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Silymarin ameliorates memory deficits and neuropathological changes in mouse model of high-fat-diet-induced experimental dementia

Abstract

A huge body evidences suggest that obesity is the single great risk factor for the development of dementia. Recently, silymarin, a flavonoid, clinically in use as a hepatoprotectant, has been reported to prevent amyloid beta-induced memory impairment by reducing oxidative stress and inflammation in mice brain. However, its potential in high-fat-diet (HFD)-induced dementia has not yet been investigated. Therefore, the present study is designed to explore the role of silymarin in HFD-induced experimental dementia in mice. Morris water maze test was employed to assess learning and memory. Various biochemical estimations including brain acetylcholinerstarse activity (AchE), thiobarbituric acid-reactive species (TBARS) level, reduced glutathione level (GSH), nirate/nitrite, and myeloperoxidase (MPO) activity were measured. Serum cholesterol level was also determined. HFD significantly impaired the cognitive abilities, along with increasing brain AchE, TBARS, MPO, nitrate/nitrite, and serum cholesterol levels. Marked reduction of brain GSH levels was observed. On the contrary, silymarin significantly reversed HFD-induced cognitive deficits and the biochemical changes. The present study indicates strong potential of silymarin in HFD-induced experimental dementia.

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References

  • Allain CC, Pool LS, Chan CSG, Richmound W, Paul CF (1974) Enzymatic determination of total serum cholesterol. Clin Chem 20:470–475

    CAS  PubMed  Google Scholar 

  • Barnes PJ, Karin M (1997) NF- κB a pivotal transcription factor in chronic inflammatory diseases. N Engl J Med 336:1066–1071

    Article  CAS  PubMed  Google Scholar 

  • Barone F, Hillegrass L, Price W, White R, Lee E, Feuerstein G, Sarau H, Clark R, Griswold D (1991) Polymorphonuclear leukocyte infiltration into cerebral focal ischemic tissue: myeloperoxidase activity assay and histologic verification. J Neurol Res 29:336–345

    Article  CAS  Google Scholar 

  • Beutler RG, Duron O, Kelly B (1963) Improved methods for determination of blood reduced glutathion estimation. J Lab Clin Med 61:882–888

    CAS  PubMed  Google Scholar 

  • Bretillon L, Lutjohann D, Stahel L, Widhe T, Bindl L, Eggerstsen G, Diczfalusy U, Bjorkhem I (2000) Plasma levels of 24S-hydroxycholesterol reflect the balance between cerebral production and hepatic metabolism and are inversely related to body surface. J Lipid Res 41:840–845

    CAS  PubMed  Google Scholar 

  • Chan C, Dharmarajan A, Atwood C, Huang X, Tanzi R, Bush A (1999) Anti-apoptotic action of Alzheimer beta amyloid. Alz Rep 2:113–119

    Google Scholar 

  • Chandalia M, Abate N (2007) Metabolic complications of obesity: inflated or inflamed? J Diabetes Complicat 21:128–136

    Article  PubMed  Google Scholar 

  • Dalla Y, Singh N, Jaggi AS, Singh D (2010) Memory restorative role of statins in experimental dementia: an evidence of their cholesterol dependent and independent actions. Pharmacol Rep 62:784–796

    Article  CAS  PubMed  Google Scholar 

  • Ellman GL, Courtney KD, Valentino A, Featherstone RM (1961) A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 7:88–95

    Article  CAS  PubMed  Google Scholar 

  • Emma RF, David JS, Claire EW, Huw D, Brian MA (1999) The role of cholesterol in biosynthesis of β-amyloid. Neuro Rep 10:1699–1705

    Google Scholar 

  • Fang L, Gou S, Fang X, Cheng L, Fleck C (2013) Current progresses of novel natural products and their derivatives/ analogs as anti-Alzheimer candidates: an update. Mini Rev Med Chem 13(6):870–887

    Article  CAS  PubMed  Google Scholar 

  • Henderson ST (2004) High carbohydrates diet and Alzheimer’s disease. Med Hypotheses 62:689–700

    Article  CAS  PubMed  Google Scholar 

  • Hofman A, Ott A, Breteler MMB, Bots ML, Slooter AJC, Harskamp FV, Duijn CNV, Van Broeckhoven C, Grobbee DE (1997) Atherosclerosis, apolipoprotein E and prevalence of dementia and Alzheimer’s disease in the Rotterdam study. Lancet 349:151–154

    Article  CAS  PubMed  Google Scholar 

  • Jadhav GB, Upasani CD (2011) Effect of silymarin on DOCA salt streptozotocin induced diabetic hypertension in unilateral nephrectomised rats. IJPR 3:27–32

    CAS  Google Scholar 

  • Juma'a KM, Ahmed ZA, Numan IT, Hussain SAR (2009) Dose-dependent anti-inflammatory effect of silymarin in experimental animal model of chronic inflammation. Afr J Pharm Pharmacol 3:242–247

    Google Scholar 

  • Kang JS, Jeon YJ, Kim HM, Han SH, Yang KH (2003) Inhibition of inducible nitric-oxide synthase expression by silymarin in lipopolysaccharide-stimulated macrophages. J Pharmacol Exp Ther 302:138–144

    Article  Google Scholar 

  • Karimi G, Vahabzadeh M, Lari P, Rashedinia M, Moshiri M (2011) “Silymarin”, a promising pharmacological agent for treatment of diseases. IJBMS 14:308–317

    CAS  PubMed Central  PubMed  Google Scholar 

  • Knopman D, Boland LL, Mosley T, Howard G, Liao D, Szklo M, McGovern P, Folsom AR (2001) Cardiovascular risk factors and cognitive decline in middle-aged adults. Neurology 56:42–48

    Article  CAS  PubMed  Google Scholar 

  • Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with Folin-phenol reagent. J Biol Chem 193:265–275

    CAS  PubMed  Google Scholar 

  • Maelicke A, Hoeffle-Maas A, Ludwig J, Maus A, Samochocki M, Jordis U, Koepke AK (2010) Memogain is a galantamine pro-drug having dramatically reduced adverse effects and enhanced efficacy. J Mol Neurosci 40:135–137

    Article  CAS  PubMed  Google Scholar 

  • Metwally MAA, El-Gellal AM, El-Sawaisi SM (2009) Effect of silymarin on lipid metabolism in rats. World Appl Sci J 6:1634–1637

    CAS  Google Scholar 

  • Molteni R, Barnard RJ, Ying Z, Roberts CK, Gomez-Pinilla F (2002) A high-fat, refined sugar diet reduces hippocampal brain-derived neurotrophic factor, neuronal plasticity, and learning. Neuroscience 112:803–814

    Article  CAS  PubMed  Google Scholar 

  • Morris RGM (1984) Development of a water maze producer for studying spatial learning in the rats. J Neurosci Methods 11:47–60

    Article  CAS  PubMed  Google Scholar 

  • Murata N, Murakami K, Ozawa Y, Kinoshita N, Irie K, Shirasawa T, Shimizu T (2010) Silymarin attenuated the amyloid β plaque burden and improved behavioral abnormalities in an Alzheimer’s disease mouse model. Biosci Biotechnol Biochem 74:2299–2306

    Article  CAS  PubMed  Google Scholar 

  • Nassuato G, Lemmolo RM, Strazzabosco M, Lirussi F, Deana R, Francesconi MA, Muraca M, Passera D, Fragasso A, Orlando R, Gsomos G, Okolicsanyi L (1991) Effect of silibinin on bilary lipid composition: experimental and clinical study. J Hepatol 12:290–295

    Article  CAS  PubMed  Google Scholar 

  • Nencini C, Giorgi G, Micheli L (2007) Protective effect of silymarin on oxidative stress in rat brain. Phytomedicine 14:129–135

    Article  CAS  PubMed  Google Scholar 

  • Ohokawa H, Ohishi N, Yagi K (1979) Assay of lipid peroxides in animals tissue by thiobarbituraic acid reaction. Anal Biochem 95:351–358

    Article  Google Scholar 

  • Packard MG, Teather LA, Bazan NG (1996) Effect of intra-striated injections of platelet-activating factor and PAF antagonist BN 52021 on memory. Neurobiol Learn Mem 66:176–182

    Article  CAS  PubMed  Google Scholar 

  • Parle M, Singh N (2004) Animal models for testing memory. Asia Pac J Pharmacol 16:101–120

    Google Scholar 

  • Parle M, Singh N (2007) Reversal of memory deficits by Atorvastatin and Simvastatin in rats. Yakugaku Zasshi 127:1125–1137

    Article  CAS  PubMed  Google Scholar 

  • Pathan AR, Viswanad B, Sonkusare SK, Ramarao P (2006) Chronic administration of pioglitazone attenuates intracerebroventricular streptozotocin induced-memory impairment in rats. Life Sci 79:2209–2216

    Article  CAS  PubMed  Google Scholar 

  • Pathan AR, Gaikwad AB, Viswanad B, Ramarao P (2008) Rosiglitazone attenuates the cognitive deficits induced by high fat diet feeding in rats. Eur J Pharmacol 589:176–179

    Article  CAS  PubMed  Google Scholar 

  • Pistell PJ, Morrison CD, Gupta S, Knight AG, Keller JN, Ingram DK, Bruce-Keller AJ (2010) Cognitive impairment following high fat diet consumption is associated with brain inflammation. J Neuroimmunol 219:25–32

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Plassman BL, Langa KM, McCammon RJ, Fisher GG, Potter GG, Burke JR, Steffens DC, Foster NL, Giordani B, Unverzagt FW, Welsh-Bohmer KA, Heeringa SG, Weir DR, Wallace RB (2011) Incidence of dementia and cognitive impairment, not dementia in the united states. Ann Neurol 70:418–426

    Article  PubMed Central  PubMed  Google Scholar 

  • Pluta R, Jablonski M, Ulamek-Koziol M, Kocki J, Brzozowska J, Januszewski S, Furmaga-Jablonska W, Bogucka-Kocka A, Maciejewski R, Czuczwar SJ (2013) Sporadic Alzheimer's disease begins as episodes of brain ischemia and ischemically dysregulated Alzheimer's disease genes. Mol Neurobiol 48(3):500–515

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Pradhan SC, Girish C (2006) Hepatoprotective herbal drug, silymarin from experimental pharmacology to clinical medicine. Indian J Med Res 124:491–504

    CAS  PubMed  Google Scholar 

  • Prakash A, Singh N, Singh M (2007) Beneficial effects of statins on experimental Amnesia. IJPT 6:125–132

    CAS  Google Scholar 

  • Roher AE, Kuo YM, Kokjohn KM, Emmerling MR, Gracon S (1999) Amyloid and lipids in the pathology of Alzheimer disease. Inter J Exp Clin Invest 6:136–145

    CAS  Google Scholar 

  • Sagar SM (2007) Future directions for research on silybum marianum for cancer patient. Integr Cancer Ther 6:166–173

    Article  CAS  PubMed  Google Scholar 

  • Sastry KVH, Moudgal RP, Mohan J, Tyagi JS, Rao GS (2002) Spectrophotometric determination of serum nitrite and nitrate by copper–cadmium alloy. Anal Biochem 306:79–82

    Article  CAS  PubMed  Google Scholar 

  • Sharma B, Singh N (2010) Pitavastatin and 4′-hydroxy-3′-methoxyacetophenone (HMAP). Reduce cognitive dysfunction in vascular dementia during experimental diabetes. Curr Neurovasc Res 7:180–191

    Article  CAS  PubMed  Google Scholar 

  • Sharma B, Singh N (2011) Attenuation of vascular dementia by sodium butyrate in streptozotocin diabetic rats. Psychopharmacology 215:677–687

    Article  CAS  PubMed  Google Scholar 

  • Sharma B, Singh N, Singh M (2008a) Modulation of celecoxib and streptozotocin-induced experimental dementia of Alzheimer’s disease type by pitavastatin and donepezil. J Psychopharmacol 22:162–171

    Article  CAS  PubMed  Google Scholar 

  • Sharma B, Singh N, Jaggi AS (2008b) Exploration of HIV protease inhibitor Indinavir as a memory restorative agent in experimental induced dementia. Pharmacol Biochem Behav 89:535–545

    Article  CAS  PubMed  Google Scholar 

  • Shie FS, Jin LW, Cook DG, Leverenz JB, LeBoeuf RC (2002) Diet-induced hypercholesterolemia enhances brain A beta accumulation in transgenic mice. NeuroReport 13:455–459

    Article  CAS  PubMed  Google Scholar 

  • Singh B, Sharma B, Jaggi AS, Singh N (2013) Attenuating effect of lisinopril and telmisartan in intracerebroventricular streptozotocin induced experimental dementia of Alzheimer's disease type: possible involvement of PPAR-γ agonistic property. J Renin-Angiotensin-Aldosterone Syst 14(2):124–136

    Article  PubMed  Google Scholar 

  • Sodhi RK, Singh N (2013) Defensive effect of lansoprazole in dementia of AD type in mice exposed to streptozotocin and cholesterol enriched diet. PLoS One 8(7):70487

    Article  Google Scholar 

  • Sparks DL (1997) Coronary artery disease, hypertension, ApoE, and cholesterol: a link to Alzheimer’s disease? Ann N Y Acad Sci 826:128–146

    Article  CAS  PubMed  Google Scholar 

  • Stephan BC, Wells JC, Brayne C, Albanese E, Siervo M (2010) Increased fructose intake as a risk factor for dementia. J Gerontol A Biol Sci Med Sci 65:809–814

    Article  CAS  PubMed  Google Scholar 

  • Terry AV Jr, Callahan PM, Hall B, Webstar BH (2011) Alzheimer’s disease and age related memory decline (preclinical). Pharmacol Biochem Behav 99:190–210

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Vardy ER, Hussain I (2006) Emerging therapeutics for Alzheimer’s disease. Expert Rev Neurother 6:695–704

    Article  CAS  PubMed  Google Scholar 

  • Voss G, Sachsse K (1970) Red cell and plasma cholinesterase activities in microsamples of human and animal blood determined simultaneously by a modified acetylcholine / DTNB procedure. Toxicol Appl Pharmacol 16:764–772

    Article  CAS  PubMed  Google Scholar 

  • Wang MJ, Lin WW, Chen HL, Chang YH, Ou HC, Kuo JS, Hong JS, Jeng KC (2002) Silymarin protects dopaminergic neurons against lipopolysaccharide-induced neurotoxicity by inhibiting microglia activation. Eur J Neurosci 16:2103–2112

    Article  PubMed  Google Scholar 

  • Yao J, Zhi M, Chen M (2011) Effect of Silybin on high fat induced fatty liver in rats. Braz J Med Biol Res 44(7):652–659

    CAS  PubMed  Google Scholar 

  • Zhang X, Dong F, Ren J, Driscoll MJ, Culver B (2005) High dietary fat induces NADPH oxidase-associated oxidative stress and inflammation in rat cerebral cortex. Exp Neurol 191:318–325

    Article  CAS  PubMed  Google Scholar 

  • Zhang GL, Deng JP, Wang BH, Zhao ZW, Li J, Gao L, Liu BL, Xong JR, Guo XD, Yan ZQ, Gao GD (2011) Gypenosides improve cognitive impairment induced by chronic cerebral hypoperfusion in rats by suppressing oxidative stress and astrocytic activation. Behav Pharmacol 22(7):633–644

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors are thankful to the Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala (India) for supporting this study and providing technical facilities for the work.

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Correspondence to Nirmal Singh.

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Neha, Kumar, A., Jaggi, A.S. et al. Silymarin ameliorates memory deficits and neuropathological changes in mouse model of high-fat-diet-induced experimental dementia. Naunyn-Schmiedeberg's Arch Pharmacol 387, 777–787 (2014). https://doi.org/10.1007/s00210-014-0990-4

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  • DOI: https://doi.org/10.1007/s00210-014-0990-4

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