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ISSN (Online): 2589-9783

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Review Article

Preclinical Evidence-based Neuroprotective Potential of Silibinin

Author(s): Niraj Kumar Singh* and Bharat Bhushan

Volume 16, Issue 1, 2024

Published on: 14 April, 2023

Page: [43 - 56] Pages: 14

DOI: 10.2174/2589977515666230327154800

Price: $65

Abstract

Neurodegeneration is an elucidating feature of many neuronal disorders including Alzheimer’s, disease, Parkinson’s disease, and cerebral ischemia. These neurodegenerative disorders are a major public health concern with high mortality and morbidity rates around the world. Presently, researchers have concentrated their efforts on determining the neuroprotective activity of natural products for the management of neurological manifestation associated with neurodegeneration or aging. Silibinin, an active component of the plant Silybum marianum (family: Asteraceae) was used for the treatment of liver diseases from ancient times. Recently several preclinical studies provide supportive evidence for the neuroprotective activity of silibinin in experimental animals. Besides its antioxidant effect, silibinin exhibits neuroprotective activities by altering several cellular and molecular signaling pathways like BDNF, ER/PI3/Akt, NfκB, JNK, IR & IGF-IR, mTOR, and many more against brain-related neurotoxicity. This review provided a comprehensive summary of the chemistry, pharmacokinetics, side effects, and pharmacological effects of silibinin against various neurodegenerative disorders with a prominent cellular and molecular mechanism. The literature reviews and preclinical studies demonstrated that silibinin could be an alternate candidate for the management of neurodegenerative disorders. Thus, there is a scope for further preclinical and clinical research to introduce this phytoconstituent as a therapeutic alternative candidate.

Keywords: Silybum marianum, silibinin, neuroprotection, neurotoxicity, Alzheimer’s disease, parkinson’s disease.

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[1]
Razavi BM, Hosseinzadeh H. Saffron as an antidote or a protective agent against natural or chemical toxicities. Daru 2015; 23(1): 31.
[http://dx.doi.org/10.1186/s40199-015-0112-y] [PMID: 25928729]
[2]
Abenavoli L, Capasso R, Milic N, Capasso F. Milk thistle in liver diseases: Past, present, future. Phytother Res 2010; 24(10): 1423-32.
[http://dx.doi.org/10.1002/ptr.3207] [PMID: 20564545]
[3]
Kawaguchi-Suzuki M, Frye RF, Zhu HJ, et al. The effects of milk thistle (Silybum marianum) on human cytochrome P450 activity. Drug Metab Dispos 2014; 42(10): 1611-6.
[http://dx.doi.org/10.1124/dmd.114.057232] [PMID: 25028567]
[4]
Karkhanis V, Hu YJ, Baiocchi RA, Imbalzano AN, Sif S. Versatility of PRMT5-induced methylation in growth control and development. Trends Biochem Sci 2011; 36(12): 633-41.
[http://dx.doi.org/10.1016/j.tibs.2011.09.001] [PMID: 21975038]
[5]
Post-White J, Ladas EJ, Kelly KM. Advances in the use of milk thistle (Silybum marianum). Integr Cancer Ther 2007; 6(2): 104-9.
[http://dx.doi.org/10.1177/1534735407301632] [PMID: 17548789]
[6]
Hellwig K, Gold R, Marousi S, et al. Immune reconstitution inflammatory syndrome after withdrawal of natalizumab? Neurology 2011; 76(15): 1362-3.
[http://dx.doi.org/10.1212/WNL.0b013e318210e5d0] [PMID: 21618740]
[7]
Umetsu T, Inoue J, Kogure T, et al. Inhibitory effect of silibinin on hepatitis B virus entry. Biochem Biophys Rep 2018; 14: 20-5.
[http://dx.doi.org/10.1016/j.bbrep.2018.03.003] [PMID: 29872730]
[8]
Fischer N, Seo EJ, Efferth T. Prevention from radiation damage by natural products. Phytomedicine 2018; 47: 192-200.
[http://dx.doi.org/10.1016/j.phymed.2017.11.005] [PMID: 30166104]
[9]
Sati J, Mohanty BP, Garg ML, Koul A. Pro-oxidant role of silibinin in DMBA/TPA induced skin cancer: 1H NMR metabolomic and biochemical study. PLoS One 2016; 11(7): e0158955.
[http://dx.doi.org/10.1371/journal.pone.0158955] [PMID: 27414401]
[10]
Song X, Liu B, Cui L, et al. Estrogen receptors are involved in the neuroprotective effect of silibinin in Aβ1–42-treated rats. Neurochem Res 2018; 43(4): 796-805.
[http://dx.doi.org/10.1007/s11064-018-2481-3] [PMID: 29397533]
[11]
Abenavoli L, Izzo AA, Milić N, Cicala C, Santini A, Capasso R. Milk thistle (Silybum marianum): A concise overview on its chemistry, pharmacological, and nutraceutical uses in liver diseases. Phytother Res 2018; 32(11): 2202-13.
[http://dx.doi.org/10.1002/ptr.6171] [PMID: 30080294]
[12]
Pelter A, Hänsel R. The structure of silybin (silybum substance E6), the first flavonolignan. Tetrahedron Lett 1968; 9(25): 2911-6.
[http://dx.doi.org/10.1016/S0040-4039(00)89610-0]
[13]
Porwal O, Mohammed Ameen MS, Anwer ET, Uthirapathy S, Ahamad J, Tahsin A. Silybum marianum (Milk Thistle): Review on Its chemistry, morphology, ethno medical uses, phytochemistry and pharmacological activities. J Drug Deliv Ther 2019; 9(5): 199-206.
[http://dx.doi.org/10.22270/jddt.v9i5.3666]
[14]
Althagafy HS, Meza-Aviña ME, Oberlies NH, Croatt MP. Mechanistic study of the biomimetic synthesis of flavonolignan diastereoisomers in milk thistle. J Org Chem 2013; 78(15): 7594-600.
[http://dx.doi.org/10.1021/jo4011377] [PMID: 23876147]
[15]
Biedermann D, Vavříková E, Cvak L, Křen V. Chemistry of silybin. Nat Prod Rep 2014; 31(9): 1138-57.
[http://dx.doi.org/10.1039/C3NP70122K] [PMID: 24977260]
[16]
Bai TC, Zhu JJ, Hu J, Zhang H-L, Huang C-G. Solubility of silybin in aqueous hydrochloric acid solution. Fluid Phase Equilib 2007; 254(1-2): 204-10.
[http://dx.doi.org/10.1016/j.fluid.2007.03.009]
[17]
van Wenum E, Jurczakowski R, Litwinienko G. Media effects on the mechanism of antioxidant action of silybin and 2,3-dehydrosilybin: Role of the enol group. J Org Chem 2013; 78(18): 9102-12.
[http://dx.doi.org/10.1021/jo401296k] [PMID: 24006901]
[18]
Rickling B, Hans B, Kramarczyk R, Krumbiegel G, Weyhenmeyer R. Two high-performance liquid chromatographic assays for the determination of free and total silibinin diastereomers in plasma using column switching with electrochemical detection and reversed-phase chromatography with ultraviolet detection. J Chromatogr, Biomed Appl 1995; 670(2): 267-77.
[http://dx.doi.org/10.1016/0378-4347(95)00168-9] [PMID: 8548017]
[19]
Napolitano JG, Lankin DC, Graf TN, et al. HiFSA fingerprinting applied to isomers with near-identical NMR spectra: The silybin/isosilybin case. J Org Chem 2013; 78(7): 2827-39.
[http://dx.doi.org/10.1021/jo302720h] [PMID: 23461697]
[20]
Romanucci V, Di Fabio G, Zarrelli A. A new class of synthetic flavonolignan-like dimers: Still few molecules, but with attractive properties. Molecules 2018; 24(1): 108.
[http://dx.doi.org/10.3390/molecules24010108] [PMID: 30597952]
[21]
Wu W, Wang Y, Que L. Enhanced bioavailability of silymarin by self-microemulsifying drug delivery system. Eur J Pharm Biopharm 2006; 63(3): 288-94.
[http://dx.doi.org/10.1016/j.ejpb.2005.12.005] [PMID: 16527467]
[22]
Zhu HJ, Brinda BJ, Chavin KD, Bernstein HJ, Patrick KS, Markowitz JS. An assessment of pharmacokinetics and antioxidant activity of free silymarin flavonolignans in healthy volunteers: A dose escalation study. Drug Metab Dispos 2013; 41(9): 1679-85.
[http://dx.doi.org/10.1124/dmd.113.052423] [PMID: 23835761]
[23]
Li WY, Yu G, Hogan RM, et al. Relative bioavailability of silybin a and silybin b from 2 multiconstituent dietary supplement formulations containing milk thistle extract: A single-dose study. Clin Ther 2018; 40(1): 103-113.e1.
[http://dx.doi.org/10.1016/j.clinthera.2017.11.013] [PMID: 29273470]
[24]
Lorenz D, Lücker PW, Mennicke WH, Wetzelsberger N. Pharmacokinetic studies with silymarin in human serum and bile. Methods Find Exp Clin Pharmacol 1984; 6(10): 655-61.
[PMID: 6513680]
[25]
Saller R, Brignoli R, Melzer J, Meier R. An updated systematic review with meta-analysis for the clinical evidence of silymarin. Forsch Komplement Med 2008; 15(1): 9-20.
[http://dx.doi.org/10.1159/000113648] [PMID: 18334810]
[26]
Sridar C, Goosen TC, Kent UM, Williams JA, Hollenberg PF. Silybin inactivates cytochromes P450 3A4 and 2C9 and inhibits major hepatic glucuronosyltransferases. Drug Metab Dispos 2004; 32(6): 587-94.
[http://dx.doi.org/10.1124/dmd.32.6.587] [PMID: 15155549]
[27]
Wen Z, Dumas TE, Schrieber SJ, Hawke RL, Fried MW, Smith PC. Pharmacokinetics and metabolic profile of free, conjugated, and total silymarin flavonolignans in human plasma after oral administration of milk thistle extract. Drug Metab Dispos 2008; 36(1): 65-72.
[http://dx.doi.org/10.1124/dmd.107.017566] [PMID: 17913795]
[28]
Wu JW, Lin LC, Tsai TH. Drug–drug interactions of silymarin on the perspective of pharmacokinetics. J Ethnopharmacol 2009; 121(2): 185-93.
[http://dx.doi.org/10.1016/j.jep.2008.10.036] [PMID: 19041708]
[29]
Calani L, Brighenti F, Bruni R, Del Rio D. Absorption and metabolism of milk thistle flavanolignans in humans. Phytomedicine 2012; 20(1): 40-6.
[http://dx.doi.org/10.1016/j.phymed.2012.09.004] [PMID: 23072776]
[30]
Xie Y, Zhang D, Zhang J, Yuan J. Metabolism, transport and drug–drug interactions of silymarin. Molecules 2019; 24(20): 3693.
[http://dx.doi.org/10.3390/molecules24203693] [PMID: 31615114]
[31]
Tan ZR, Zhou YX, Liu J, et al. The influence of ABCB1 polymorphism C3435T on the pharmacokinetics of silibinin. J Clin Pharm Ther 2015; 40(6): 685-8.
[http://dx.doi.org/10.1111/jcpt.12336] [PMID: 26595166]
[32]
Loguercio C, Festi D. Silybin and the liver: From basic research to clinical practice. World J Gastroenterol 2011; 17(18): 2288-301.
[http://dx.doi.org/10.3748/wjg.v17.i18.2288] [PMID: 21633595]
[33]
Drugs and Lactation Database (LactMed®) Available from: https://www.ncbi.nlm.nih.gov/books/NBK501771/
[34]
Yin F, Liu J, Ji X, Wang Y, Zidichouski J, Zhang J. Silibinin: A novel inhibitor of Aβ aggregation. Neurochem Int 2011; 58(3): 399-403.
[http://dx.doi.org/10.1016/j.neuint.2010.12.017] [PMID: 21185897]
[35]
Leem E, Oh YS, Shin WH, et al. Effects of silibinin against prothrombin kringle-2-induced neurotoxicity in the nigrostriatal dopaminergic system in vivo. J Med Food 2019; 22(3): 277-85.
[http://dx.doi.org/10.1089/jmf.2018.4266] [PMID: 30632945]
[36]
Liu P, Cui L, Liu B, et al. Silibinin ameliorates STZ-induced impairment of memory and learning by up- regulating insulin signaling pathway and attenuating apoptosis. Physiol Behav 2020; 213: 112689.
[http://dx.doi.org/10.1016/j.physbeh.2019.112689] [PMID: 31669775]
[37]
Andrade VM, Aschner M, Marreilha dos Santos AP. Neurotoxicity of metal mixtures. Adv Neurobiol 2017; 18: 227-65.
[http://dx.doi.org/10.1007/978-3-319-60189-2_12] [PMID: 28889271]
[38]
Costa LG, Manzo L. Biochemical markers of neurotoxicity: Research strategies and epidemiological applications. Toxicol Lett 1995; 77(1-3): 137-44.
[http://dx.doi.org/10.1016/0378-4274(95)03283-5] [PMID: 7618127]
[39]
Costa LG. Biochemical and molecular neurotoxicology: Relevance to biomarker development, neurotoxicity testing and risk assessment. Toxicol Lett 1998; 102-103: 417-21.
[http://dx.doi.org/10.1016/S0378-4274(98)00248-3] [PMID: 10022289]
[40]
Rachakonda V, Pan TH, Le WD. Biomarkers of neurodegenerative disorders: How good are they? Cell Res 2004; 14(5): 349-58.
[http://dx.doi.org/10.1038/sj.cr.7290235] [PMID: 15538967]
[41]
Fernandes V, Sharma D, Kalia K, Tiwari V. Neuroprotective effects of silibinin: an in silico and in vitro study. Int J Neurosci 2018; 128(10): 935-45.
[http://dx.doi.org/10.1080/00207454.2018.1443926] [PMID: 29465317]
[42]
Liu B, Liu W, Liu P, et al. Silibinin alleviates the learning and memory defects in overtrained rats accompanying reduced neuronal apoptosis and senescence. Neurochem Res 2019; 44(8): 1818-29.
[http://dx.doi.org/10.1007/s11064-019-02816-2] [PMID: 31102026]
[43]
Jangra A, Kasbe P, Pandey SN, et al. Hesperidin and silibinin ameliorate aluminum-induced neurotoxicity: Modulation of antioxidants and inflammatory cytokines level in mice hippocampus. Biol Trace Elem Res 2015; 168(2): 462-71.
[http://dx.doi.org/10.1007/s12011-015-0375-7] [PMID: 26018497]
[44]
Di Cesare Mannelli L, Zanardelli M, Failli P, Ghelardini C. Oxaliplatin-induced oxidative stress in nervous system-derived cellular models: Could it correlate with in vivo neuropathy? Free Radic Biol Med 2013; 61: 143-50.
[http://dx.doi.org/10.1016/j.freeradbiomed.2013.03.019] [PMID: 23548635]
[45]
Song X, Zhou B, Zhang P, et al. Protective effect of silibinin on learning and memory impairment in LPS-treated rats viaROS–BDNF–TrkB pathway. Neurochem Res 2016; 41(7): 1662-72.
[http://dx.doi.org/10.1007/s11064-016-1881-5] [PMID: 26961891]
[46]
Xie Z, Ding S, Shen Y. Silibinin activates AMP-activated protein kinase to protect neuronal cells from oxygen and glucose deprivation-re-oxygenation. Biochem Biophys Res Commun 2014; 454(2): 313-9.
[http://dx.doi.org/10.1016/j.bbrc.2014.10.080] [PMID: 25450395]
[47]
Lu P, Mamiya T, Lu L, et al. Silibinin attenuates cognitive deficits and decreases of dopamine and serotonin induced by repeated methamphetamine treatment. Behav Brain Res 2010; 207(2): 387-93.
[http://dx.doi.org/10.1016/j.bbr.2009.10.024] [PMID: 19857526]
[48]
Fernandes Veloso Borges F, Ribeiro e Silva C, Moreira Goes W, et al. Protective effects of silymarin and silibinin against dna damage in human blood cells. BioMed Res Int 2018; 2018: 1-8.
[http://dx.doi.org/10.1155/2018/6056948] [PMID: 30370304]
[49]
Molavi O, Narimani F, Asiaee F, et al. Silibinin sensitizes chemo-resistant breast cancer cells to chemotherapy. Pharm Biol 2017; 55(1): 729-39.
[http://dx.doi.org/10.1080/13880209.2016.1270972] [PMID: 28027688]
[50]
Azadpour M, Farajollahi MM, Varzi AM, Hashemzadeh P, Mahmoudvand H, Barati M. Extraction, chemical composition, antioxidant property, and in-vitro anticancer activity of silymarin from silybum marianum on kb and a549 cell lines. Curr Drug Discov Technol 2021; 18(4): 511-7.
[http://dx.doi.org/10.2174/1570163817666200827111127] [PMID: 32860361]
[51]
Megur A, Baltriukienė D, Bukelskienė V, Burokas A. The microbiota–gut–brain axis and alzheimer’s disease: Neuroinflammation is to blame? Nutrients 2020; 13(1): 37.
[http://dx.doi.org/10.3390/nu13010037] [PMID: 33374235]
[52]
Mishra A, Kim HJ, Shin AH, et al. Synapse loss induced by interleukin-1β requires pre- and post-synaptic mechanisms. J Neuroimmune Pharmacol 2012; 7(3): 571-8.
[http://dx.doi.org/10.1007/s11481-012-9342-7]
[53]
DiSabato DJ, Quan N, Godbout JP. Neuroinflammation: The devil is in the details. J Neurochem 2016; 139(S2): 136-53.
[http://dx.doi.org/10.1111/jnc.13607] [PMID: 26990767]
[54]
Heneka MT, Kummer MP, Latz E. Innate immune activation in neurodegenerative disease. Nat Rev Immunol 2014; 14(7): 463-77.
[http://dx.doi.org/10.1038/nri3705] [PMID: 24962261]
[55]
Leng F, Edison P. Neuroinflammation and microglial activation in Alzheimer disease: Where do we go from here? Nat Rev Neurol 2021; 17(3): 157-72.
[http://dx.doi.org/10.1038/s41582-020-00435-y] [PMID: 33318676]
[56]
Joshi R, Garabadu D, Teja GR, Krishnamurthy S. Silibinin ameliorates LPS-induced memory deficits in experimental animals. Neurobiol Learn Mem 2014; 116: 117-31.
[http://dx.doi.org/10.1016/j.nlm.2014.09.006] [PMID: 25444719]
[57]
Garikapati DR, Shaik PB, Penchalaiah H. Evaluate neuroprotective effect of silibinin using chronic unpredictable stress (cus) model. Int J Physiol Pathophysiol Pharmacol 2018; 10(6): 184-91.
[PMID: 30697365]
[58]
Varshney V, Garabadu D. Ang (1–7)/Mas receptor-axis activation promotes amyloid beta-induced altered mitochondrial bioenergetics in discrete brain regions of Alzheimer’s disease-like rats. Neuropeptides 2021; 86: 102122.
[http://dx.doi.org/10.1016/j.npep.2021.102122] [PMID: 33508525]
[59]
Varshney V, Garabadu D. Ang(1–7) exerts Nrf2-mediated neuroprotection against amyloid beta-induced cognitive deficits in rodents. Mol Biol Rep 2021; 48(5): 4319-31.
[http://dx.doi.org/10.1007/s11033-021-06447-1] [PMID: 34075536]
[60]
Varshney V, Garabadu D. Naringin exhibits mas receptor–mediated neuroprotection against amyloid beta–induced cognitive deficits and mitochondrial toxicity in rat brain. Neurotox Res 2021; 39(4): 1023-43.
[http://dx.doi.org/10.1007/s12640-021-00336-y] [PMID: 33534126]
[61]
Garwood CJ, Pooler AM, Atherton J, Hanger DP, Noble W. Astrocytes are important mediators of Aβ-induced neurotoxicity and tau phosphorylation in primary culture. Cell Death Dis 2011; 2(6): e167.
[http://dx.doi.org/10.1038/cddis.2011.50] [PMID: 21633390]
[62]
Trouillas P, Marsal P, Svobodová A, et al. Mechanism of the antioxidant action of silybin and 2,3-dehydrosilybin flavonolignans: A joint experimental and theoretical study. J Phys Chem A 2008; 112(5): 1054-63.
[http://dx.doi.org/10.1021/jp075814h] [PMID: 18193843]
[63]
Youn CK, Park SJ, Lee MY, et al. Silibinin inhibits LPS-induced macrophage activation by blocking p38 MAPK in RAW 264.7 Cells. Biomol Ther 2013; 21(4): 258-63.
[http://dx.doi.org/10.4062/biomolther.2013.044] [PMID: 24244809]
[64]
Gazák R, Walterová D, Kren V. Silybin and silymarin--new and emerging applications in medicine. Curr Med Chem 2007; 14(3): 315-38.
[http://dx.doi.org/10.2174/092986707779941159] [PMID: 17305535]
[65]
Kim M, Kim SH, Yang W. Mechanisms of action of phytochemicals from medicinal herbs in the treatment of Alzheimer’s disease. Planta Med 2014; 80(15): 1249-58.
[http://dx.doi.org/10.1055/s-0034-1383038] [PMID: 25210998]
[66]
Song X, Liu B, Cui L, et al. Silibinin ameliorates anxiety/depression-like behaviors in amyloid β-treated rats by upregulating BDNF/TrkB pathway and attenuating autophagy in hippocampus. Physiol Behav 2017; 179: 487-93.
[http://dx.doi.org/10.1016/j.physbeh.2017.07.023] [PMID: 28735062]
[67]
Huo Q, Shi Y, Qi Y, Huang L, Sui H, Zhao L. Biomimetic silibinin-loaded macrophage-derived exosomes induce dual inhibition of Aβ aggregation and astrocyte activation to alleviate cognitive impairment in a model of Alzheimer’s disease. Mater Sci Eng C 2021; 129: 112365.
[http://dx.doi.org/10.1016/j.msec.2021.112365] [PMID: 34579884]
[68]
Lu P, Mamiya T, Lu LL, et al. Silibinin attenuates amyloid β(25-35) peptide-induced memory impairments: Implication of inducible nitric-oxide synthase and tumor necrosis factor-α in mice. J Pharmacol Exp Ther 2009; 331(1): 319-26.
[http://dx.doi.org/10.1124/jpet.109.155069] [PMID: 19638571]
[69]
Song X, Zhou B, Cui L, et al. Silibinin ameliorates Aβ25-35-induced memory deficits in rats by modulating autophagy and attenuating neuroinflammation as well as oxidative stress. Neurochem Res 2017; 42(4): 1073-83.
[http://dx.doi.org/10.1007/s11064-016-2141-4] [PMID: 28004303]
[70]
Sciacca MFM, Romanucci V, Zarrelli A, et al. Inhibition of Aβ amyloid growth and toxicity by silybins: The crucial role of stereochemistry. ACS Chem Neurosci 2017; 8(8): 1767-78.
[http://dx.doi.org/10.1021/acschemneuro.7b00110] [PMID: 28562008]
[71]
García-Viñuales S, Ahmed R, Sciacca MFM, et al. Trehalose conjugates of silybin as prodrugs for targeting toxic aβ aggregates. ACS Chem Neurosci 2020; 11(17): 2566-76.
[http://dx.doi.org/10.1021/acschemneuro.0c00232] [PMID: 32687307]
[72]
Chen X, Zenger K, Lupp A, et al. Tacrine-silibinin codrug shows neuro- and hepatoprotective effects in vitro and pro-cognitive and hepatoprotective effects in vivo. J Med Chem 2012; 55(11): 5231-42.
[http://dx.doi.org/10.1021/jm300246n] [PMID: 22624880]
[73]
Duan S, Guan X, Lin R, et al. Silibinin inhibits acetylcholinesterase activity and amyloid β peptide aggregation: A dual-target drug for the treatment of Alzheimer’s disease. Neurobiol Aging 2015; 36(5): 1792-807.
[http://dx.doi.org/10.1016/j.neurobiolaging.2015.02.002] [PMID: 25771396]
[74]
Tota S, Kamat PK, Shukla R, Nath C. Improvement of brain energy metabolism and cholinergic functions contributes to the beneficial effects of silibinin against streptozotocin induced memory impairment. Behav Brain Res 2011; 221(1): 207-15.
[http://dx.doi.org/10.1016/j.bbr.2011.02.041] [PMID: 21382422]
[75]
Bai D, Jin G, Yin S, et al. Antioxidative and anti-apoptotic roles of silibinin in reversing learning and memory deficits in APP/PS1 mice. Neurochem Res 2017; 42(12): 3439-45.
[http://dx.doi.org/10.1007/s11064-017-2389-3] [PMID: 28852940]
[76]
Shen L, Liu L, Li XY, Ji HF. Regulation of gut microbiota in Alzheimer’s disease mice by silibinin and silymarin and their pharmacological implications. Appl Microbiol Biotechnol 2019; 103(17): 7141-9.
[http://dx.doi.org/10.1007/s00253-019-09950-5] [PMID: 31236617]
[77]
Jin G, Bai D, Yin S, et al. Silibinin rescues learning and memory deficits by attenuating microglia activation and preventing neuroinflammatory reactions in SAMP8 mice. Neurosci Lett 2016; 629: 256-61.
[http://dx.doi.org/10.1016/j.neulet.2016.06.008] [PMID: 27276653]
[78]
Esselun C, Bruns B, Hagl S, Grewal R, Eckert GP. Impact of silibinin A on bioenergetics in PC12APPsw cells and mitochondrial membrane properties in murine brain mitochondria. Antioxidants 2021; 10(10): 1520.
[http://dx.doi.org/10.3390/antiox10101520] [PMID: 34679655]
[79]
Saravanan K, Sugarthi S, Suganya S, Kumaradhas P. Probing the intermolecular interactions, binding affinity, charge density distribution and dynamics of silibinin in dual targets AChE and BACE1: QTAIM and molecular dynamics perspective. J Biomol Struct Dyn 2021; 40(23): 1-15.
[PMID: 34637680]
[80]
Goyal A, Gopika S, Kumar A, et al. A comprehensive review on preclinical evidence based neuroprotective potential of bacopa monnieri against parkinson's disease. Curr Drug Targets 2022; 10: 2174/1389450123666220316091734.
[http://dx.doi.org/10.2174/1389450123666220316091734]
[81]
Goyal A, Verma A, Agrawal N. Dietary phytoestrogens: Neuroprotective role in parkinson’s disease. Curr Neurovasc Res 2021; 18(2): 254-67.
[http://dx.doi.org/10.2174/1567202618666210604121233] [PMID: 34086550]
[82]
Hamza TH, Zabetian CP, Tenesa A, et al. Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson’s disease. Nat Genet 2010; 42(9): 781-5.
[http://dx.doi.org/10.1038/ng.642] [PMID: 20711177]
[83]
Pan PY, Li X, Wang J, et al. Parkinson’s disease-associated lrrk2 hyperactive kinase mutant disrupts synaptic vesicle trafficking in ventral midbrain neurons. J Neurosci 2017; 37(47): 11366-76.
[http://dx.doi.org/10.1523/JNEUROSCI.0964-17.2017] [PMID: 29054882]
[84]
Patel N, Jankovic J, Hallett M. Sensory aspects of movement disorders. Lancet Neurol 2014; 13(1): 100-12.
[http://dx.doi.org/10.1016/S1474-4422(13)70213-8] [PMID: 24331796]
[85]
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.
[http://dx.doi.org/10.1016/j.neulet.2010.06.038] [PMID: 20600617]
[86]
Chen H, Wang X, Wang M, et al. Behavioral and neurochemical deficits in aging rats with increased neonatal iron intake: Silibinin’s neuroprotection by maintaining redox balance. Front Aging Neurosci 2015; 7: 206.
[http://dx.doi.org/10.3389/fnagi.2015.00206] [PMID: 26578951]
[87]
Lee Y, Chun HJ, Lee KM, Jung YS, Lee J. Silibinin suppresses astroglial activation in a mouse model of acute Parkinson׳s disease by modulating the ERK and JNK signaling pathways. Brain Res 2015; 1627: 233-42.
[http://dx.doi.org/10.1016/j.brainres.2015.09.029] [PMID: 26434409]
[88]
Liu X, Wang C, Liu W, et al. Oral administration of silibinin ameliorates cognitive deficits of parkinson’s disease mouse model by restoring mitochondrial disorders in hippocampus. Neurochem Res 2021; 46(9): 2317-32.
[http://dx.doi.org/10.1007/s11064-021-03363-5] [PMID: 34097239]
[89]
Jung UJ, Jeon MT, Choi MS, Kim SR. Silibinin attenuates MPP+-induced neurotoxicity in the substantia nigra in vivo. J Med Food 2014; 17(5): 599-605.
[http://dx.doi.org/10.1089/jmf.2013.2926] [PMID: 24660866]
[90]
Liu X, Liu W, Wang C, et al. Silibinin attenuates motor dysfunction in a mouse model of Parkinson’s disease by suppression of oxidative stress and neuroinflammation along with promotion of mitophagy. Physiol Behav 2021; 239: 113510.
[http://dx.doi.org/10.1016/j.physbeh.2021.113510] [PMID: 34181930]
[91]
Geed M, Garabadu D, Ahmad A, Krishnamurthy S. Silibinin pretreatment attenuates biochemical and behavioral changes induced by intrastriatal MPP+ injection in rats. Pharmacol Biochem Behav 2014; 117: 92-103.
[http://dx.doi.org/10.1016/j.pbb.2013.12.008] [PMID: 24345573]
[92]
Lee Y, Park HR, Chun HJ, Lee J. Silibinin prevents dopaminergic neuronal loss in a mouse model of Parkinson’s disease viamitochondrial stabilization. J Neurosci Res 2015; 93(5): 755-65.
[http://dx.doi.org/10.1002/jnr.23544] [PMID: 25677261]
[93]
Liu X, Chen W, Wang C, et al. Silibinin ameliorates depression/anxiety-like behaviors of Parkinson’s disease mouse model and is associated with attenuated STING-IRF3-IFN-β pathway activation and neuroinflammation. Physiol Behav 2021; 241: 113593.
[http://dx.doi.org/10.1016/j.physbeh.2021.113593] [PMID: 34536434]
[94]
Klijn CJM, Hankey GJ. Management of acute ischaemic stroke: New guidelines from the american stroke association and european stroke initiative. Lancet Neurol 2003; 2(11): 698-701.
[http://dx.doi.org/10.1016/S1474-4422(03)00558-1] [PMID: 14572738]
[95]
Virani SS, Alonso A, Benjamin EJ, et al. Heart disease and stroke statistics—2020 update: A report from the american heart association. Circulation 2020; 141(9): e139-596.
[http://dx.doi.org/10.1161/CIR.0000000000000757] [PMID: 31992061]
[96]
Shin TH, Lee DY, Basith S, et al. Metabolome changes in cerebral ischemia. Cells 2020; 9(7): 1630.
[http://dx.doi.org/10.3390/cells9071630] [PMID: 32645907]
[97]
Sarrafzadeh AS, Vajkoczy P, Bijlenga P, Schaller K. Monitoring in neurointensive care – the challenge to detect delayed cerebral ischemia in high-grade aneurysmal SAH. Front Neurol 2014; 5: 134.
[http://dx.doi.org/10.3389/fneur.2014.00134] [PMID: 25101052]
[98]
Sanganalmath SK, Gopal P, Parker JR, Downs RK, Parker JC Jr, Dawn B. Global cerebral ischemia due to circulatory arrest: Insights into cellular pathophysiology and diagnostic modalities. Mol Cell Biochem 2017; 426(1-2): 111-27.
[http://dx.doi.org/10.1007/s11010-016-2885-9] [PMID: 27896594]
[99]
Piccardi B, Biagini S, Iovene V, Palumbo V. Blood biomarkers of parenchymal damage in ischemic stroke patients treated with revascularization therapies. Biomark Insights 2019; 14.
[http://dx.doi.org/10.1177/1177271919888225] [PMID: 31903021]
[100]
Murray NM, Unberath M, Hager GD, Hui FK. Artificial intelligence to diagnose ischemic stroke and identify large vessel occlusions: A systematic review. J Neurointerv Surg 2020; 12(2): 156-64.
[http://dx.doi.org/10.1136/neurintsurg-2019-015135] [PMID: 31594798]
[101]
Reid C, Edwards J, Wang M, et al. Prevention by a silymarin/phospholipid compound of ethanol-induced social learning deficits in rats. Planta Med 1999; 65(5): 421-4.
[http://dx.doi.org/10.1055/s-1999-14085] [PMID: 10418328]
[102]
Wang MJ, Lin WW, Chen HL, et al. Silymarin protects dopaminergic neurons against lipopolysaccharide-induced neurotoxicity by inhibiting microglia activation. Eur J Neurosci 2002; 16(11): 2103-12.
[http://dx.doi.org/10.1046/j.1460-9568.2002.02290.x] [PMID: 12473078]
[103]
Hou YC, Liou KT, Chern CM, et al. Preventive effect of silymarin in cerebral ischemia–reperfusion-induced brain injury in rats possibly through impairing NF-κB and STAT-1 activation. Phytomedicine 2010; 17(12): 963-73.
[http://dx.doi.org/10.1016/j.phymed.2010.03.012] [PMID: 20833521]
[104]
Wang C, Wang Z, Zhang X, et al. Protection by silibinin against experimental ischemic stroke: Up-regulated pAkt, pmTOR, HIF-1α and Bcl-2, down-regulated Bax, NF-κB expression. Neurosci Lett 2012; 529(1): 45-50.
[http://dx.doi.org/10.1016/j.neulet.2012.08.078] [PMID: 22999929]
[105]
Wang M, Li YJ, Ding Y, et al. Silibinin prevents autophagic cell death upon oxidative stress in cortical neurons and cerebral ischemia-reperfusion injury. Mol Neurobiol 2016; 53(2): 932-43.
[http://dx.doi.org/10.1007/s12035-014-9062-5] [PMID: 25561437]
[106]
Liu BN, Han BX, Liu F. Neuroprotective effect of pAkt and HIF-1 α on ischemia rats. Asian Pac J Trop Med 2014; 7(3): 221-5.
[http://dx.doi.org/10.1016/S1995-7645(14)60025-0] [PMID: 24507644]
[107]
Bai D, Jin G, Zhang D, et al. Natural silibinin modulates amyloid precursor protein processing and amyloid-β protein clearance in APP/PS1 mice. J Physiol Sci 2019; 69(4): 643-52.
[http://dx.doi.org/10.1007/s12576-019-00682-9] [PMID: 31087219]
[108]
Yaghmaei P, Azarfar K, Dezfulian M, Ebrahim-Habibi A. Silymarin effect on amyloid-β plaque accumulation and gene expression of APP in an Alzheimer’s disease rat model. Daru 2014; 22(1): 24.
[http://dx.doi.org/10.1186/2008-2231-22-24] [PMID: 24460990]

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