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Silibinin Alleviates the Learning and Memory Defects in Overtrained Rats Accompanying Reduced Neuronal Apoptosis and Senescence

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Abstract

Excessive physical exercise (overtraining; OT) increases oxidative stress and induces damage in multiple organs including the brain, especially the hippocampus that plays an important role in learning and memory. Silibinin, a natural flavonoid derived from milk thistle of Silybum marianum, has been reported to exert neuroprotective effect. In this study, rats were subjected to overtraining exercise, and the protective effects of silibinin were investigated in these models. Morris water maze and novel object recognition tests showed that silibinin significantly attenuated memory defects in overtrained rats. At the same time, the results of Nissl, TUNEL and SA-β-gal staining showed that silibinin reversed neuronal loss caused by apoptosis, and delayed cell senescence of the hippocampus in the overtrained rats, respectively. In addition, silibinin decreased malondialdehyde (MDA) levels which is associated with reactive oxygen species (ROS) generation. Silibinin prevented impairment of learning and memory caused by excessive physical exercise in rats, accompanied by reduced apoptosis and senescence in hippocampus cells.

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References

  1. Fiuza-Luces C, Santos-Lozano A, Joyner M, Carrera-Bastos P, Picazo O, Zugaza JL, Izquierdo M, Ruilope LM, Lucia A (2018) Exercise benefits in cardiovascular disease: beyond attenuation of traditional risk factors. Nat Rev Cardiol 15:731–743

    Article  CAS  PubMed  Google Scholar 

  2. Cai H, Li G, Zhang P, Xu D, Chen L (2017) Effect of exercise on the quality of life in type 2 diabetes mellitus: a systematic review. Qual Life Res 26:515–530

    Article  PubMed  Google Scholar 

  3. Panza GA, Taylor BA, MacDonald HV, Johnson BT, Zaleski AL, Livingston J, Thompson PD, Pescatello LS (2018) Can exercise improve cognitive symptoms of Alzheimer's disease? J Am Geriatr Soc 66:487–495

    Article  PubMed  Google Scholar 

  4. Meeusen R, Duclos M, Foster C, Fry A, Gleeson M, Nieman D, Raglin J, Rietjens G, Steinacker J, Urhausen A European College of Sport S, American College of Sports M (2013) Prevention, diagnosis, and treatment of the overtraining syndrome: joint consensus statement of the European College of Sport Science and the American College of Sports Medicine. Med Sci Sports Exerc 45:186–205

    Article  PubMed  Google Scholar 

  5. Kadaja L, Eimre M, Paju K, Roosimaa M, Podramagi T, Kaasik P, Pehme A, Orlova E, Mudist M, Peet N, Piirsoo A, Seene T, Gellerich FN, Seppet EK (2010) Impaired oxidative phosphorylation in overtrained rat myocardium. Exp Clin Cardiol 15:e116–127

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Wu GL, Chen YS, Huang XD, Zhang LX (2012) Exhaustive swimming exercise related kidney injury in rats—protective effects of acetylbritannilactone. Int J Sports Med 33:1–7

    Article  CAS  PubMed  Google Scholar 

  7. Smith LL (2000) Cytokine hypothesis of overtraining: a physiological adaptation to excessive stress? Med Sci Sports Exerc 32:317–331

    Article  CAS  PubMed  Google Scholar 

  8. Eich TS, Metcalfe J (2009) Effects of the stress of marathon running on implicit and explicit memory. Psychon Bull Rev 16:475–479

    Article  PubMed  Google Scholar 

  9. Sun LN, Li XL, Wang F, Zhang J, Wang DD, Yuan L, Wu MN, Wang ZJ, Qi JS (2017) High-intensity treadmill running impairs cognitive behavior and hippocampal synaptic plasticity of rats via activation of inflammatory response. J Neurosci Res 95:1611–1620

    Article  CAS  PubMed  Google Scholar 

  10. Bartsch T, Wulff P (2015) The hippocampus in aging and disease: from plasticity to vulnerability. Neuroscience 309:1–16

    Article  CAS  PubMed  Google Scholar 

  11. Dimauro I, Mercatelli N, Caporossi D (2016) Exercise-induced ROS in heat shock proteins response. Free Radic Biol Med 98:46–55

    Article  CAS  PubMed  Google Scholar 

  12. Li H, Miao W, Ma J, Xv Z, Bo H, Li J, Zhang Y, Ji LL (2016) Acute exercise-induced mitochondrial stress triggers an inflammatory response in the myocardium via NLRP3 inflammasome activation with mitophagy. Oxid Med Cell Longev 2016:1987149

    PubMed  Google Scholar 

  13. Morton JP, Kayani AC, McArdle A, Drust B (2009) The exercise-induced stress response of skeletal muscle, with specific emphasis on humans. Sports Med 39:643–662

    Article  PubMed  Google Scholar 

  14. Sliter DA, Martinez J, Hao L, Chen X, Sun N, Fischer TD, Burman JL, Li Y, Zhang Z, Narendra DP, Cai H, Borsche M, Klein C, Youle RJ (2018) Parkin and PINK1 mitigate STING-induced inflammation. Nature 561:258–262

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Aguiar AS Jr, Tuon T, Pinho CA, Silva LA, Andreazza AC, Kapczinski F, Quevedo J, Streck EL, Pinho RA (2008) Intense exercise induces mitochondrial dysfunction in mice brain. Neurochem Res 33:51–58

    Article  CAS  PubMed  Google Scholar 

  16. Wang Q, Zou L, Liu W, Hao W, Tashiro S, Onodera S, Ikejima T (2011) Inhibiting NF-kappaB activation and ROS production are involved in the mechanism of silibinin's protection against D-galactose-induced senescence. Pharmacol Biochem Behav 98:140–149

    Article  CAS  PubMed  Google Scholar 

  17. Fougere B, Boulanger E, Nourhashemi F, Guyonnet S, Cesari M (2017) Chronic inflammation: accelerator of biological aging. J Gerontol A Biol Sci Med Sci 72:1218–1225

    Article  CAS  PubMed  Google Scholar 

  18. He L, Chen Y, Feng J, Sun W, Li S, Ou M, Tang L (2017) Cellular senescence regulated by SWI/SNF complex subunits through p53/p21 and p16/pRB pathway. Int J Biochem Cell Biol 90:29–37

    Article  CAS  PubMed  Google Scholar 

  19. Christian M, Beauséjour AK, Francesco Galimi MN, Scott W. Lowe PY, Judith (2003) Reversal of human cellular senescence: roles of the p53 and p16 pathways. EMBO J 22:4212–4222

    Article  Google Scholar 

  20. Bussian TJ, Aziz A, Meyer CF, Swenson BL, van Deursen JM, Baker DJ (2018) Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline. Nature 562:578–582

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Jiang W, Guo M, Gong M, Chen L, Bi Y, Zhang Y, Shi Y, Qu P, Liu Y, Chen J, Li T (2018) Vitamin A bio-modulates apoptosis via the mitochondrial pathway after hypoxic-ischemic brain damage. Mol Brain 11:14

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Chang KW, Zong HF, Ma KG, Zhai WY, Yang WN, Hu XD, Xu JH, Chen XL, Ji SF, Qian YH (2018) Activation of alpha7 nicotinic acetylcholine receptor alleviates Abeta1-42-induced neurotoxicity via downregulation of p38 and JNK MAPK signaling pathways. Neurochem Int 120:238–250

    Article  CAS  PubMed  Google Scholar 

  23. Peng S, Wang C, Ma J, Jiang K, Jiang Y, Gu X, Sun C (2018) Achyranthes bidentata polypeptide protects dopaminergic neurons from apoptosis in Parkinson's disease models both in vitro and in vivo. Br J Pharmacol 175:631–643

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Mira L, Silva M, Manso CF (1994) Scavenging of reactive oxygen species by silibinin dihemisuccinate. Biochem Pharmacol 48:753–759

    Article  CAS  PubMed  Google Scholar 

  25. Federico A, Dallio M, Loguercio C (2017) Silymarin/Silybin and chronic liver disease: a marriage of many years. Molecules 22:191

    Article  CAS  PubMed Central  Google Scholar 

  26. Song X, Liu B, Cui L, Zhou B, Liu L, Liu W, Yao G, Xia M, Hayashi T, Hattori S, Ushiki-Kaku Y, Tashiro SI, Ikejima T (2018) Estrogen receptors are involved in the neuroprotective effect of Silibinin in abeta1-42-treated rats. Neurochem Res 43:796–805

    Article  CAS  PubMed  Google Scholar 

  27. Yang J, Sun Y, Xu F, Liu W, Hayashi T, Onodera S, Tashiro SI, Ikejima T (2018) Involvement of estrogen receptors in silibinin protection of pancreatic beta-cells from TNFalpha- or IL-1beta-induced cytotoxicity. Biomed Pharmacother 102:344–353

    Article  CAS  PubMed  Google Scholar 

  28. Song X, Zhou B, Cui L, Lei D, Zhang P, Yao G, Xia M, Hayashi T, Hattori S, Ushiki-Kaku Y, Tashiro SI, Onodera S, Ikejima T (2017) Silibinin ameliorates Abeta25-35-induced memory deficits in rats by modulating autophagy and attenuating neuroinflammation as well as oxidative stress. Neurochem Res 42:1073–1083

    Article  CAS  PubMed  Google Scholar 

  29. Lu P, Mamiya T, Lu LL, Mouri A, Zou L, Nagai T, Hiramatsu M, Ikejima T, Nabeshima T (2009) Silibinin prevents amyloid beta peptide-induced memory impairment and oxidative stress in mice. Br J Pharmacol 157:1270–1277

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Tota S, Kamat PK, Shukla R, Nath C (2011) Improvement of brain energy metabolism and cholinergic functions contributes to the beneficial effects of silibinin against streptozotocin induced memory impairment. Behav Brain Res 221:207–215

    Article  CAS  PubMed  Google Scholar 

  31. Bennett BT, Mohamed JS, Alway SE (2013) Effects of resveratrol on the recovery of muscle mass following disuse in the plantaris muscle of aged rats. PLoS ONE 8:e83518

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Kan NW, Ho CS, Chiu YS, Huang WC, Chen PY, Tung YT, Huang CC (2016) Effects of resveratrol supplementation and exercise training on exercise performance in middle-aged mice. Molecules 21:661

    Article  CAS  PubMed Central  Google Scholar 

  33. Wu RE, Huang WC, Liao CC, Chang YK, Kan NW, Huang CC (2013) Resveratrol protects against physical fatigue and improves exercise performance in mice. Molecules 18:4689–4702

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Jardim FR, de Rossi FT, Nascimento MX, da Silva Barros RG, Borges PA, Prescilio IC, de Oliveira MR (2018) Resveratrol and brain mitochondria: a review. Mol Neurobiol 55:2085–2101

    Article  CAS  PubMed  Google Scholar 

  35. Wiciński M, Leis K, Szyperski P, Węclewicz MM, Mazur E, Pawlak-Osińska K (2018) Impact of resveratrol on exercise performance: a review. Sci Sports 33:207–212

    Article  Google Scholar 

  36. Hohl R, Ferraresso RL, De Oliveira RB, Lucco R, Brenzikofer R, De Macedo DV (2009) Development and characterization of an overtraining animal model. Med Sci Sports Exerc 41:1155–1163

    Article  PubMed  Google Scholar 

  37. Song X, Zhou B, Zhang P, Lei D, Wang Y, Yao G, Hayashi T, Xia M, Tashiro S, Onodera S, Ikejima T (2016) Protective effect of Silibinin on learning and memory impairment in LPS-treated rats via ROS-BDNF-TrkB pathway. Neurochem Res 41:1662–1672

    Article  CAS  PubMed  Google Scholar 

  38. Garman RH (2011) Histology of the central nervous system. Toxicol Pathol 39:22–35

    Article  PubMed  Google Scholar 

  39. Fletcher GF, Landolfo C, Niebauer J, Ozemek C, Arena R, Lavie CJ (2018) Reprint of: Promoting physical activity and exercise: JACC ealth promotion series. J Am Coll Cardiol 72:3053–3070

    Article  PubMed  Google Scholar 

  40. Tuan TC, Hsu TG, Fong MC, Hsu CF, Tsai KK, Lee CY, Kong CW (2008) Deleterious effects of short-term, high-intensity exercise on immune function: evidence from leucocyte mitochondrial alterations and apoptosis. Br J Sports Med 42:11–15

    Article  PubMed  Google Scholar 

  41. Liu H, Lei H, Shi Y, Wang JJ, Chen N, Li ZH, Chen YF, Ye QF, Yang Y (2017) Autophagy inhibitor 3-methyladenine alleviates overload-exercise-induced cardiac injury in rats. Acta Pharmacol Sin 38:990–997

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Halson SL, Jeukendrup AE (2004) Does overtraining exist? An analysis of overreaching and overtraining research. Sports Med 34:967–981

    Article  PubMed  Google Scholar 

  43. Zoppi CC, Macedo DV (2008) Overreaching-induced oxidative stress, enhanced HSP72 expression, antioxidant and oxidative enzymes downregulation. Scand J Med Sci Sports 18:67–76

    Article  CAS  PubMed  Google Scholar 

  44. Julien Finaud GLaEF (2006) Oxidative stress relationship with exercise and training. Sports Med 36:327–358

    Article  Google Scholar 

  45. Riezzo I, Cerretani D, Fiore C, Bello S, Centini F, D'Errico S, Fiaschi AI, Giorgi G, Neri M, Pomara C, Turillazzi E, Fineschi V (2010) Enzymatic-nonenzymatic cellular antioxidant defense systems response and immunohistochemical detection of MDMA, VMAT2, HSP70, and apoptosis as biomarkers for MDMA (Ecstasy) neurotoxicity. J Neurosci Res 88:905–916

    CAS  PubMed  Google Scholar 

  46. Falkowska A, Gutowska I, Goschorska M, Nowacki P, Chlubek D, Baranowska-Bosiacka I (2015) Energy metabolism of the brain, including the cooperation between astrocytes and neurons, especially in the context of glycogen metabolism. Int J Mol Sci 16:25959–25981

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Camiletti-Moiron D, Aparicio VA, Aranda P, Radak Z (2013) Does exercise reduce brain oxidative stress? A systematic review. Scand J Med Sci Sports 23:e202–e212

    Article  CAS  PubMed  Google Scholar 

  48. Gegentonglaga Yoshizato H, Higuchi Y, Toyota Y, Hanai Y, Ando Y, Yoshimura A (2013) Variable alteration of regional tissue oxygen pressure in rat hippocampus by acute swimming exercise. Life Sci 93:773–777

    Article  CAS  PubMed  Google Scholar 

  49. Zheng JH, Viacava Follis A, Kriwacki RW, Moldoveanu T (2016) Discoveries and controversies in BCL-2 protein-mediated apoptosis. FEBS J 283:2690–2700

    Article  CAS  PubMed  Google Scholar 

  50. Huang CC, Lin TJ, Chen CC, Lin WT (2009) Endurance training accelerates exhaustive exercise-induced mitochondrial DNA deletion and apoptosis of left ventricle myocardium in rats. Eur J Appl Physiol 107:697–706

    Article  CAS  PubMed  Google Scholar 

  51. Mancuso M, Coppede F, Migliore L, Siciliano G, Murri L (2006) Mitochondrial dysfunction, oxidative stress and neurodegeneration. J Alzheimers Dis 10:59–73

    Article  CAS  PubMed  Google Scholar 

  52. Bouzid MA, Filaire E, McCall A, Fabre C (2015) Radical oxygen species, exercise and aging: an update. Sports Med 45:1245–1261

    Article  PubMed  Google Scholar 

  53. Tv Zglinicki (2002) Oxidative stress shortens telomeres. Trends Biochem Sci 27:339–343

    Article  Google Scholar 

  54. Joseph J, Cole G, Head E, Ingram D (2009) Nutrition, brain aging, and neurodegeneration. J Neurosci 29:12795–12801

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Narita M, Nuñez S, Heard E, Narita M, Lin AW, Hearn SA, Spector DL, Hannon GJ, Lowe SW (2003) Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell 113:703–716

    Article  CAS  PubMed  Google Scholar 

  56. Wang JXQ, Rottinghaus GE (2002) Resveratrol protects against global cerebral ischemic injury in gerbils. Brain Res 958:439–447

    Article  CAS  PubMed  Google Scholar 

  57. Li YR, Li S, Lin CC (2018) Effect of resveratrol and pterostilbene on aging and longevity. BioFactors 44:69–82

    Article  CAS  PubMed  Google Scholar 

  58. Folbergrova J, Jesina P, Kubova H, Otahal J (2018) Effect of resveratrol on oxidative stress and mitochondrial dysfunction in immature brain during epileptogenesis. Mol Neurobiol 55:7512–7522

    Article  CAS  PubMed  Google Scholar 

  59. Cadonic C, Sabbir MG, Albensi BC (2016) Mechanisms of mitochondrial dysfunction in Alzheimer's disease. Mol Neurobiol 53:6078–6090

    Article  CAS  PubMed  Google Scholar 

  60. Ullah H, Khan H (2018) Anti-Parkinson potential of Silymarin: mechanistic insight and therapeutic standing. Front Pharmacol 9:422

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Duan S, Guan X, Lin R, Liu X, Yan Y, Lin R, Zhang T, Chen X, Huang J, Sun X, Li Q, Fang S, Xu J, Yao Z, Gu H (2015) Silibinin inhibits acetylcholinesterase activity and amyloid beta peptide aggregation: a dual-target drug for the treatment of Alzheimer's disease. Neurobiol Aging 36:1792–1807

    Article  CAS  PubMed  Google Scholar 

  62. Wang M, Li YJ, Ding Y, Zhang HN, Sun T, Zhang K, Yang L, Guo YY, Liu SB, Zhao MG, Wu YM (2016) Silibinin prevents autophagic cell death upon oxidative stress in cortical neurons and cerebral ischemia-reperfusion injury. Mol Neurobiol 53:932–943

    Article  CAS  PubMed  Google Scholar 

  63. Xie Z, Ding SQ, Shen YF (2014) Silibinin activates AMP-activated protein kinase to protect neuronal cells from oxygen and glucose deprivation-re-oxygenation. Biochem Biophys Res Commun 454:313–319

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, Liaoning, People’s Republic of China

    Bo Liu, Weiwei Liu, Panwen Liu, Xiumin Liu, Xiaoyu Song, Toshihiko Hayashi & Takashi Ikejima

  2. Medical Research Center, Shenzhen University Health Science Center, Shenzhen, 518060, People’s Republic of China

    Xiaoyu Song

  3. Department of Chemistry and Life Science, School of Advanced Engineering, Kogakuin University, 2665-1 Nakanomachi, Hachioji, Tokyo, 192-0015, Japan

    Toshihiko Hayashi

  4. Medical Research Institute of Curing Mibyo, 1-6-28 Narusedai, Mechida, Tokyo, 194-0042, Japan

    Satoshi Onodera

  5. Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research & Development, Shenyang Pharmaceutical University, Shenyang, 110016, Liaoning, People’s Republic of China

    Takashi Ikejima

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  1. Bo Liu
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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 44, 1818–1829 (2019). https://doi.org/10.1007/s11064-019-02816-2

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