Drugs Induced Alzheimer’s Disease in Animal Model

  • Samira Malekzadeh 1 Department of Biology, College of Sciences, Fars Science and Research Branch, Islamic Azad University, Fars, Iran 2 Department of Biology, College of Sciences, Shiraz Branch, Islamic Azad University, Shiraz, Iran
  • Mohammad Amin Edalatmanesh Department of Physiology, College of Sciences, Shiraz Branch, Islamic Azad University, Shiraz, Iran
  • Davood Mehrabani Stem Cell and Transgenic Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
  • Mehrdad Shariati Associate Professor, Department of Biology, Kazerun Branch, Islamic Azad University, Kazerun, Iran
Keywords: Alzheimer’s Disease, Hippocampus, Memory, Trimethyltin, Colchicine


Alzheimer’s disease (AD) can be described by characteristics like dementia, mental and cognitive dysfunctions, and memory impairment. Nowadays, with progresses of science, attempts to treat many diseases have increased. Laboratory animals help to discover new ways of treating disease. AD induced by chemical drugs in animal models can be useful in better understanding the mechanisms of disease and treatment of AD. In recent decades, many researchers have reported transgenic rat models of AD but this modeling has a great problem and does not contain all kinds of AD. There are two types of AD, including familial (5% of all AD) and sporadic, but the transgenic model does not show the complete model of AD, especially in sporadic form of AD, which is 95% of AD cases. We decided to describe another modeling of AD using chemical drugs such as colchicine, scopolamine, okadaic acid, streptozotocin, and trimethyltin.[GMJ.2017;6(3):185-196] DOI:10.22086/gmj.v6i3.820

Author Biography

Samira Malekzadeh, 1 Department of Biology, College of Sciences, Fars Science and Research Branch, Islamic Azad University, Fars, Iran 2 Department of Biology, College of Sciences, Shiraz Branch, Islamic Azad University, Shiraz, Iran
Department of Physiology


De la Torre JC. Is Alzheimer's disease a neurodegenerative or a vascular disorder? Data, dogma, and dialectics. Lancet Neurol. 2004;3(3):184-90.

Kumar A, Dogra S, Prakash A. Protective effect of narining, a citrus flavonoid against colchicine- induced cognitive dysfunction and oxidative damage in rats. J Med Food. 2010;13(4):976–84.

Gotz J, Ittner M. Animals models of Alzheimer’s disease and frontotemporal dementia. Nat Rev Neurosci. 2008;9(7): 532–44.

Nordberg A, Svensson AL. Cholinesterase inhibitors in the treatment of Alzheimer’s disease: a comparison of tolerability and pharmacology. Drugs Saf. 1998; 19(6): 465–80.

Christian KM, Song H, Ming GL. Functions and dysfunctions of adult hippocampal neurogenesis. Annu Rev Neurosci. 2014; 37: 243–62.

Castren E, Hen R. Neuronal plasticity and antidepressant actions. Trends Neurosci. 2013; 36(5): 259–67.

Drapeau E, Mayo W, Aurousseau C, Le MM, Piazza PV, Abrous DN. Spatial memory performances of aged rats in the water maze predict levels of hippocampal neurogenesis. Proc Natl Acad Sci U S A. 2003; 100(24): 14385–90.

Veena J, Rao BS, Srikumar BN. Regulation of adult neurogenesis in the hippocampus by stress, acetylcholine and dopamine. J Nat Sci Biol Med. 2011;2(1):26–37.

Altman J, Das GD. Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J Comp Neurol. 1965;124(3):319-35.

Cameron HA, McKay RD. Adult neurogenesis produces a large pool of new granule cells in the dentate gyrus. J Comp Neurol. 2001; 435(4):406-17.

Mu Y, Lee SW, Gage FH. Signaling in adult neurogenesis. Curr Opin Neurobiol. 2010; 20 :416-23.

Seib DR, Corsini NS, Ellwanger K, Plaas C, Mateos A, Pitzer C, et al. Loss of Dickkopf-1 restores neurogenesis in old age and counteracts cognitive decline. Cell Stem Cell. 2013; 12(2): 204–14.

Ben Abdallah NM, Slomianka L, Vyssotski AL, Lipp HP. Early age-related changes in adult hippocampal neurogenesis in C57 mice. Neurobiol Aging. 2010; 31(1): 151–61.

Lugert S, Basak O, Knuckles P, Haussler U, Fabel K, Götz M, et al. Quiescent and active hippocampal neural stem cells with distinct morphologies respond selectively to physiological and pathological stimuli and aging. Cell stem cell. 2010;6(5):445-56.

Seib DR, Martin-Villalba A. Neurogenesis in the normal ageing hippocampus: a mini-review. Gerontology. 2015;61(4):327-35.

Pollina EA, Brunet A. Epigenetic regulation of aging stem cells. Oncogene. 2011;30(28):3105-26.

Evrard PA, Ragusi C, Boschi G, Verbeeck RK, Scherrmann JM. Simultaneous microdialysis in brain and blood of the mouse: extracellular and intracellular brain colchicine disposition. Brain Res. 1998;786(1):122-7.

Meyers CA, Kudelka AP, Conrad CA, Gelke CK, Grove W, Pazdur R. Neurotoxicity of CI-980, a novel mitotic inhibitor. Clin Cancer Res. 1997;3(3):419-22.

Kumar A, Seghal N, Naidu PS, Padi SS, Goyal R. Colchicines-induced neurotoxicity as an animal model of sporadic dementia of Alzheimer's type. Pharmacol Rep. 2007;59(3):274-83.

Emerich DF, Walsh TJ. Cholinergic cell loss and cognitive impairments following intraventricular or intradentate injection of colchicine. Brain Res. 1990;517(1):157-67.

Mohamed AR, Soliman GY, Ismail CA, Mannaa HF. Neuroprotective role of vitamin D3 in colchicine-induced Alzheimer’s disease in rats. Alexandria Med J. 2015;51(2):127-36.

Emerich DF, Walsh TJ. Ganglioside AGF2 promotes task-specific recovery and attenuates the cholinergic hypofunction induced by AF64A. Brain Res. 1990;527(2):299-307.

Raghavendra M, Maiti R, Kumar S, Acharya SB. Role of Ocimum sanctum in the experimental model of Alzheimer’s disease in rats. Int J Green Pharm (IJGP). 2009;3(1):6-15.

Oh JH, Choi BJ, Chang MS, Park SK. Nelumbo nucifera semen extract improves memory in rats with scopolamine-induced amnesia through the induction of choline acetyltransferase expression. Neurosci Lett. 2009;461(1):41-4.

Fan Y, Hu J, Li J, Yang Z, Xin X, Wang J, et al. Effect of acidic oligosaccharide sugar chain on scopolamine-induced memory impairment in rats and its related mechanisms. Neurosci Lett. 2005;374(3):222-6.

Perry EK, Tomlinson BE, Blessed G, Bergmann K, Gibson PH, Perry RH. Correlation of cholinergic abnormalities with senile plaques and mental test scores in senile dementia. Br Med J. 1978;2(6150):1457-9.

Richardson JS, Miller PS, Lemay JS, Jyu CA, Neil SG, Kilduff CJ, et al. Mental dysfunction and the blockade of muscarinic receptors in the brains of the normal elderly. Prog Neuropsychopharmacol. 1985;9(5):651-4.

Grasby PM, Frith CD, Paulesu E, Friston KJ, Frackowiak RS, Dolan RJ. The effect of the muscarinic antagonist scopolamine on regional cerebral blood flow during the performance of a memory task. Exp Brain Res. 1995;104(2):337-48.

Sunderland T, Esposito G, Molchan SE, Coppola R, Jones DW, Gorey J, et al. Differential cholinergic regulation in Alzheimer's patients compared to controls following chronic blockade with scopolamine: a SPECT study. Psychopharmacology. 1995;121(2):231-41.

Cohen HA, McGovern SA. Identity of “dumbbell” profiles in synaptosomal fractions from rat brain. J Neurobiol. 1973;4(6):583-7.

Torrent L, Ferrer I. PP2A and Alzheimer disease. Curr Alzheimer Res. 2012;9(2):248-56.

Kamat PK, Tota S, Saxena G, Shukla R, Nath C. Okadaic acid (ICV) induced memory impairment in rats: a suitable experimental model to test anti-dementia activity. Brain Res. 2010;1309:66-74.

Díaz-Hernández M, Gómez-Ramos A, Rubio A, Gómez-Villafuertes R, Naranjo JR, Miras-Portugal MT, et al. Tissue-nonspecific alkaline phosphatase promotes the neurotoxicity effect of extracellular tau. J Biol Chem. 2010;285(42):32539-48.

Leuner K, Müller WE, Reichert AS. From mitochondrial dysfunction to amyloid beta formation: novel insights into the pathogenesis of Alzheimer’s disease. Mol Neurobiol. 2012;46(1):186-93.

Kamat PK, Rai S, Swarnkar S, Shukla R, Ali S, Najmi AK, et al. Okadaic acid-induced Tau phosphorylation in rat brain: role of NMDA receptor. Neurosci. 2013;238:97-113.

Chen LQ,Wei JS, Lei ZN, Zhang LM, Liu Y, Sun FY. Induction of Bcl-2 and BaxWas Related to Hyper-phosphorylation of Tau and Neuronal Death Induced by Okadaic Acid in Rat Brain. Anat Rec A Discov Mol Cell Evol Biol. 2005; 287(2):1236–1245. PMID: 16265626.

Chung CW, Hong YM, Song S, Woo HN, Choi YH, Rohn T, et al. Atypical role of proximal caspase-8 in truncated Tau-induced neurite regression and neuronal cell death. Neurobiol Dis. 2003;14(3):557-66.

Jiang W, Luo T, Li S, Zhou Y, Shen XY, He F, et al. Quercetin Protects against Okadaic Acid-Induced Injury via MAPK and PI3K/Akt/GSK3β Signaling Pathways in HT22 Hippocampal Neurons. PloS one. 2016;11(4):e0152371.

Nada SE, Williams EF, Shah ZA. Development of a Novel and Robust Pharmacological Model of Okadaic Acid-induced Alzheimer’s Disease in Zebrafish. CNS Neurol Disord Drug Targets. 2016; 15(1): 86-94.

Reynolds CH, Garwood CJ, Wray S, Price C, Kellie S, Perera T, Zvelebil M, et al. Phosphorylation regulates Tau interactions with Src homology 3 domains of phosphatidylinositol 3-kinase, phospholipase Cgamma1, Grb2, and Src family kinases. J Biol Chem. 2008;283(26):18177-86.

Correia SC, Santos RX, Santos MS, Casadesus G, Lamanna JC, Perry G, et al. Mitochondrial abnormalities in a streptozotocin-induced rat model of sporadic Alzheimer's disease. Curr Alzheimer Res. 2013;10(4):406-19.

Chen Y, Liang Z, Tian Z, Blanchard J, Dai CL, Chalbot S, et al. Intracerebroventricular streptozotocin exacerbates Alzheimer-like changes of 3xTg-AD mice. Mol Neurobiol. 2014;49(1):547-62.

Shoham S, Bejar C, Kovalev E, Weinstock M. Intracerebroventricular injection of streptozotocin causes neurotoxicity to myelin that contributes to spatial memory deficits in rats. Exp Neurol. 2003;184(2):1043-52.

Kraska A, Santin MD, Dorieux O, Joseph-Mathurin N, Bourrin E, Petit F, et al. In vivo cross-sectional characterization of cerebral alterations induced by intracerebroventricular administration of streptozotocin. PloS one. 2012;7(9):e46196.

Chang LW, Dyer RS. A time-course study of trimethyltin induced neuropathology in rats. Neurobehav Toxicol Teratol. 1982;5(4):443-59.

Dyer RS, Walsh TJ, Wonderlin WF, Bercegeay M. The trimethyltin syndrome in rats. Neurobehav Toxicol Teratol. 1982; 4(2): 127–33.

Ishikawa K, Kubo T, Shibanoki S, Matsumoto A, Hata H, Asai S. Hippocampal degeneratino inducing impairment of learning in rats: model of dementia?. Behav Brain Res. 1997; 83: 39–44.

Whittington DL, Woodruff ML, Baisden RH. The time-course of trimethyltin-induced fiber and terminal degeneration in hippocampus. Neurotoxicol Teratol. 1989;11(1):21-33.

Rose MS, Aldridge WN. The interaction of triethyltin with components of animal tissues. Biochem J. 1968;106(4):821-8.

Richter‐Landsberg C, Besser A. Effects of organotins on rat brain astrocytes in culture. J Neurochem. 1994;63(6):2202-9.

Aschner M, Aschner JL. Cellular and molecular effects of trimethyltin and triethyltin: relevance to organotin neurotoxicity. Neurosci Behav Rev. 1992;16(4):427-35.

Moghadas M, Edalatmanesh MA, Robati R. Histopathological Analysis from Gallic Acid Administration on Hippocampal Cell Density, Depression, and Anxiety Related Behaviors in A Trimethyltin Intoxication Model. Cell Journal (Yakhteh). 2016; 17(4): 659.‏

Zhang L, Li L, Prabhakaran K, Borowitz JL, Isom GE. Trimethyltin-induced apoptosis is associated with upregulation of inducible nitric oxide synthase and Bax in a hippocampal cell line. Toxicol Appl Pharmacol. 2006;216(1):34-43.

Ishida N, Akaike M, Tsutsumi S, Kanai H, Masui A, Sadamatsu M, et al. Trimethyltin syndrome as a hippocampal degeneration model: temporal changes and neurochemical features of seizure susceptibility and learning impairment. Neurosci. 1997;81(4):1183-91.

Shin EJ, Nah SY, Chae JS, Bing G, Shin SW, Yen TP, Baek IH, Kim WK, Maurice T, Nabeshima T, Kim HC. Dextromethorphan attenuates trimethyltin-induced neurotoxicity via σ 1 receptor activation in rats. Neurochem int. 2007;50(6):791-9.

Stanton ME. Neonatal exposure to triethyltin disrupts olfactory discrimination learning in preweanling rats. Neurotoxicol Teratol. 1991;13(5):515-24.

Stanton ME, Jensen KF, Pickens CV. Neonatal exposure to trimethyltin disrupts spatial delayed alternation learning in preweanling rats. Neurotoxicol Teratol. 1991;13(5):525-30.

Miller DB, Eckerman DA, Krigman MR, Grant LD. Chronic neonatal organotin exposure alters radial arm maze performance in adult rats. Neurobehav Toxicol Teratol. 1982; 4:185–90.

Miller DB, O'Callaghan JP. Biochemical, functional and morphological indicators of neurotoxicity: effects of acute administration of trimethyltin to the developing rat. J Pharmacol Exp Ther. 1984;231(3):744-51.

Ruppert PH, Dean KF, Reiter LW. Developmental and behavioral toxicity following acute postnatal exposure of rat pups to trimethyltin. Neurobehav Toxicol Teratol. 1983; 5:421–9.

Ruppert PH, Dean KF, Reiter LW. Development of locomotor activity of rat pups exposed to heavy metals. Toxicol Appl Pharmacol. 1985;78(1):69-77.

Philbert MA, Billingsley ML, Reuhl KR. Mechanisms of Injury in the Central Nervous System. Toxicol Pathol. 2000; 28(1):43–53.

Thompson TA, Lewis JM, Dejneka NS, Severs WB, Polavarapu R, Billingsley ML. Induction of apoptosis by organotin compounds in vitro: neuronal protection with antisense oligonucleotides directed against stannin. J Pharmacol Exp Ther. 1996;276(3):1201-16.

Mattson MP, Chan SL. Calcium orchestrates apoptosis. Nat Cell Biol. 2003;5(12):1041-3.

Golestani SH, Edalatmanesh MA, Hosseini M. The Effects of Sodium Valproate on Learning and Memory Prossesses in Trimethyltin Model of Alzheimer’s Disease. Neuroscience J Shefaye Khatam. 2014; 2(3): 19-26.

Moghadas M, Edalatmanesh MA. The Lithium Chloride Effect on Anxiety, Exploratory Activity, and Brain Derived Neurotrophic Factor Levels of the Hippocampus in a Rat Model of TMT Intoxication. Neuroscience J Shefaye Khatam. 2015; 3(2): 1-10.

Fiedorowicz A, Figiel I, Kaminska B, Zaremba M, Wilk S, Oderfeld-Nowak B, et al. Dentate granule neuron apoptosis and glia activation in murine hippocampus induced by trimethyltin exposure. Brain Res. 2001; 912(2): 116-27.

Ogita K, Nitta Y, Watanabe M, Nakatani Y, Nishiyama N, Sugiyama C, et al. In vivo activation of c-Jun N-terminal kinase signaling cascade prior to granule cell death induced by trimethyltin in the dentate gyrus of mice. Neuropharmacology. 2004; 47(4):619-30.

Geloso MC, Corvino V, Michetti F. Trimethyltin-induced hippocampal degeneration as a tool to investigate neurodegenerative processes. Neurochemistry international. 2011;58(7):729-38.

Koczyk D. How does trimethyltin affect the brain: facts and hypotheses. Acta Neurobiol Exp. 1995;56(2):587-96.

Fornai F, Trabucco A, Di Pietro P, Nori SL, Fulceri F, Fumagalli L, Paparelli A. Methylated tin toxicity a reappraisal using rodents models. Arch Ital Biol. 2009;147(4):141-53.

Chang LW, Tiemeyer TM, Wenger GR, McMillan DE. Neuropathology of mouse hippocampus in acute trimethyltin intoxication. Neurobehav Toxicol Teratol. 1981;4(2):149-56.

Chang LW. Neuropathology of trimethyltin: a proposed pathogenetic mechanism. Fundam Appl Toxicol. 1986;6(2):217-32.

Maurice T, Phan VL, Noda Y, Yamada K, Privat A, Nabeshima T. The attenuation of learning impairments induced after exposure to CO or trimethyltin in mice by sigma (σ) receptor ligands involves both σ1 and σ2 sites. Br J Pharmacol. 1999;127(2):335-42.

Brown AW, Aldridge WN, Street BW, Verschoyle RD. The behavioral and neuropathologic sequelae of intoxication by trimethyltin compounds in the rat. Am J Pathol. 1979;97(1):59-81.

Chang LW, Tiemeyer TM, Wenger GR, McMillan DE. Neuropathology of mouse hippocampus in acute trimethyltin intoxication. Neurobehav Toxicol Teratol. 1981; 4(2): 149-56.

Brown AW, Aldridge WN, Street BW, Verschoyle RD. The behavioral and neuropathologic sequelae of intoxication by trimethyltin compounds in the rat. Am J Pathol. 1979;97(1):59-77.

Florea AM, Splettstoesser F, Dopp E, Rettenmeier AW, Büsselberg D. Modulation of intracellular calcium homeostasis by trimethyltin chloride in human tumour cells: neuroblastoma SY5Y and cervix adenocarcinoma HeLa S3. Toxicology. 2005;216(1):1-8.

Kassed CA, Butler TL, Patton GW, Demesquita DD, Navidomskis MT, Mémet S, et al. Injury-induced NF-κB activation in the hippocampus: implications for neuronal survival. FASEB J. 2004;18(6):723-4.

Tsutsumi S, Akaike M, Arimitsu H, Imai H, Kato N. Circulating corticosterone alters the rate of neuropathological and behavioral changes induced by trimethyltin in rats. Exp Neurol. 2002;173(1):86-94.

Kim JJ, Diamond DM. The stressed hippocampus, synaptic plasticity and lost memories. Nat Rev Neurosci. 2002;3(6):453-62.

Tang X, Wu X, Dubois AM, Sui G, Wu B, Lai G, et al. Toxicity of trimethyltin and dimethyltin in rats and mice. Bull Environ Contam Toxicol. 2013;90(5):626–33.

Mignini F, Nasuti C, Artico M, Giovannetti F, Fabrizi C, Fumagalli L, et al. Effects of trimethyltin on hippocampal dopaminergic markers and cognitive behaviour. Int J Immunopathol Pharmacol. 2012; 25(4): 1107–19.

Ishikawa K, Kubo T, Shibanoki S, Matsumoto A, Hata H, Asai S. Hippocampal degeneration inducing impairment of learning in rats: model of dementia?. Behav Brain Res. 1997; 83(1-2): 39–44.

Lee VM, Brunden KR, Hutton M, Trojanowski JQ. Developing therapeutic approaches to tau, selected kinases, and related neuronal protein targets. Cold Spring Harb Perspect Med. 2011;1(1):a006437.

Holtzman DM, Morris JC, Goate AM. Alzheimer’s disease: the challenge of the second century. Sci Transl Med. 2011;3(77):77sr1.

Avramopoulos D. Genetics of Alzheimer's disease: recent advances. Genome Med. 2009;1(3):34.

Ali SF, Newport GD, Slikker W, Bondy SC. Effect of trimethyltin on ornithine decarboxylase in various regions of the mouse brain. Toxicol Lett. 1987;36(1):67-72.

Gunasekar P, Li L, Prabhakaran K, Eybl V, Borowitz JL, Isom GE. Mechanisms of the apoptotic and necrotic actions of trimethyltin in cerebellar granule cells. Toxicol Sci. 2001; 64(1), 83-9.

Chen J, Huang C, Zheng L, Simonich M, Bai C, Tanguay R, Dong Q. Trimethyltin chloride (TMT) neurobehavioral toxicity in embryonic zebrafish. Neurotoxicol Teratol. 2011; 33(6): 721-6.

Gasparova Z, Janega P, Stara V, Ujhazy E. Early and late stage of neurodegeneration induced by trimethyltin in hippocampus and cortex of male Wistar rats. Neuro Endocrinol Lett. 2012; 33(7): 689-96.

Kim J, Yang M, Kim SH, Kim JC, Wang H, Shin T, et al. Possible role of the glycogen synthase kinase-3 signaling pathway in trimethyltin-induced hippocampal neurodegeneration in mice. PloS one. 2013; 8(8): e70356.

Jung EY, Lee MS, Ahn CJ, Cho SH, Bae H, Shim I. The neuroprotective effect of gugijihwang-tang on trimethyltin-induced memory dysfunction in the rat. Evid Based Complement Alternat Med. 2013; 1-6.

Yoneyama M, Shiba T, Hasebe S, Umeda K, Yamaguchi T, Ogita K. Lithium promotes neuronal repair and ameliorates depression-like behavior following trimethyltin-induced neuronal loss in the dentate gyrus. PloS one. 2014; 9(2): e87953.

Shams-Alam S, Edalatmanesh MA.The Effete of Lithium Chloride on the Granular Cell Density in Cerebellar Folia V and VI in a Trimethyltin Intoxication Model. Neuroscience J Shefaye Khatam. 2015; 3(2): 41-8.

Zare M, Zar A, Edalatmanesh MA. The Implementation of Eight Weeks of Endurance Training and Chloride Administration on Brain-Derived Neurotrophic Factor (BDNF) Serum Levels in Rats with Alzheimer's Disease. ZUMS Journal. 2015; 24(103): 62-70.

Rafiei S, Bazyar Y, Edalatmanesh MA. Effect of Gallic Acid and Endurance Exercise Training on BDNF in a Model of Hippocampal Degeneration. Neuroscience J Shefaye Khatam. 2016; 4(1): 1-6.

Sakhaie MH, Soleimani M, Pirhajati V, Asl SS, Madjd Z, Mehdizadeh M. Coenzyme Q10 Ameliorates Trimethyltin Chloride Neurotoxicity in Experimental Model of Injury in Dentate Gyrus of Hippocampus: A Histopathological and Behavioral Study. Iran Red Crescent Med J. 2016; 18(8): e30297.

Kim YS. Magnolol protects against trimethyltin-induced neuronal damage and glial activation in vitro and in vivo. Neurotoxicology. 2016;53:173-85.

How to Cite
Malekzadeh, S., Edalatmanesh, M. A., Mehrabani, D., & Shariati, M. (2017). Drugs Induced Alzheimer’s Disease in Animal Model. Galen Medical Journal, 6(3), 185-196. https://doi.org/10.31661/gmj.v6i3.820
Review Article