Ameliorative Effect of Silymarin on Scopolamine-induced Dementia in Rats
DOI:
https://doi.org/10.3889/oamjms.2018.257Keywords:
Silymarin, Scopolamine, Object recognition test, Dementia, Donepezil, RatsAbstract
AIM: This study aims to elucidate the possible ameliorative effect of silymarin on scopolamine-induced dementia using the object recognition test (ORT) in rats.
METHODS: The study was extended to demonstrate the role of cholinergic activity, oxidative stress, neuroinflammation, brain neurotransmitters and histopathological changes in the anti-amnestic effect of silymarin in demented rats. Wistar rats were pre-treated with silymarin (200, 400, 800 mg/kg) or donepezil (10 mg/kg) orally for 14 consecutive days. Dementia was induced after the last drug administration by a single intraperitoneal dose of scopolamine (16 mg/kg). Then behavioural, biochemical, histopathological, and immunohistochemical analyses were then performed.
RESULTS: Rats pre-treated with silymarin counteracted scopolamine-induced non-spatial working memory impairment in the ORT and decreased acetylcholinesterase (AChE) activity, reduced malondialdehyde (MDA), elevated reduced glutathione (GSH), restored gamma-aminobutyric acid (GABA) and dopamine (DA) contents in the cortical and hippocampal brain homogenates. Silymarin reversed scopolamine-induced histopathological changes. Immunohistochemical analysis showed that silymarin mitigated protein expression of the glial fibrillary acidic protein (GFAP) and nuclear factor kappa-B (NF-κB) in the brain cortex and hippocampus. All these effects of silymarin were similar to that of the standard anti-amnestic drug, donepezil.
CONCLUSION: This study reveals that the ameliorative effect of silymarin on scopolamine-induced dementia in rats using the ORT maybe in part mediated by, enhancement of cholinergic activity, anti-oxidant and anti-inflammatory activities as well as mitigation in brain neurotransmitters and histopathological changes.
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Crawford TJ, Higham S. Distinguishing between impairments of working memory and inhibitory control in cases of early dementia. Neuropsychologia. 2016; 81: 61-7. https://doi.org/10.1016/j.neuropsychologia.2015.12.007 PMid:26687733
Duan H, Jiang J, Xu J, Zhou H, Huang Z, Yu Z, al. Differences in Abeta brain networks in Alzheimer's disease and healthy controls. Brain Res. 2017; 1655:77-89. https://doi.org/10.1016/j.brainres.2016.11.019 PMid:27867033
Walsh C, Drinkenburg WH, Ahnaou A. Neurophysiological assessment of neural network plasticity and connectivity: Progress towards early functional biomarkers for disease interception therapies in Alzheimer's disease. Neurosci Biobehav Rev. 2017; 73:340-58. https://doi.org/10.1016/j.neubiorev.2016.12.020 PMid:28027953
Hajilou BB, Done DJ. Evidence for dissociation of structural and semantic knowledge in dementia of the Alzheimer type (DAT). Neuropsychologia. 2007; 45(4):810-6. https://doi.org/10.1016/j.neuropsychologia.2006.08.008 PMid:17034821
Pitsikas N, Gravanis A. The novel dehydroepiandrosterone (DHEA) derivative BNN27 counteracts delay-dependent and scopolamine-induced recognition memory deficits in rats. Neurobiol Learn Mem. 2017; 140:145-53. https://doi.org/10.1016/j.nlm.2017.03.004 PMid:28274826
Pitsikas N. The role of nitric oxide in the object recognition memory. Behav Brain Res. 2015; 285: 200-7. https://doi.org/10.1016/j.bbr.2014.06.008 PMid:24933185
Palmer D, Creighton S, Prado VF, Prado MAM, Choleris E, Winters BD. Mice are deficient for striatal Vesicular Acetylcholine Transporter (VAChT) display impaired short-term but normal long-term object recognition memory. Behav Brain Res. 2016; 311:267-78. https://doi.org/10.1016/j.bbr.2016.05.050 PMid:27233822
Navarro NM, Krawczyk MC, Boccia MM, Blake MG. Extinction and recovery of an avoidance memory impaired by scopolamine. Physiol Behav. 2017; 171:192-8. https://doi.org/10.1016/j.physbeh.2016.12.042 PMid:28069463
Hwang ES, Kim HB, Lee S, Kim MJ, Lee SO, Han SM, al. Logan in enhances long-term potentiation and recovers scopolamine-induced learning and memory impairments. Physiol Behav. 2017; 171:243-8. https://doi.org/10.1016/j.physbeh.2016.12.043 PMid:28069458
Liu W, Rabinovich A, Nash Y, Frenkel D, Wang Y, Youdim MB, al. Anti-inflammatory and protective effects of MT-031, a novel multitarget MAO-A and AChE/BuChE inhibitor in scopolamine mouse model and inflammatory cells. Neuropharmacology. 2017;113:445e456.
Godyn J, Jonczyk J, Panek D, Malawska B. Therapeutic strategies for Alzheimer's disease in clinical trials. Pharmacol Rep. 2016; 68(1): 127-38. https://doi.org/10.1016/j.pharep.2015.07.006 PMid:26721364
Yuan Q, Wang CW, Shi J, Lin ZX. Effects of Ginkgo biloba on dementia: An overview of systematic reviews. J Ethnopharmacol. 2017; 195:1-9. https://doi.org/10.1016/j.jep.2016.12.005 PMid:27940086
Younis N, Shaheen MA, Abdallah MH. Silymarin-loaded Eudragit((R)) RS100 nanoparticles improved the ability of silymarin to resolve hepatic fibrosis in bile duct ligated rats. Biomed Pharmacother. 2016; 81:93-103. https://doi.org/10.1016/j.biopha.2016.03.042 PMid:27261582
Younis NN, Shaheen MA, Mahmoud MF. Silymarin preconditioning protected insulin resistant rats from liver ischemia-reperfusion injury: the role of endogenous H2S. J Surg Res. 2016; 204(2):398-409. https://doi.org/10.1016/j.jss.2016.04.069 PMid:27565076
Svobodova A, Zdarilova A, Maliskova J, Mikulkova H, Walterova D, Vostalova J. Attenuation of UVA-induced damage to human keratinocytes by silymarin. J Dermatol Sci. 2007; 46(1):21-30. https://doi.org/10.1016/j.jdermsci.2006.12.009 PMid:17289350
Khorsandi L, Saki G, Bavarsad N, Mombeini M. Silymarin induces a multi-targeted cell death process in the human colon cancer cell line HT-29. Biomed Pharmacother. 2017; 94:890-7. https://doi.org/10.1016/j.biopha.2017.08.015 PMid:28810529
Raza SS, Khan MM, Ashafaq M, Ahmad A, Khuwaja G, Khan A, al. Silymarin protects neurons from oxidative stress associated damages in focal cerebral ischemia: a behavioral, biochemical and immunohistological study in Wistar rats. J Neurol Sci. 2011; 309(1-2):45-54. https://doi.org/10.1016/j.jns.2011.07.035 PMid:21840019
Senturk H, Kabay S, Bayramoglu G, Ozden H, Yaylak F, Yucel M, al. Silymarin attenuates the renal ischemia/reperfusion injury-induced morphological changes in the rat kidney. World J Urol. 2008; 26(4): 401-7. https://doi.org/10.1007/s00345-008-0256-1 PMid:18408933
Rao PR, Viswanath RK. Cardioprotective activity of silymarin in ischemia-reperfusion-induced myocardial infarction in albino rats. Exp Clin Cardiol. 2007; 12(4):179-87. PMid:18651002 PMCid:PMC2359609
Borah A, Paul R, Choudhury S, Choudhury A, Bhuyan B, Das Talukdar A, al. Neuroprotective potential of silymarin against CNS disorders: insight into the pathways and molecular mechanisms of action. CNS Neurosci Ther. 2013; 19(11):847-53. https://doi.org/10.1111/cns.12175 PMid:24118806
Hirayama K, Oshima H, Yamashita A, Sakatani K, Yoshino A, Katayama Y. Neuroprotective effects of silymarin on ischemia-induced delayed neuronal cell death in rat hippocampus. Brain Res. 2016; 1646:297-303. https://doi.org/10.1016/j.brainres.2016.06.018 PMid:27312091
Sarubbo F, Ramis MR, Kienzer C, Aparicio S, Esteban S, Miralles A, al. Chronic Silymarin, Quercetin and Naringenin Treatments Increase Monoamines Synthesis and Hippocampal Sirt1 Levels Improving Cognition in Aged Rats. J Neuroimmune Pharmacol. 2017; 2017.
Yaghmaei P, Azarfar K, Dezfulian M, Ebrahim-Habibi A. Silymarin effect on amyloid-beta plaque accumulation and gene expression of APP in an Alzheimer's disease rat model. Daru. 2014; 22(1): 24. https://doi.org/10.1186/2008-2231-22-24 PMid:24460990 PMCid:PMC3904165
El-Marasy SA, El-Shenawy SM, El-Khatib AS, El-Shabrawy OA, Kenawy SA. Effect of Nigella sativa and wheat germ oils on scopolamine-induced memory impairment in rats. Bulletin of Faculty of Pharmacy, Cairo University. 2012; 50:81-8. https://doi.org/10.1016/j.bfopcu.2012.05.001
Galhardi F, Mesquita K, Monserrat JM, Barros DM. Effect of silymarin on biochemical parameters of oxidative stress in aged and young rat brain. Food Chem Toxicol. 2009; 47(10):2655-60. https://doi.org/10.1016/j.fct.2009.07.030 PMid:19647779
Schreiber R, Vivian J, Hedley L, Szczepanski K, Secchi RL, Zuzow M, al. Effects of the novel 5-HT(6) receptor antagonist RO4368554 in rat models for cognition and sensorimotor gating. Eur Neuropsychopharmacol. 2007; 17(4):277-88. https://doi.org/10.1016/j.euroneuro.2006.06.009 PMid:16989988
Ennaceur A , Delacour J. A new one-trial test for neurobiological studies of memory in rats. 1: Behavioral data. Behav Brain Res. 1988; 31(1): 47-59. https://doi.org/10.1016/0166-4328(88)90157-X
Ellman GL, Courtney KD, Andres V, Jr., Feather-Stone RM. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol. 1961; 7: 88-95. https://doi.org/10.1016/0006-2952(61)90145-9
Gorun V, Proinov I, Baltescu V, Balaban G, Barzu O. Modified Ellman procedure for assay of cholinesterases in crude enzymatic preparations. Anal Biochem. 1978; 86(1): 324-6. https://doi.org/10.1016/0003-2697(78)90350-0
Ruiz-Larrea MB, Leal AM, Liza M, Lacort M, de Groot H. Antioxidant effects of estradiol and 2-hydroxyestradiol on iron-induced lipid peroxidation of rat liver microsomes. Steroids. 1994; 59(6): 383-8. https://doi.org/10.1016/0039-128X(94)90006-X
Ellman GL. Tissue sulfhydryl groups. Arch Biochem Biophys. 1959; 82(1): 70-7. https://doi.org/10.1016/0003-9861(59)90090-6
Pagel P, Blome J, Wolf HU. High-performance liquid chromatographic separation and measurement of various biogenic compounds possibly involved in the pathomechanism of Parkinson's disease. J Chromatogr B Biomed Sci Appl. 2000; 746(2): 297-304. https://doi.org/10.1016/S0378-4347(00)00348-0
Heinrikson RL, Meredith SC. Amino acid analysis by reverse-phase high-performance liquid chromatography: precolumn derivatization with phenylisothiocyanate. Anal Biochem. 1984; 136(1): 65-74. https://doi.org/10.1016/0003-2697(84)90307-5
Bancroft JD, Stevens A. The haematoxylin and eosin. Theory and Practice of Histological Techniques. fourth ed. Churchill Livingstone, London, New York & Tokyo, 1996: 99-112 (Ch 6).
Ogaly HA, Khalaf AA, Ibrahim MA, Galal MK, Abd-Elsalam RM. Influence of green tea extract on oxidative damage and apoptosis induced by deltamethrin in rat brain. Neurotoxicol Teratol. 2015; 50: 23-31. https://doi.org/10.1016/j.ntt.2015.05.005 PMid:26013673
de Bruin NM, Prickaerts J, van Loevezijn A, Venhorst J, de Groote L, Houba P, et al. Two novel 5-HT6 receptor antagonists ameliorate scopolamine-induced memory deficits in the object recognition and object location tasks in Wistar rats. Neurobiol Learn Mem. 2011; 96(2): 392-402. https://doi.org/10.1016/j.nlm.2011.06.015 PMid:21757018
Li J, Gao L, Sun K, Xiao D, Li W, Xiang L et al. Benzoate fraction from Gentiana rigescens Franch alleviates scopolamine-induced impaired memory in mice model in vivo. J Ethnopharmacol. 2016; 193: 107-16. https://doi.org/10.1016/j.jep.2016.08.001 PMid:27492328
Zaki HF, Abd-El-Fattah MA, Attia AS. Naringenin protects against scopolamine-induced dementia in rats. Bulletin of Faculty of Pharmacy, Cairo University. 2014; 52: 15-25. https://doi.org/10.1016/j.bfopcu.2013.11.001
Haider A, Inam W, Khan SA, Hifza, Mahmood W, Abbas G. Beta-glucan attenuated scopolamine induced cognitive impairment via hippocampal acetylcholinesterase inhibition in rats. Brain Res. 2016; 1644: 141-8. https://doi.org/10.1016/j.brainres.2016.05.017 PMid:27180103
Yang W, Yu J, Zhao L, Ma N, Fang Y, Pei F, et al. Polysaccharides from Flammulina velutipes improve scopolamine-induced impairment of learning and memory of rats. Journal of Functional Foods. 2015; 18: 411-22. https://doi.org/10.1016/j.jff.2015.08.003
Qu Z, Zhang J, Yang H, Gao J, Chen H, Liu C et al. Prunella vulgaris L., an Edible and Medicinal Plant, Attenuates Scopolamine-Induced Memory Impairment in Rats. J Agric Food Chem. 2017; 65(2): 291-300. https://doi.org/10.1021/acs.jafc.6b04597 PMid:28001065
Chtourou Y, Fetoui H, Garoui el M, Boudawara T, Zeghal N. Improvement of cerebellum redox states and cholinergic functions contribute to the beneficial effects of silymarin against manganese-induced neurotoxicity. Neurochem Res. 2012; 37(3): 469-79. https://doi.org/10.1007/s11064-011-0632-x PMid:22033861
Neha, Kumar A, Jaggi AS, Sodhi RK, Singh N. Silymarin ameliorates memory deficits and neuropathological changes in mouse model of high-fat-diet-induced experimental dementia. Naunyn Schmiedebergs Arch Pharmacol. 2014; 387(8): 777-87. https://doi.org/10.1007/s00210-014-0990-4 PMid:24866499
Asgharzade S, Rabiei Z, Rafieian-Kopaei M. Effects of Matricaria chamomilla extract on motor coordination impairment induced by scopolamine in rats. Asian Pac J Trop Biomed 2015; 5(10). https://doi.org/10.1016/j.apjtb.2015.06.006
Rabiei Z, Mokhtari S, Asgharzade S, Gholami M, Rahnama S, Rafieian-kopaei M. Inhibitory effect of Thymus vulgaris extract on memory impairment induced by scopolamine in rat. Asian Pac J Trop Biomed. 2015; 5(10): 845-51. https://doi.org/10.1016/j.apjtb.2015.07.006
Baluchnejadmojarad T, Roghani M, Mafakheri M. Neuroprotective effect of silymarin in 6-hydroxydopamine hemi-parkinsonian rat: involvement of estrogen receptors and oxidative stress. Neurosci Lett. 2010; 480(3):206-10. https://doi.org/10.1016/j.neulet.2010.06.038 PMid:20600617
Muley MM, Thakare VN, Patil RR, Bafna PA, Naik SR. Amelioration of cognitive, motor and endogenous defense functions with silymarin, piracetam and protocatechuic acid in the cerebral global ischemic rat model. Life Sci. 2013; 93(1): 51-7. https://doi.org/10.1016/j.lfs.2013.05.020 PMid:23743171
Myhrer T. Neurotransmitter systems involved in learning and memory in the rat: a meta-analysis based on studies of four behavioral tasks. Brain Res Brain Res Rev. 2003; 41(2-3): 268-87. https://doi.org/10.1016/S0165-0173(02)00268-0
Gueli MC, Taibi G. Alzheimer's disease: amino acid levels and brain metabolic status. Neurol Sci. 2013; 34(9):1575-9. https://doi.org/10.1007/s10072-013-1289-9 PMid:23354600
Kumar A, Singh A, Ekavali. A review on Alzheimer's disease pathophysiology and its management: an update. Pharmacol Rep. 2015; 67(2): 195-203. https://doi.org/10.1016/j.pharep.2014.09.004 PMid:25712639
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. https://doi.org/10.1016/j.ejphar.2013.11.008 PMid:24315930
Salat K, Podkowa A, Mogilski S, Zareba P, Kulig K, Salat R et al. The effect of GABA transporter 1 (GAT1) inhibitor, tiagabine, on scopolamine-induced memory impairments in mice. Pharmacol Rep. 2015; 67(6):1155-62. https://doi.org/10.1016/j.pharep.2015.04.018 PMid:26481535
Perez HJ, Carrillo SC, Garcia E, Ruiz-Mar G, Perez-Tamayo R, Chavarria A. Neuroprotective effect of silymarin in a MPTP mouse model of Parkinson's disease. Toxicology. 2014; 319: 38-43. https://doi.org/10.1016/j.tox.2014.02.009 PMid:24607817
Thakare VN, Dhakane VD, Patel BM. Potential antidepressant-like activity of silymarin in the acute restraint stress in mice: Modulation of corticosterone and oxidative stress response in cerebral cortex and hippocampus. Pharmacol Rep. 2016; 68(5):1020-7. https://doi.org/10.1016/j.pharep.2016.06.002 PMid:27428764
Singh M, Kaur M, Kukreja H, Chugh R, Silakari O, Singh D. Acetylcholinesterase inhibitors as Alzheimer therapy: from nerve toxins to neuroprotection. Eur J Med Chem. 2013; 70:165-88. https://doi.org/10.1016/j.ejmech.2013.09.050 PMid:24148993
Ghumatkar PJ, Patil SP, Jain PD, Tambe RM, Sathaye S. Nootropic, neuroprotective and neurotrophic effects of phloretin in scopolamine induced amnesia in mice. Pharmacol Biochem Behav. 2015; 135:182-91. https://doi.org/10.1016/j.pbb.2015.06.005 PMid:26071678
Xu T, Shen X, Yu H, Sun L, Lin W, Zhang C. Water-soluble ginseng oligosaccharides protect against scopolamine-induced cognitive impairment by functioning as an antineuroinflammatory agent. J Ginseng Res. 2016; 40(3):211-9. https://doi.org/10.1016/j.jgr.2015.07.007 PMid:27635118 PMCid:PMC5005308
Zhang L, Wu C, Zhao S, Yuan D, Lian G, Wang X et al. Demethoxycurcumin, a natural derivative of curcumin attenuates LPS-induced pro-inflammatory responses through down-regulation of intracellular ROS-related MAPK/NF-kappaB signaling pathways in N9 microglia induced by lipopolysaccharide. Int Immunopharmacol. 2010; 10(3):331-8. https://doi.org/10.1016/j.intimp.2009.12.004 PMid:20018257
Soetikno V, Sari FR, Lakshmanan AP, Arumugam S, Harima M, Suzuki K, et al. Curcumin alleviates oxidative stress, inflammation, and renal fibrosis in remnant kidney through the Nrf2-keap1 pathway. Mol Nutr Food Res. 2013; 57(9): 1649-59. https://doi.org/10.1002/mnfr.201200540 PMid:23174956
Ahmed SM, Luo L, Namani A, Wang XJ, Tang X. Nrf2 signaling pathway: Pivotal roles in inflammation. Biochim Biophys Acta. 2017; 1863(2): 585-97. https://doi.org/10.1016/j.bbadis.2016.11.005 PMid:27825853
Hou YC, Liou KT, Chern CM, Wang YH, Liao JF, Chang S et al. Preventive effect of silymarin in cerebral ischemia-reperfusion-induced brain injury in rats possibly through impairing NF-kappaB and STAT-1 activation. Phytomedicine. 2010; 17(12):963-73. https://doi.org/10.1016/j.phymed.2010.03.012 PMid:20833521
Ashkavand Z, Malekinejad H, Amniattalab A, Rezaei-Golmisheh A, Vishwanath BS. Silymarin potentiates the anti-inflammatory effects of Celecoxib on chemically induced osteoarthritis in rats. Phytomedicine. 2012; 19(13):1200-5. https://doi.org/10.1016/j.phymed.2012.07.008 PMid:22925727
Atawia RT, Tadros MG, Khalifa AE, Mosli HA, Abdel-Naim AB. Role of the phytoestrogenic, pro-apoptotic and anti-oxidative properties of silymarin in inhibiting experimental benign prostatic hyperplasia in rats. Toxicol Lett. 2013; 219(2): 160-9. https://doi.org/10.1016/j.toxlet.2013.03.002 PMid:23500659
Heeba GH, Mahmoud ME. Therapeutic potential of morin against liver fibrosis in rats: modulation of oxidative stress, cytokine production and nuclear factor kappa B. Environ Toxicol Pharmacol. 2014; 37(2): 662-71. https://doi.org/10.1016/j.etap.2014.01.026 PMid:24583409
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