Toxic Substance-induced Hippocampal Neurodegeneration in Rodents as Model of Alzheimer’s Dementia

Titis Nurmasitoh; Dwi Cahyani Ratna Sari; Rina Susilowati

doi:10.3889/oamjms.2021.6984

Authors

Titis Nurmasitoh Department of Histology and Cell Biology, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia; Department of Physiology, Faculty of Medicine, Universitas Islam Indonesia, Yogyakarta, Indonesia https://orcid.org/0000-0002-8201-5251
Dwi Cahyani Ratna Sari Department of Anatomy, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia https://orcid.org/0000-0002-1126-4939
Rina Susilowati Department of Histology and Cell Biology, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia https://orcid.org/0000-0001-8248-5803

DOI:

https://doi.org/10.3889/oamjms.2021.6984

Keywords:

Toxic substance, Model of Alzheimer’s dementia, Hippocampal degeneration

Abstract

BACKGROUND: Alzheimer’s Dementia (AD) cases are increasing with the global elderly population. To study the part of the brain affected by AD, animal models for hippocampal degeneration are still necessary to better understand AD pathogenesis and develop treatment and prevention measures.

AIM: This study was a systematic review of toxic substance-induced animal models of AD using the Morris Water Maze method in determining hippocampal-related memory impairment. Our aim was reviewing the methods of AD induction using toxic substances in laboratory rodents and evaluating the report of the AD biomarkers reported in the models.

METHODS: Data were obtained from articles in the PubMed database, then compiled, categorized, and analyzed. Eighty studies published in the past 5 years were included for analysis.

RESULTS AND DISCUSSION: The most widely used method was intracerebroventricular injection of amyloid-β _substances. However, some less technically challenging techniques using oral or intraperitoneal administration of other toxic substances also produce successful models. Instead of hippocampal neurodegeneration, many studies detected biomarkers of the AD pathological process while some reported inflammation, oxidative stress, neurotrophic factors, and changes of cholinergic activity. Female animals were underrepresented despite a high incidence of AD in women.

CONCLUSION: Toxic substances may be used to develop AD animal models characterized with appropriate AD pathological markers. Characterization of methods with the most easy-handling techniques and more studies in female animal models should be encouraged.

Downloads

Download data is not yet available.

Metrics

Metrics Loading ...

Plum Analytics Artifact Widget Block

References

World Health Organization. Global Status Report on the Public Health Response to Dementia. Geneva: World Health Organization; 2021. p. 1-251. DOI: https://doi.org/10.1007/978-3-030-05325-3_125-1

Barnes JN. Exercise, cognitive function, and aging. Adv Physiol Educ. 2015;39(2):55-62. PMid:26031719 DOI: https://doi.org/10.1152/advan.00101.2014

Brini S, Sohrabi HR, Peiffer JJ, Karrasch M, Hämäläinen H, Martins RN, et al. Physical activity in preventing Alzheimer’s disease and cognitive decline: A narrative review. Sport Med. 2018;48(1):29-44. https://doi.org/10.1007/s40279-017-0787-y PMid:28940148 DOI: https://doi.org/10.1007/s40279-017-0787-y

Manavalan A, Mishra M, Feng L, Sze SK, Akatsu H, Heese K. Brain site-specific proteome changes in aging-related dementia. Exp Mol Med. 2013;45(e39):1-17. https://doi.org/10.1038/emm.2013.76 DOI: https://doi.org/10.1038/emm.2013.76

Durani LW, Hamezah HS, Ibrahim NF, Yanagisawa D, Makpol S, Damanhuri HA, et al. Age-related changes in the metabolic profiles of rat hippocampus, medial prefrontal cortex and striatum. Biochem Biophys Res Commun. 2017;493(3):1356-63. https://doi.org/10.1016/j.bbrc.2017.09.164 PMid:28970069 DOI: https://doi.org/10.1016/j.bbrc.2017.09.164

Hamezah HS, Durani LW, Yanagisawa D, Ibrahim NF, Aizat WM, Bellier JP, et al. Proteome profiling in the hippocampus, medial prefrontal cortex, and striatum of aging rat. Exp Gerontol. 2018;111:53-64. https://doi.org/10.1016/j.exger.2018.07.002 PMid:29981398 DOI: https://doi.org/10.1016/j.exger.2018.07.002

Salazar C, Valdivia G, Ardiles AO, Ewer J, Palacios AG. Genetic variants associated with neurodegenerative Alzheimer disease in natural models. Biol Res. 2016;49(1):1-9. https://doi.org/10.1186/s40659-016-0072-9 PMid:26919851 DOI: https://doi.org/10.1186/s40659-016-0072-9

Esquerda-Canals G, Montoliu-Gaya L, Güell-Bosch J, Villegas S. Mouse models of Alzheimer’s disease. J Alzheimers Dis. 2017;57(4):1171-83. https://doi.org/10.3233/jad-170045 DOI: https://doi.org/10.3233/JAD-170045

Myers A, McGonigle P. Overview of transgenic mouse models for Alzheimer’s disease. Curr Protoc Neurosci. 2019;89(1):1-21. PMid:31532917 DOI: https://doi.org/10.1002/cpns.81

Bromley-Brits K, Deng Y, Song W. Morris water maze test for learning and memory deficits in Alzheimer’s disease model mice. J Vis Exp. 2011;53:1-5. https://doi.org/10.3791/2920 PMid:21808223 DOI: https://doi.org/10.3791/2920

Tian H, Ding N, Guo M, Wang S, Wang Z, Liu H, et al. Analysis of learning and memory ability in an Alzheimer’s disease mouse model using the Morris Water Maze. J Vis Exp. 2019;152:1-6. https://doi.org/10.3791/60055 PMid:31736488 DOI: https://doi.org/10.3791/60055

Jin L, Li YP, Feng Q, Ren L, Wang F, Bo GJ, et al. Cognitive deficits and Alzheimer-like neuropathological impairments during adolescence in a rat model of type 2 diabetes mellitus. Neural Regen Res. 2018;13(11):1995-2004. https://doi.org/10.4103/1673-5374.239448 PMid:30233075 DOI: https://doi.org/10.4103/1673-5374.239448

Huang SW, Wang W, Zhang MY, Liu QB, Luo SY, Peng Y, et al. The effect of ethyl acetate extract from persimmon leaves on Alzheimer’s disease and its underlying mechanism. Phytomedicine. 2016;23(7):694-704. https://doi.org/10.1016/j.phymed.2016.03.009 PMid:27235708 DOI: https://doi.org/10.1016/j.phymed.2016.03.009

Mohammadi M, Guan J, Khodagholi F, Yans A, Khalaj S, Gholami M, et al. Reduction of autophagy markers mediated protective effects of JNK inhibitor and bucladesine on memory deficit induced by Aβ in rats. Naunyn Schmiedebergs Arch Pharmacol. 2016;389(5):501-10. https://doi.org/10.1007/s00210-016-1222-x PMid:26899864 DOI: https://doi.org/10.1007/s00210-016-1222-x

Aghsami M, Sharifzadeh M, Sepand MR, Yazdankhah M, Seyednejad SA, Pourahmad J. A cAMP analog attenuates betaamyloid (1-42)-induced mitochondrial dysfunction and spatial learning and memory deficits. Brain Res Bull. 2018;140:34-42. https://doi.org/10.1016/j.brainresbull.2018.03.016 PMid:29605485 DOI: https://doi.org/10.1016/j.brainresbull.2018.03.016

Hooshmandi E, Motamedi F, Moosavi M, Katinger H, Zakeri Z, Zaringhalam J, et al. CEPO-Fc (an EPO derivative) protects hippocampus against Aβ-induced memory deterioration: A behavioral and molecular study in a rat model of Aβ toxicity. Neuroscience. 2018;388:405-17. https://doi.org/10.1016/j.neuroscience.2018.08.001 PMid:30102955 DOI: https://doi.org/10.1016/j.neuroscience.2018.08.001

Liu Y, Wei M, Yue K, Hu M, Li S, Men L, et al. Study on urine metabolic profile of Aβ25-35-induced Alzheimer’s disease using UHPLC-Q-TOF-MS. Neuroscience. 2018;394:30-43. https://doi.org/10.1016/j.neuroscience.2018.10.001 PMid:30316910 DOI: https://doi.org/10.1016/j.neuroscience.2018.10.001

Song X, Liu B, Cui L, Zhou B, Liu L, Liu W, et al. Estrogen receptors are involved in the neuroprotective effect of silibinin in Aβ1-42-treated rats. Neurochem Res. 2018;43(4):796-805. https://doi.org/10.1007/s11064-018-2481-3 PMid:29397533 DOI: https://doi.org/10.1007/s11064-018-2481-3

Azimi M, Gharakhanlou R, Naghdi N, Khodadadi D, Heysieattalab S. Moderate treadmill exercise ameliorates amyloid-β-induced learning and memory impairment, possibly via increasing AMPK activity and up-regulation of the PGC-1α/FNDC5/BDNF pathway. Peptides. 2018;102:78-88. https://doi.org/10.1016/j.peptides.2017.12.027 PMid:29309801 DOI: https://doi.org/10.1016/j.peptides.2017.12.027

Chen C, Li B, Cheng G, Yang X, Zhao N, Shi R. Amentoflavone ameliorates Aβ1-42-induced memory deficits and oxidative stress in cellular and rat model. Neurochem Res. 2018;43(4):857-68. https://doi.org/10.1007/s11064-018-2489-8 PMid:29411261 DOI: https://doi.org/10.1007/s11064-018-2489-8

Aminyavari S, Zahmatkesh M, Farahmandfar M, Khodagholi F, Dargahi L, Zarrindast MR. Protective role of Apelin-13 on amyloid β25-35-induced memory deficit; involvement of autophagy and apoptosis process. Prog Neuropsychopharmacol Biol Psychiatry. 2019;89:322-34. https://doi.org/10.1016/j.pnpbp.2018.10.005 PMid:30296470 DOI: https://doi.org/10.1016/j.pnpbp.2018.10.005

Garabadu D, Verma J. Exendin-4 attenuates brain mitochondrial toxicity through PI3K/Akt-dependent pathway in amyloid beta (1-42)-induced cognitive deficit rats. Neurochem Int. 2019;128:39-49. https://doi.org/10.1016/j.neuint.2019.04.006 PMid:31004737 DOI: https://doi.org/10.1016/j.neuint.2019.04.006

Hu W, Feng Z, Xu J, Jiang Z, Feng M. Brain-derived neurotrophic factor modified human umbilical cord mesenchymal stem cells-derived cholinergic-like neurons improve spatial learning and memory ability in Alzheimer’s disease rats. Brain Res. 2019;1710:61-73. https://doi.org/10.1016/j.brainres.2018.12.034 PMid:30586546 DOI: https://doi.org/10.1016/j.brainres.2018.12.034

Liang S, Wang Z, Yuan J, Zhang J, Dai X, Qin F, et al. An amyloid- β 1-42 induced Alzherimer’s disease rat model using UHPLC-Q-exactive qrbitrap mass spectrometry. Molecules. 2019;24:1-24. https://doi.org/10.3390/molecules24142584 PMid:31315255 DOI: https://doi.org/10.3390/molecules24142584

Shariatpanahi M, Khodagholi F, Ashabi G, Bonakdar Yazdi B, Hassani S, Azami K, et al. The involvement of protein kinase G inhibitor in regulation of apoptosis and autophagy markers in spatial memory deficit induced by Aβ. Fundam Clin Pharmacol. 2016;30(4):364-75. https://doi.org/10.1111/fcp.12196 PMid:26990910 DOI: https://doi.org/10.1111/fcp.12196

Amiri S, Azadmanesh K, Shasaltaneh MD, Khoshkholgh-Sima B, Naghdi N. Protein kinase cε in the platelet and hippocampal tissue as a diagnostic biological marker in Alzheimer disease. Basic Clin Neurosci. 2019;10(6):545-56. https://doi.org/10.32598/bcn.9.10.80.1 PMid:32477472 DOI: https://doi.org/10.32598/bcn.9.10.80.1

Rezaei Asl Z, Sepehri G, Salami M. Probiotic treatment improves the impaired spatial cognitive performance and restores synaptic plasticity in an animal model of Alzheimer’s disease. Behav Brain Res. 2019;376:1-9. https://doi.org/10.1016/j.bbr.2019.112183 PMid:31472194 DOI: https://doi.org/10.1016/j.bbr.2019.112183

Sanati M, Khodagholi F, Aminyavari S, Ghasemi F, Gholami M, Kebriaeezadeh A, et al. Impact of gold nanoparticles on amyloid β-induced Alzheimer’s disease in a rat animal model: Involvement of STIM proteins. ACS Chem Neurosci. 2019;10(5):2299-309. https://doi.org/10.1021/acschemneuro.8b00622 PMid:30933476 DOI: https://doi.org/10.1021/acschemneuro.8b00622

Taksima T, Chonpathompikunlert P, Sroyraya M, Hutamekalin P, Limpawattana M, Klaypradit W. Effects of astaxanthin from shrimp shell on oxidative stress and behavior in animal model of Alzheimer’s disease. Mar Drugs. 2019;17:1-15. https://doi.org/10.3390/md17110628 PMid:31690015 DOI: https://doi.org/10.3390/md17110628

Zamani E, Parviz M, Roghani M, Mohseni-Moghaddam P. Key mechanisms underlying netrin-1 prevention of impaired spatial and object memory in Aβ1-42 CA1-injected rats. Clin Exp Pharmacol Physiol. 2019;46(1):86-93. https://doi.org/10.1111/1440-1681.13020 PMid:30066400 DOI: https://doi.org/10.1111/1440-1681.13020

Dara T, Vatanara A, Sharifzadeh M, Khani S, Vakilinezhad MA, Vakhshiteh F, et al. Improvement of memory deficits in the rat model of Alzheimer’s disease by erythropoietin-loaded solid lipid nanoparticles. Neurobiol Learn Mem. 2019;166:1-13. https://doi.org/10.1016/j.nlm.2019.107082 PMid:31493483 DOI: https://doi.org/10.1016/j.nlm.2019.107082

Dmytriyeva O, Belmeguenai A, Bezin L, Soud K, Drucker Woldbye DP, Gøtzsche CR, et al. Short erythropoietinderived peptide enhances memory, improves long-term potentiation, and counteracts amyloid beta-induced pathology. Neurobiol Aging. 2019;81:88-101. https://doi.org/10.1016/j.neurobiolaging.2019.05.003 DOI: https://doi.org/10.1016/j.neurobiolaging.2019.05.003

Elibol B, Beker M, Terzioglu-Usak S, Dalli T, Kilic U. Thymoquinone administration ameliorates Alzheimer’s disease-like phenotype by promoting cell survival in the hippocampus of amyloid beta1-42 infused rat model. Phytomedicine. 2020;79:1-9. https://doi.org/10.1016/j.phymed.2020.153324 PMid:32920292 DOI: https://doi.org/10.1016/j.phymed.2020.153324

Heydari S, Hedayati CM, Saadat F, Abedinzade M, Nikokar I, Aboutaleb E, et al. Diphtheria toxoid nanoparticles improve learning and memory impairment in animal model of Alzheimer’s disease. Pharmacol Reports. 2020;72(4):814-26. https://doi.org/10.1007/s43440-019-00017-w PMid:32048245 DOI: https://doi.org/10.1007/s43440-019-00017-w

Mehri N, Haddadi R, Ganji M, Shahidi S, Soleimani Asl S, Taheri Azandariani M, et al. Effects of Vitamin D in an animal model of Alzheimer’s disease: Behavioral assessment with biochemical investigation of hippocampus and serum. Metab Brain Dis. 2020;35(2):263-74. https://doi.org/10.1007/s11011-019-00529-7 PMid:31853828 DOI: https://doi.org/10.1007/s11011-019-00529-7

Soodi M, Saeidnia S, Sharifzadeh M, Hajimehdipoor H, Dashti A, Sepand MR, et al. Satureja bachtiarica ameliorate beta-amyloid induced memory impairment, oxidative stress and cholinergic deficit in animal model of Alzheimer’s disease. Metab Brain Dis. 2016;31(2):395-404. https://doi.org/10.1007/s11011-015-9773-y PMid:26638718 DOI: https://doi.org/10.1007/s11011-015-9773-y

Shakerin Z, Esfandiari E, Razavi S, Alaei H, Ghanadian M, Dashti G. Effects of Cyperus rotundus extract on spatial memory impairment and neuronal differentiation in rat model of Alzheimer’s disease. Adv Biomed Res. 2020;9(17):1-11. https://doi.org/10.4103/abr.abr_173_19 PMid:32775310 DOI: https://doi.org/10.4103/abr.abr_173_19

Shakerin Z, Esfandiari E, Ghanadian M, Razavi S, Alaei H, Dashti G. Therapeutic effects of Cyperus rotundus rhizome extract on memory impairment, neurogenesis and mitochondria in beta-amyloid rat model of Alzheimer’s disease. Metab Brain Dis. 2020;35(3):451-61. https://doi.org/10.1007/s11011-019-00493-2 PMid:31734846 DOI: https://doi.org/10.1007/s11011-019-00493-2

Tu JL, Chen WP, Cheng ZJ, Zhang G, Luo QH, Li M, et al. EGb761 ameliorates cell necroptosis by attenuating RIP1-mediated mitochondrial dysfunction and ROS production in both in vivo and in vitro models of Alzheimer’s disease. Brain Res. 2020;1736:1-9. https://doi.org/10.1016/j.brainres.2020.146730 PMid:32081533 DOI: https://doi.org/10.1016/j.brainres.2020.146730

Deng Y, Zhang J, Sun X, Ma G, Luo G, Miao Z, et al. miR132 improves the cognitive function of rats with Alzheimer’s disease by inhibiting the MAPK1 signal pathway. Exp Ther Med. 2020;20(6):1-9. https://doi.org/10.3892/etm.2020.9288 PMid:33093897 DOI: https://doi.org/10.3892/etm.2020.9288

Wang P, Sui HJ, Li XJ, Bai LN, Bi J, Lai H. Melatonin ameliorates microvessel abnormalities in the cerebral cortex and hippocampus in a rat model of Alzheimer’s disease. Neural Regen Res. 2021;16(4):757-64. https://doi.org/10.4103/1673-5374.295349 PMid:33063739 DOI: https://doi.org/10.4103/1673-5374.295349

Hui S, Yang Y, Peng WJ, Sheng CX, Gong W, Chen S, et al. Protective effects of Bushen tiansui decoction on hippocampal synapses in a rat model of Alzheimer’s disease. Neural Regen Res. 2017;12(10):1680-6. https://doi.org/10.4103/1673-5374.217347 PMid:29171433 DOI: https://doi.org/10.4103/1673-5374.217347

Zhang J, Wei SY, Yuan L, Kong LL, Zhang SX, Wang ZJ, et al. Davunetide improves spatial learning and memory in Alzheimer’s disease-associated rats. Physiol Behav. 2017;174:67-73. https://doi.org/10.1016/j.physbeh.2017.02.038 PMid:28257938 DOI: https://doi.org/10.1016/j.physbeh.2017.02.038

Zhang M, Xv GH, Wang WX, Meng DJ, Ji Y. Electroacupuncture improves cognitive deficits and activates PPAR-γ 3 in a rat model of Alzheimer’s disease. Acupunct Med. 2017;35(1):44-51. https://doi.org/10.1136/acupmed-2015-010972 PMid:27401747 DOI: https://doi.org/10.1136/acupmed-2015-010972

Wu G, Li L, Li H, Zeng Y, Wu W. Electroacupuncture ameliorates spatial learning and memory impairment via attenuating NOX2-related oxidative stress in a rat model of Alzheimer’s disease induced by AB1-42. Cell Mol Biol. 2017;1710(1):61-73. https://doi.org/10.14715/cmb/2017.63.4.7 PMid:28478802 DOI: https://doi.org/10.14715/cmb/2017.63.4.7

Behzadfar L, Abdollahi M, Sabzevari O, Hosseini R, Salimi A, Naserzadeh P, et al. Potentiating role of copper on spatial memory deficit induced by beta amyloid and evaluation of mitochondrial function markers in the hippocampus of rats. Metallomics. 2017;9(7):969-80. https://doi.org/10.1039/c7mt00075h PMid:28644490 DOI: https://doi.org/10.1039/C7MT00075H

Dehghanian F, Kalantaripour TP, Esmaeilpour K, Elyasi L, Oloumi H, Pour FM, et al. Date seed extract ameliorates β-amyloid-induced impairments in hippocampus of male rats. Biomed Pharmacother. 2017;89:221-6. https://doi.org/10.1016/j.biopha.2017.02.037 PMid:28231543 DOI: https://doi.org/10.1016/j.biopha.2017.02.037

Adel Ghahraman M, Zahmatkesh M, Pourbakht A, Seifi B, Jalaie S, Adeli S, et al. Noisy galvanic vestibular stimulation enhances spatial memory in cognitive impairment-induced by intracerebroventricular-streptozotocin administration. Physiol Behav. 2016;157:217–24. https://doi.org/10.1016/j.physbeh.2016.02.021 PMid:26892259 DOI: https://doi.org/10.1016/j.physbeh.2016.02.021

Murtishaw AS, Heaney CF, Bolton MM, Sabbagh JJ, Langhardt MA, Kinney JW. Effect of acute lipopolysaccharideinduced inflammation in intracerebroventricular-streptozotocin injected rats. Neuropharmacology. 2016;101:110-22. https://doi.org/10.1016/j.neuropharm.2015.08.044 PMid:26327677 DOI: https://doi.org/10.1016/j.neuropharm.2015.08.044

Adeli S, Zahmatkesh M, Dezfouli MA. Simvastatin attenuates hippocampal MMP-9 expression in the streptozotocin-induced cognitive impairment. Iran Biomed J. 2019;23(4):262-71. PMid:30218997 DOI: https://doi.org/10.29252/ibj.23.4.262

Wei J, Yang F, Gong C, Shi X, Wang G. Protective effect of daidzein against streptozotocin-induced Alzheimer’s disease via improving cognitive dysfunction and oxidative stress in rat model. J Biochem Mol Toxicol. 2019 Jun;33(6):e22319. https://doi.org/10.1002/jbt.22319 PMid:30897277 DOI: https://doi.org/10.1002/jbt.22319

Demir M, Yilmaz U, Colak C, Cigremis Y, Ozyalin F, Tekedereli I, et al. Is there a new pathway relationship between melatonin and FEZ1 in experimental rat model of Alzheimer’s disease? Bratisl Med J. 2019;120(1):70-7. https://doi.org/10.4149/bll_2019_011 PMid:30685996 DOI: https://doi.org/10.4149/BLL_2019_011

Sharma Y, Garabadu D. Ruthenium red, mitochondrial calcium uniporter inhibitor, attenuates cognitive deficits in STZ-ICV challenged experimental animals. Brain Res Bull. 2020;164:121-35. https://doi.org/10.1016/j.brainresbull.2020.08.020 PMid:32858127 DOI: https://doi.org/10.1016/j.brainresbull.2020.08.020

Sharma Y, Garabadu D. Intracerebroventricular streptozotocin administration impairs mitochondrial calcium homeostasis and bioenergetics in memory-sensitive rat brain regions. Exp Brain Res. 2020;238(10):2293-306. https://doi.org/10.1007/s00221-020-05896-7 PMid:32728854 DOI: https://doi.org/10.1007/s00221-020-05896-7

Akhtar A, Bishnoi M, Sah SP. Sodium orthovanadate improves learning and memory in intracerebroventricularstreptozotocin rat model of Alzheimer’s disease through modulation of brain insulin resistance induced tau pathology. Brain Res Bull. 2020;164:83-97. https://doi.org/10.1016/j.brainresbull.2020.08.001 PMid:32784004 DOI: https://doi.org/10.1016/j.brainresbull.2020.08.001

Wang H, Wang H, Cheng H, Che Z. Ameliorating effect of luteolin on memory impairment in an Alzheimer’s disease model. Mol Med Rep. 2016;13(5):4215-20. https://doi.org/10.3892/mmr.2016.5052 PMid:27035793 DOI: https://doi.org/10.3892/mmr.2016.5052

Bhardwaj M, Deshmukh R, Kaundal M, Krishna Reddy BV. Pharmacological induction of hemeoxygenase-1 activity attenuates intracerebroventricular streptozotocin induced neurocognitive deficit and oxidative stress in rats. Eur J Pharmacol. 2016;772:43-50. https://doi.org/10.1016/j.ejphar.2015.12.037 PMid:26712378 DOI: https://doi.org/10.1016/j.ejphar.2015.12.037

Dehghan-Shasaltaneh M, Naghdi N, Choopani S, Alizadeh L, Bolouri B, Masoudi-Nejad A, et al. Determination of the best concentration of streptozotocin to create a diabetic brain using histological techniques. J Mol Neurosci. 2016;59(1):24-35. https://doi.org/10.1007/s12031-015-0702-7 PMid:26790434 DOI: https://doi.org/10.1007/s12031-015-0702-7

Majkutewicz I, Kurowska E, Podlacha M, Myślińska D, Grembecka B, Ruciński J, et al. Dimethyl fumarate attenuates intracerebroventricular streptozotocin-induced spatial memory impairment and hippocampal neurodegeneration in rats. Behav Brain Res. 2016;308:24-37. https://doi.org/10.1016/j.bbr.2016.04.012 PMid:27083302 DOI: https://doi.org/10.1016/j.bbr.2016.04.012

Shi L, Zhang Z, Li L, Hölscher C. A novel dual GLP-1/GIP receptor agonist alleviates cognitive decline by re-sensitizing insulin signaling in the Alzheimer icv. STZ rat model. Behav Brain Res. 2017;327:65-74. https://doi.org/10.1016/j.bbr.2017.03.032 PMid:28342971 DOI: https://doi.org/10.1016/j.bbr.2017.03.032

Dalli T, Beker M, Terzioglu-Usak S, Akbas F, Elibol B. Thymoquinone activates MAPK pathway in hippocampus of streptozotocin-treated rat model. Biomed Pharmacother. 2018;99:391-401. https://doi.org/10.1016/j.biopha.2018.01.047 PMid:29367108 DOI: https://doi.org/10.1016/j.biopha.2018.01.047

Huang XB, Chen YJ, Chen WQ, Wang NQ, Wu XL, Liu Y. Neuroprotective effects of tenuigenin on neurobehavior, oxidative stress, and tau hyperphosphorylation induced by intracerebroventricular streptozotocin in rats. Brain Circ. 2018;4(1):24-32. https://doi.org/10.4103/bc.bc_2_17 PMid:30276333 DOI: https://doi.org/10.4103/bc.BC_2_17

Kaundal M, Deshmukh R, Akhtar M. Protective effect of betulinic acid against intracerebroventricular streptozotocin induced cognitive impairment and neuronal damage in rats: Possible neurotransmitters and neuroinflammatory mechanism. Pharmacol Reports. 2018;70(3):540-8. https://doi.org/10.1016/j.pharep.2017.11.020 PMid:29674241 DOI: https://doi.org/10.1016/j.pharep.2017.11.020

Singh NA, Bhardwaj V, Ravi C, Ramesh N, Mandal AK, Khan ZA. EGCG nanoparticles attenuate aluminum chloride induced neurobehavioral deficits, beta amyloid and tau pathology in a rat model of Alzheimer’s disease. Front Aging Neurosci. 2018;10:1-13. https://doi.org/10.3389/fnagi.2018.00244 PMid:30150930 DOI: https://doi.org/10.3389/fnagi.2018.00244

Bazzari FH, Abdallah DM, El-Abhar HS. Chenodeoxycholic acid ameliorates AlCl3-induced Alzheimer’s disease neurotoxicity and cognitive deterioration via enhanced insulin signaling in rats. Molecules. 2019;24(10):1-17. https://doi.org/10.3390/molecules24101992 PMid:31137621 DOI: https://doi.org/10.3390/molecules24101992

Khalaf NE, El Banna FM, Youssef MY, Mosaad YM, Daba MH, Ashour RH. Clopidogrel combats neuroinflammation and enhances learning behavior and memory in a rat model of Alzheimer’s disease. Pharmacol Biochem Behav. 2020;195:172956. https://doi.org/10.1016/j.pbb.2020.172956 PMid:32474163 DOI: https://doi.org/10.1016/j.pbb.2020.172956

Ogunlade B, Adelakun SA, Agie JA. Nutritional supplementation of gallic acid ameliorates Alzheimer-type hippocampal neurodegeneration and cognitive impairment induced by aluminum chloride exposure in adult Wistar rats. Drug Chem Toxicol. 2020;2020:1-12. https://doi.org/10.1080/01480545.2020.1754849 PMid:32329360 DOI: https://doi.org/10.1080/01480545.2020.1754849

Kang JY, Park SK, Guo TJ, Ha JS, Lee DS, Kim JM, et al. Reversal of trimethyltin-induced learning and memory deficits by 3,5-dicaffeoylquinic acid. Oxid Med Cell Longev. 2016;2016:1-14. https://doi.org/10.1155/2016/6981595 DOI: https://doi.org/10.1155/2016/6981595

Gelfo F, Cutuli D, Nobili A, De Bartolo P, D’Amelio M, Petrosini L, et al. Chronic Lithium treatment in a rat model of basal forebrain cholinergic depletion: Effects on memory impairment and neurodegeneration. J Alzheimers Dis. 2017;56(4):1505-18. https://doi.org/10.3233/jad-160892 PMid:28222508 DOI: https://doi.org/10.3233/JAD-160892

Dobryakova YV, Kasianov A, Zaichenko MI, Stepanichev MY, Chesnokova EA, Kolosov PM, et al. Intracerebroventricular administration of 192IgG-saporin alters expression of microgliaassociated genes in the dorsal but not ventral hippocampus. Front Mol Neurosci. 2018;10:1-11. https://doi.org/10.3389/fnmol.2017.00429 PMid:29386992 DOI: https://doi.org/10.3389/fnmol.2017.00429

Shin J, Kong C, Lee J, Choi BY, Sim J, Koh CS, et al. Focused ultrasound-induced blood-brain barrier opening improves adult hippocampal neurogenesis and cognitive function in a cholinergic degeneration dementia rat model. Alzheimers Res Ther. 2019;11:1-15. https://doi.org/10.1186/s13195-019-0569-x PMid:31881998 DOI: https://doi.org/10.1186/s13195-019-0569-x

Gao J, Zhou R, You X, Luo F, He H, Chang X, et al. Salidroside suppresses inflammation in a d-galactose-induced rat model of Alzheimer’s disease via SIRT1/NF-κB pathway. Metab Brain Dis. 2016;31(4):771-8. https://doi.org/10.1007/s11011-016-9813-2 PMid:26909502 DOI: https://doi.org/10.1007/s11011-016-9813-2

Heidari S, Mehri S, Hosseinzadeh H. Memory enhancement and protective effects of crocin against d-galactose aging model in the hippocampus of wistar rats. Iran J Basic Med Sci. 2017;20(11):1250-9. PMid:29299203

Rehman SU, Shah SA, Ali T, Chung JI, Kim MO. Anthocyanins reversed d-galactose-induced oxidative stress and neuroinflammation mediated cognitive impairment in adult rats. Mol Neurobiol. 2017;54(1):255-71. https://doi.org/10.1007/s12035-015-9604-5 PMid:26738855 DOI: https://doi.org/10.1007/s12035-015-9604-5

Aksoz E, Gocmez SS, Sahin TD, Aksit D, Aksit H, Utkan T. The protective effect of metformin in scopolamine-induced learning and memory impairment in rats. Pharmacol Reports. 2019;71(5):818-25. https://doi.org/10.1016/j.pharep.2019.04.015 PMid:31382167 DOI: https://doi.org/10.1016/j.pharep.2019.04.015

Nikpour M, Sharafi A, Hamidi M, Andalib S. Effect of colloidal aqueous solution of fullerene (C60) in the presence of a P-glycoprotein inhibitor (verapamil) on spatial memory and hippocampal expression of Sirtuin6, SELADIN1, and AQP1 genes in a rat model of Alzheimer’s disease. ACS Chem Neurosci. 2020;11(17):2549-65. https://doi.org/10.1021/acschemneuro.0c00213 DOI: https://doi.org/10.1021/acschemneuro.0c00213

Çakır M, Tekin S, Doğanyiğit Z, Erden Y, Soytürk M, Çiğremiş Y, et al. Cannabinoid Type 2 receptor agonist JWH-133, attenuates okadaic acid induced spatial memory impairment and neurodegeneration in rats. Life Sci. 2019;217:25-33. https://doi.org/10.1016/j.lfs.2018.11.058 PMid:30500552 DOI: https://doi.org/10.1016/j.lfs.2018.11.058

Cakir M, Duzova H, Tekin S, Taslıdere E, Kaya GB, Cigremis Y, et al. ACA, an inhibitor phospholipases A2 and transient receptor potential melastatin-2 channels, attenuates okadaic acid induced neurodegeneration in rats. Life Sci. 2017;176(2016):10-20. https://doi.org/10.1016/j.lfs.2017.03.022 PMid:28363841 DOI: https://doi.org/10.1016/j.lfs.2017.03.022

Sadeghi L, Yousefi Babadi V, Tanwir F. Improving effects of Echium amoenum aqueous extract on rat model of Alzheimer’s disease. J Integr Neurosci. 2018;17(3-4):661-9. https://doi.org/10.3233/jin-180093 PMid:30103344 DOI: https://doi.org/10.3233/JIN-180093

Heysieattalab S, Sadeghi L. Effects of delphinidin on pathophysiological signs of nucleus basalis of Meynert lesioned rats as animal model of Alzheimer disease. Neurochem Res. 2020;45(7):1636-46. https://doi.org/10.1007/s11064-020-03027-w PMid:32297026 DOI: https://doi.org/10.1007/s11064-020-03027-w

Goel A, Digvijaya D, Garg A, Kumar A. Effect of Capparis spinosa Linn. Extract on lipopolysaccharide-induced cognitive impairment in rats. Indian J Exp Biol. 2016;54(2):126-32. PMid:26934780

Keymoradzadeh A, Hedayati CM, Abedinzade M, Gazor R, Rostampour M, Taleghani BK. Enriched environment effect on lipopolysaccharide-induced spatial learning, memory impairment and hippocampal inflammatory cytokine levels in male rats. Behav Brain Res. 2020;394:1-7. https://doi.org/10.1016/j.bbr.2020.112814 DOI: https://doi.org/10.1016/j.bbr.2020.112814

Yuliani S, Mustofa M, Partadiredja G. Turmeric (Curcuma longa L.) extract may prevent the deterioration of spatial memory and the deficit of estimated total number of hippocampal pyramidal cells of trimethyltin-exposed rats. Drug Chem Toxicol. 2018;41(1):62-71. https://doi.org/10.1080/0148054 5.2017.1293087 PMid:28440093 DOI: https://doi.org/10.1080/01480545.2017.1293087

Ye M, Han BH, Kim JS, Kim K, Shim I. Neuroprotective effect of bean phosphatidylserine on TMT-induced memory deficits in a rat model. Int J Mol Sci. 2020;21(14):1-13. https://doi.org/10.3390/ijms21144901 PMid:32664537 DOI: https://doi.org/10.3390/ijms21144901

Cai H Bin, Fan ZZ, Tian T, Zhao CC, Ge ZM. Epigenetic control of CDK5 promoter regulates diabetes-associated development of Alzheimer’s disease. J Alzheimers Dis. 2019;69(3):743-50. https://doi.org/10.3233/jad-190227 PMid:31156174 DOI: https://doi.org/10.3233/JAD-190227

Yossef RR, Al-Yamany MF, Saad MA, El-Sahar AE. Neuroprotective effects of vildagliptin on drug induced Alzheimer’s disease in rats with metabolic syndrome: Role of hippocampal klotho and AKT signaling pathways. Eur J Pharmacol. 2020;889:1-11. https://doi.org/10.1016/j.ejphar.2020.173612 PMid:33035520 DOI: https://doi.org/10.1016/j.ejphar.2020.173612

Chavoshinezhad S, Mohseni Kouchesfahani H, Ahmadiani A, Dargahi L. Interferon beta ameliorates cognitive dysfunction in a rat model of Alzheimer’s disease: Modulation of hippocampal neurogenesis and apoptosis as underlying mechanism. Prog Neuropsychopharmacol Biol Psychiatry. 2019;94:1-15. https://doi.org/10.1016/j.pnpbp.2019.109661 PMid:31152860 DOI: https://doi.org/10.1016/j.pnpbp.2019.109661

Pourkhodadad S, Alirezaei M, Moghaddasi M, Ahmadvand H, Karami M, Delfan B, et al. Neuroprotective effects of oleuropein against cognitive dysfunction induced by colchicine in hippocampal CA1 area in rats. J Physiol Sci. 2016;66(5):397-405. https://doi.org/10.1007/s12576-016-0437-4 PMid:26892487 DOI: https://doi.org/10.1007/s12576-016-0437-4

Ogunlade B, Fidelis OP, Afolayan OO, Agie JA. Neurotherapeutic and antioxidant response of d-ribose-l-cysteine nutritional dietary supplements on Alzheimer-type hippocampal neurodegeneration induced by cuprizone in adult male Wistar rat model. Food Chem Toxicol. 2020;147:111862. https://doi.org/10.1016/j.fct.2020.111862 PMid:33217524 DOI: https://doi.org/10.1016/j.fct.2020.111862

Husain I, Akhtar M, Vohora D, Abdin MZ, Islamuddin M, Akhtar MJ, et al. Rosuvastatin attenuates high-salt and cholesterol diet induced neuroinflammation and cognitive impairment via preventing nuclear factor kappaB Pathway. Neurochem Res. 2017;42(8):2404-16. https://doi.org/10.1007/s11064-017-2264-2 PMid:28417263 DOI: https://doi.org/10.1007/s11064-017-2264-2

Saad MA, Eltarzy MA, Abdel Salam RM, Ahmed MA. Liraglutide mends cognitive impairment by averting notch signaling pathway overexpression in a rat model of polycystic ovary syndrome. Life Sci. 2020;265:118731 https://doi.org/10.1016/j.lfs.2020.118731 PMid:33160995 DOI: https://doi.org/10.1016/j.lfs.2020.118731

Atkinson AJ. Intracerebroventricular drug administration. Transl Clin Pharmacol. 2017;25(3):117-24. DOI: https://doi.org/10.12793/tcp.2017.25.3.117

Turner PV, Brabb T, Pekow C, Vasbinder MA. Administration of substances to laboratory animals: Routes of administration and factors to consider. J Am Assoc Lab Anim Sci. 2011;50(5):600-13. PMid:22330705

Widyastuti K, Putri Laksmidewi AA, Adnyana IM, Purwa Samatra DP. Differences in spatial memory impairment in mice after oral d-galactose administration and intraperitoneal injection. Open Access Maced J Med Sci. 2020;8:342-4. https://doi.org/10.3889/oamjms.2020.4149 DOI: https://doi.org/10.3889/oamjms.2020.4149

Butler R, Radhakrishnan R. Dementia. BMJ Clin Evid. 2012;09(1001):1-27. PMid:23870856

Wang R, Holsinger RM. Exercise-induced brain-derived neurotrophic factor expression: Therapeutic implications for Alzheimer’s dementia. Ageing Res Rev. 2018;48:109-21. https://doi.org/10.1016/j.arr.2018.10.002 PMid:30326283 DOI: https://doi.org/10.1016/j.arr.2018.10.002

Šerý O, Povová J, Míšek I, Pešák L, Janout V. Molecular mechanisms of neuropathological changes in Alzheimer’s disease: A review. Folia Neuropathol. 2013;51(1):1-9. https://doi.org/10.5114/fn.2013.34190 PMid:23553131 DOI: https://doi.org/10.5114/fn.2013.34190

Brown BM, Peiffer J, Rainey-Smith SR. Exploring the relationship between physical activity, beta-amyloid and tau: A narrative review. Ageing Res Rev. 2019;50:9-18. https://doi.org/10.1016/j.arr.2019.01.003 PMid:30615936 DOI: https://doi.org/10.1016/j.arr.2019.01.003

Geloso MC, Corvino V, Michetti F. Trimethyltin-induced hippocampal degeneration as a tool to investigate neurodegenerative processes. Neurochem Int. 2011;58(7):729-38. https://doi.org/10.1016/j.neuint.2011.03.009 PMid:21414367 DOI: https://doi.org/10.1016/j.neuint.2011.03.009

Lee S, Yang M, Kim J, Son Y, Kim J, Kang S, et al. Involvement of BDNF/ERK signaling in spontaneous recovery from trimethyltin-induced hippocampal neurotoxicity in mice. Brain Res Bull. 2016;121:48-58. https://doi.org/10.1016/j.brainresbull.2016.01.002 PMid:26772626 DOI: https://doi.org/10.1016/j.brainresbull.2016.01.002

Little AR, Miller DB, Li S, Kashon ML, O’Callaghan JP. Trimethyltin-induced neurotoxicity: Gene expression pathway analysis, q-RT-PCR and immunoblotting reveal early effects associated with hippocampal damage and gliosis. Neurotoxicol Teratol. 2012;34(1):72-82. https://doi.org/10.1016/j.ntt.2011.09.012 PMid:22108043 DOI: https://doi.org/10.1016/j.ntt.2011.09.012

Yuliani S, Mustofa, Partadiredja G. The neuroprotective effects of an ethanolic turmeric (Curcuma longa L.) extract against trimethyltin-induced oxidative stress in rats. Nutr Neurosci. 2019;22(11):797-804. https://doi.org/10.1080/1028415x.2018.1447267 PMid:29513140 DOI: https://doi.org/10.1080/1028415X.2018.1447267

Brooks SW, Dykes AC, Schreurs BG. A high-cholesterol diet increases 27-hydroxycholesterol and modifies estrogen receptor expression and neurodegeneration in rabbit hippocampus. J Alzheimers Dis. 2017;56(1):185-96. https://doi.org/10.3233/jad-160725 PMid:27911307 DOI: https://doi.org/10.3233/JAD-160725

Schmitz C, Hof PR. Design-based stereology in neuroscience. Neuroscience. 2005;130(4):813-31. https://doi.org/10.1016/j.neuroscience.2004.08.050 PMid:15652981 DOI: https://doi.org/10.1016/j.neuroscience.2004.08.050

Leger M, Neill JC. A systematic review comparing sex differences in cognitive function in schizophrenia and in rodent models for schizophrenia, implications for improved therapeutic strategies. Neurosci Biobehav Rev. 2016;68:979-1000. https://doi.org/10.1016/j.neubiorev.2016.06.029 PMid:27344000 DOI: https://doi.org/10.1016/j.neubiorev.2016.06.029

Nebel RA, Aggarwal NT, Barnes LL, Gallagher A, Jill M, Kantarci K, et al. Understanding the impact of sex and gender in Alzheimer’s disease: A call to action. Alzheimers Dement. 2018;14(9):1171-83. PMid:29907423 DOI: https://doi.org/10.1016/j.jalz.2018.04.008