1997; 40:133-43.
[138] Riedel G, Kang SH, Choi DY, Platt B. Scopolamine-induced deficits in social memory in mice: reversal by donepezil. Behav Brain Res. 2009; 204:217-25.
[139] Lindner MD, Hogan JB, Hodges DB Jr, Orie AF, Chen P, Corsa JA et al. Donepezil primarily attenuates scopolamine-induced deficits in psychomotor function, with moderate effects on simple conditioning and attention, and small effects on working memory and spatial mapping. Psychopharmacology. 2006; 188:629-40.
[140] Agrawal R, Tyagi E, Shukla R, Nath C. Effect of insulin and melatonin on acetylcholinesterase activity in the brain of amnesic mice. Behav Brain Res. 2008; 189: 381-86
[141] 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; 1:126-35.
[142] Sumanth M, Sowmya H, Nagaraj SV, Narasimharaju K efficacy of donepezil and galantamine in retrograde amnesia. AJPCR. 2010; 3: 23-25
[143] Alkalay A, Rabinovici GD, Zimmerman G, Agarwal N, Kaufer D, Miller BL, et al. Plasma acetylcholinesterase activity correlates with intracerebral β-amyloid load. Curr Alzheimer Res. 2013; 10:48-56.
[144] Sharma M, Gupta YK. Intracerebroventricular injection of streptozotocin in rats produces bothoxidative stress in the brain and cognitive impairment. Life Sci. 2001; 68:1021-9.
[145] Morris R. Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods. 1984; 11:47-60.
[146] Kumar A, Dogra S, Prakash A. Neuroprotective Effects of Centella asiatica against Intracerebroventricular Colchicine-Induced Cognitive Impairment and Oxidative Stress. Int J Alzheimers Dis. 2009; 2009: 972178.
[147] Ellman GL, Courtney KD, Anders V, Featherstone RM. A new and rapid colorimetric determination of acetylcholinesterase activity.Biochem Pharmacol. 1961; 7:88-94.
[148] Wills ED. Mechanism of lipid peroxide formation in animal tissue. Biochem J. 1966; 99:667-76.
[149] Ellman GL. Tissue sulfhydryl groups. Arch Biochem Biophys.1959; 82:70-4.
[150] Misra HP, Fridovich I. The role of superoxide anion in the autoxidation of epinephrine and a simple assay for superoxide dismutase. J Biol Chem. 1972; 247:3170-5.
[151] Aebi H, Wyss, Scherz B, Skvaril F. Heterogeneity of Erythrocyte Catalase II. Isolation and Characterization of Normal and Variant Erythrocyte Catalase and Their Subunits. Eur J Biochem. 1974; 48:137-45.
[152] Annicchiarico R, Federici A, Pettenati C, Caltagirone C. Rivastigmine in Alzheimer's disease: Cognitive function and quality of life. Ther Clin Risk Manag. 2007; 3:1113-23.
[153] Fisher A. Cholinergic treatments with emphasis on m1 muscarinic agonists as potential disease-modifying agents for Alzheimer’s disease.Neurotherapeutics. 2008; 5:433-42.
[154] Raskind MA, Peskind ER, Wessel T, Yuan W. Galantamine in AD: A 6-month randomized, placebo-controlled trial with a 6-month extension. The Galantamine USA-1 Study Group. Neurology. 2000; 54:2261-8.
[155] Rockwood K, Mintzer J, Truyen L, Wessel T, Wilkinson D. Effects of a flexible galantamine dose in Alzheimer’s disease: a randomized, controlled trial. J Neurol Neurosurg Psychiatry. 2001; 71:589-95.
[156] Mahadevan S, Park Y. Multifaceted therapeutic benefits of Ginkgo biloba L.: chemistry, efficacy, safety, and uses. J Food Sci. 2008; 73:R14-9.
[157] Goswami S, Saoji A, Kumar N, Thawani V, Tiwari M, Thawani M. Effect of Bacopa monnieri on Cognitive functions in Alzheimer’s disease patients. Int J Collab Res Internal Med Public Health. 2011; 3:285-92.
[158] Hajiaghaee R, Akhondzadeh S. Herbal Medicine in the Treatment of Alzheimer’s disease. J Med Plants. 2012; 11:2-7.
[159] Downey LA, Kean J, Nemeh F, Lau A, Poll A, Gregory R et al. An acute, double-blind, placebo-controlled crossover study of 320 mg and 640 mg doses of a special extract of Bacopa monnieri (CDRI 08) on sustained cognitive performance. Phytother Res. 2013; 27:1407-13.
[160] Canevelli M, Adali N, Kelaiditi E, Cantet C, Ousset PJ, Cesari M et al. Effects of Gingko biloba supplementation in Alzheimer's disease patients receiving cholinesterase inhibitors: Data from the ICTUS study. Phytomedicine. 2014; 21:888-92.
[161] Di Matteo V, Esposito E. Biochemical and therapeutic effects of antioxidants in the treatment of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Curr Drug Targets CNS Neurol Disord. 2003; 2:95-107.
[162] McGhie TK, Walton MC, Barnett LE, Vather R, Martin H, Au J, Alspach PA, Booth CL, Kruger MC. Boysenberry and blackcurrant drinks increased the plasma antioxidant capacity in an elderly population but had little effect on other markers of oxidative stress. J Sci Food Agri. 2007; 87: 2519-27.
[163] Zhou C, Huang Y, Przedborski S. Oxidative stress in Parkinson's disease: a mechanism of pathogenic and therapeutic significance. Ann N Y Acad Sci. 2008; 1147:93-104.
[164] Beninger RJ, Jhamandas K, Boegman RJ, el-Defrawy SR. Effects of scopolamine and unilateral lesions of the basal forebrain on T-maze spatial discrimination and alternation in rats. Pharmacol Biochem Behav. 1986; 24:1353-60.
[165] Smith G. Animal models of Alzheimer's disease: experimental cholinergic denervation. Brain Res. 1988; 472:103-18.
[166] Ennaceur A, Meliani K. Effects of physostigmine and scopolamine on rats performances in object-recognition and radial-maze tests. Psychopharmacology (Berl). 1992; 109:321-30.
[167] Wolff M, Benhassine N, Costet P, Hen R, Segu L, Buhot MC. Delay-dependent working memory impairment in young-adult and aged 5-HT1BKO mice as assessed in a radial-arm water maze. Learn Mem. 2003; 10:401-9.
[168] Carballo-Márquez A, Vale-Martínez A, Guillazo-Blanch G, Torras-Garcia M, Boix-Trelis N, Martí-Nicolovius M. Differential effects of muscarinic receptor blockade in prelimbic cortex on acquisition and memory formation of anodor-reward task. Learn Mem. 2007; 14:616-24.
[169] Halder S, Mehta AK, Kar R, Mustafa M, Mediratta PK, Sharma KK. Clove oil reverses learning and memory deficits in scopolamine-treated mice. Planta Med. 2011; 77:830-4.
[170] Ebert U, Kirch W. Scopolamine model of dementia: electroencephalogram findings and cognitive performance. Eur J Clin Invest. 1998; 28:944-9.
[171] Itoh J, Nabeshima T, Kameyama T. Utility of an elevated plus-maze for the evaluation of memory in mice: effects of nootropics, scopolamine and electroconvulsive shock. Psychopharmacology (Berl). 1990; 101:27-33.
[172] Miyazaki S, Imaizumi M, Onodera K. Ameliorating effects of histidine on scopolamine-induced learning deficits using an elevated plus-maze test in mice. Life Sci. 1995; 56:1563-70.
[173] Kruk-Słomka M, Budzyńska B, Biała G. Involvement of cholinergic receptors in the different stages of memory measured in the modified elevated plus maze test in mice. Pharmacol Rep. 2012; 64:1066-80.
[174] D'Hooge R, De Deyn PP. Applications of the Morris water maze in the study of learning and memory. Brain Res Rev. 2001; 36:60-90.
[175] Wisman LA, Sahin G, Maingay M, Leanza G, Kirik D. Functional convergence of dopaminergic and cholinergic input is critical for hippocampus-dependent workingmemory. J Neurosci. 2008; 28: 7797-807.
[176] Hosseini-Sharifabad A, Mohammadi-Eraghi S, Tabrizian K, Soodi M, Khorshidahmad T, Naghdi N, et al. Effects of training in the Morris water maze on the spatial learning acquisition and VAChT expression in male rats. Daru. 2011; 19:166-72.
[177] Ma Y, Wang S, Tian Y, Chen L, Li G, Mao J. Disruption of persistent nociceptive behavior in rats with learning impairment. PLoS One. 2013; 8: e74533.
[178] Wan D, Xue L, Zhu H, Luo Y. Catalpol Induces Neuroprotection and Prevents Memory Dysfunction through the Cholinergic System and BDNF. Evid Based Complement Alternat Med. 2013; 2013:134852.
[179] Francis PT, Palmer AM, Snape M, Wilcock GK. The cholinergic hypothesis of Alzheimer’s disease: a review of progress. J Neurol Neurosurg Psychiatry. 1999; 66:137-47.
[180] Deshmukh R, Sharma V, Mehan S, Sharma N, Bedi KL. Amelioration of intracerebroventricular streptozotocin induced cognitive dysfunction and oxidative stress by vinpocetine - a PDE1 inhibitor. Eur J Pharmacol. 2009; 620:49-56.
[181] Sharma R, Thakur V, Singh SN, Guleria R. Tumor Necrosis Factor and Alzheimer’s disease: A Cause and Consequence Relationship. Bulletin of Clinical Psychopharmacology. 2012; 22:86-97
[182] Praticò D, Delanty N. Oxidative injury in diseases of the central nervous system: focus on Alzheimer's disease. Am J Med. 2000; 109:577-85.
[183] Zana M, Janka Z, Kálmán J. Oxidative stress: a bridge between Down's syndrome and Alzheimer's disease. Neurobiol Aging. 2007; 28:648-76.
[184] Yan Z, Feng J. Alzheimer’s Disease: Interactions between Cholinergic Functions and beta-amyloid. Curr Alzheimer Res. 2004; 1:241-8.
[185] Smith MA, Rottkamp CA, Nunomura A, Raina AK, Perry G. Oxidative stress in Alzheimer's disease. Biochim Biophys Acta. 2000; 1502:139-44.
[186] McGrath LT, McGleenon BM, Brennan S, McColl D, McILroy S, Passmore AP. Increased oxidative stress in Alzheimer's disease as assessed with 4-hydroxynonenal but not malondialdehyde. QJM. 2001; 94:485-90.
[187] Perry G, Cash AD, Smith MA. Alzheimer Disease and Oxidative Stress. J Biomed Biotechnol. 2002; 2:120-123.
[188] Gella A, Durany N. Oxidative stress in Alzheimer disease. Cell Adh Migr. 2009; 3:88-93.
[189] Balu M, Sangeetha P, Haripriya D, Panneerselvam C. Rejuvenation of antioxidant system in central nervous system of aged rats by grape seed extract. Neurosci Lett. 2005; 383:295-300.
[190] Attrey DP, Singh AK, Naved T, Roy B. Effect of seabuckthorn extract on scopolamine induced cognitive impairment. Indian J Exp Biol. 2012; 50:690-5.
[191] Lobo V, Patil A, Phatak A, Chandra N. Free radicals, antioxidants and functional foods: Impact on human health. Pharmacogn Rev. 2010; 4: 118–126.
[192] Rahman K. Studies on free radicals, antioxidants, and co-factors. Clin Interv Aging. 2007; 2:219-36.
[193] Mangialasche F, Polidori MC, Monastero R, Ercolani S, Camarda C, Cecchetti R, Mecocci P. Biomarkers of oxidative and nitrosative damage in Alzheimer's disease and mild cognitive impairment. Ageing Res Rev. 2009; 8:285-305.
[194] Uttara B, Singh AV, Zamboni P, Mahajan RT. Oxidative stress and neurodegenerative diseases: a review of upstream and downstream antioxidant therapeuticoptions.Curr Neuropharmacol.2009; 7:65-74.
[195] Younes M, Siegers CP. Mechanistic aspects of enhanced lipid peroxidation following glutathione depletion in vivo. Chem Biol Interact. 1981; 34:257-66.
[196] Casini AF, Pompella A, Comporti M. Liver glutathione depletion induced by bromobenzene, iodobenzene, and diethylmaleate poisoning and its relation to lipid peroxidation and necrosis. Am J Pathol. 1985; 118:225-37.
[197] Schuessel K, Leutner S, Cairns NJ, Müller WE, Eckert A. Impact of gender on upregulation of antioxidant defence mechanisms in Alzheimer's disease brain. J Neural Transm. 2004; 111:1167-82.
[198] Desagher S, Glowinski J, Premont J. Astrocytes protect neurons from hydrogen peroxide toxicity. J Neurosci. 1996; 16:2553-62.
[199] Mulier B, Rahman I, Watchorn T, Donaldson K, MacNee W, Jeffery PK. Hydrogen peroxide-induced epithelial injury: the protective role of intracellular nonprotein thiols (NPSH). Eur Respir J. 1998; 11:384-91.
[200] Dringen R, Gutterer JM, Hirrlinger J. Glutathione metabolism in brain metabolic interaction between astrocytes and neurons in the defense against reactive oxygen species. Eur J Biochem. 2000; 267:4912-6.
[201] Mann H, McCoy MT, Subramaniam J, Van Remmen H, Cadet JL. Overexpression of superoxide dismutase and catalase in immortalized neural cells: toxic effects of hydrogenperoxide. Brain Res. 1997; 770:163-8.
[202] Blokland A. Acetylcholine: a neurotransmitter for learning and memory? Brain Res Brain Res Rev. 1995; 21:285-300.
[203] Oda Y. Choline acetyltransferase: the structure, distribution and pathologic changes in the central nervous system. Pathol Int. 1999; 49:921-37.
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