Skip to main content
Log in

Sericin modulates learning and memory behaviors by tuning of antioxidant, inflammatory, and apoptotic markers in the hippocampus of aged mice

  • Original Article
  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

Sericin is a protein derived from silkworm cocoons and identified as an anti-aging agent. This study aimed to examine the effects of sericin administration on episodic and avoidance memories, social interaction behavior, and molecular mechanisms including oxidative stress, inflammation, and apoptosis in the hippocampus of aged mice. Sericin was administered at 250 mg/kg/day (oral gavage) to 2-year-old BALB/c mice for a duration of 21 consecutive days. Lashley III Maze and Shuttle-Box tests were performed to assess episodic and avoidance memories, respectively. Subjects also underwent social interaction test to reveal any changes in their social behavior. Besides, markers of oxidative stress (TAC, SOD, GPx, and MDA) and neuroinflammation mediators (TNF-α, IL-1β, and IL-10) were measured in the hippocampus. The extent of apoptosis in the hippocampal tissue was further determined by TUNEL assay and histological assessment. The obtained results suggest that sericin promotes episodic and avoidance memories and social behaviors in aged mice. As of the molecular assay outcomes, it was noted that sericin regulates hippocampal inflammation by inhibiting the pro-inflammatory cytokines, TNF-α and IL-1β, and by increasing the anti-inflammatory factor IL-10. Moreover, sericin suppressed oxidative stress by enhancing antioxidant markers (TAC, SOD, and GPx) and inhibiting MDA. It was also identified that sericin can substantially suppress the apoptosis in the hippocampal tissue. Overall, sericin modulates memory and sociability behavior by tuning hippocampal antioxidant, inflammatory, and apoptotic markers in the aged mice.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Rehman SU, Shah SA, Ali T, Chung JI, Kim MO (2017) Anthocyanins reversed D-galactose-induced oxidative stress and neuroinflammation mediated cognitive impairment in adult rats. Mol Neurobiol 54(1):255–271

    PubMed  Google Scholar 

  2. Wang X, Zhao B, Li X (2015) Dexmedetomidine attenuates isoflurane-induced cognitive impairment through antioxidant, anti-inflammatory and anti-apoptosis in aging rat. Int J Clin Exp Med 8(10):17281

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Chakrabarti S, Munshi S, Banerjee K, Thakurta IG, Sinha M, Bagh MB (2011) Mitochondrial dysfunction during brain aging: role of oxidative stress and modulation by antioxidant supplementation. Aging dis 2(3):242

    PubMed  PubMed Central  Google Scholar 

  4. Netto MB, de Oliveira Junior AN, Goldim M, Mathias K, Fileti ME, da Rosa N et al (2018) Oxidative stress and mitochondrial dysfunction contributes to postoperative cognitive dysfunction in elderly rats. Brain Behav Immun 73:661–669

    CAS  PubMed  Google Scholar 

  5. Simen AA, Bordner KA, Martin MP, Moy LA, Barry LC (2011) Cognitive dysfunction with aging and the role of inflammation. Ther Adv Chronic Dis 2(3):175–195

    PubMed  PubMed Central  Google Scholar 

  6. Wennberg AM, Hagen CE, Machulda MM, Knopman DS, Petersen RC, Mielke MM (2019) The cross-sectional and longitudinal associations between IL-6, IL-10, and TNFα and cognitive outcomes in the Mayo Clinic Study of Aging. J Gerontol A Biol Sci Med Sci 74(8):1289–1295

    CAS  PubMed  Google Scholar 

  7. Trollor JN, Smith E, Agars E, Kuan SA, Baune BT, Campbell L et al (2012) The association between systemic inflammation and cognitive performance in the elderly: the Sydney Memory and Ageing Study. Age 34(5):1295–1308

    CAS  PubMed  Google Scholar 

  8. Pourmemar E, Majdi A, Haramshahi M, Talebi M, Karimi P, Sadigh-Eteghad S (2017) Intranasal cerebrolysin attenuates learning and memory impairments in D-galactose-induced senescence in mice. Exp Gerontol 87:16–22

    CAS  PubMed  Google Scholar 

  9. Koster R, Chadwick MJ, Chen Y, Berron D, Banino A, Düzel E et al (2018) Big-loop recurrence within the hippocampal system supports integration of information across episodes. Neuron 99(6):1342-1354.e6

    CAS  PubMed  Google Scholar 

  10. Anacker C, Hen R (2017) Adult hippocampal neurogenesis and cognitive flexibility—linking memory and mood. Nat Rev Neurosci 18(6):335–346

    CAS  PubMed  PubMed Central  Google Scholar 

  11. VanGuilder HD, Bixler GV, Brucklacher RM, Farley JA, Yan H, Warrington JP et al (2011) Concurrent hippocampal induction of MHC II pathway components and glial activation with advanced aging is not correlated with cognitive impairment. J Neuroinflammation 8(1):138

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Peera K, Yellamma K (2016) Evaluation of potential antioxidant activity of silk protein–sericin against Alzheimer’s disease induced rat brain. Sci Spectrum 1:384–395

    Google Scholar 

  13. Wang W-Y, Liu Y, Wang H-F, Tan L, Sun F-R, Tan M-S et al (2017) Impacts of CD33 genetic variations on the atrophy rates of hippocampus and parahippocampal gyrus in normal aging and mild cognitive impairment. Mol Neurobiol 54(2):1111–1118

    CAS  PubMed  Google Scholar 

  14. Erickson KI, Miller DL, Roecklein KA (2012) The aging hippocampus: interactions between exercise, depression, and BDNF. Neuroscientist 18(1):82–97

    CAS  PubMed  Google Scholar 

  15. Hong S, Dissing-Olesen L, Stevens B (2016) New insights on the role of microglia in synaptic pruning in health and disease. Curr Opin Neurobiol 36:128–134

    CAS  PubMed  Google Scholar 

  16. Almeida MF, Silva CM, D’Unhao AM, Ferrari MF (2016) Aged Lewis rats exposed to low and moderate doses of rotenone are a good model for studying the process of protein aggregation and its effects upon central nervous system cell physiology. Arq Neuropsiquiatr 74(9):737–744

    PubMed  Google Scholar 

  17. Lana D, Iovino L, Nosi D, Wenk GL, Giovannini MG (2016) The neuron-astrocyte-microglia triad involvement in neuroinflammaging mechanisms in the CA3 hippocampus of memory-impaired aged rats. Exp Gerontol 83:71–88

    PubMed  Google Scholar 

  18. Lana D, Ugolini F, Wenk GL, Giovannini MG, Zecchi-Orlandini S, Nosi D (2019) Microglial distribution, branching, and clearance activity in aged rat hippocampus are affected by astrocyte meshwork integrity: evidence of a novel cell-cell interglial interaction. FASEB J 33(3):4007–4020

    CAS  PubMed  Google Scholar 

  19. Li Q, Zeng J, Su M, He Y, Zhu B (2018) Acetylshikonin from Zicao attenuates cognitive impairment and hippocampus senescence in d-galactose-induced aging mouse model via upregulating the expression of SIRT1. Brain Res Bull 137:311–318

    CAS  PubMed  Google Scholar 

  20. Li X-m, Zhou M-t, Wang X-m, Ji M-h, Zhou Z-q, Yang J-j (2014) Resveratrol pretreatment attenuates the isoflurane-induced cognitive impairment through its anti-inflammation and-apoptosis actions in aged mice. J Mol Neurosci 52(2):286–293

    CAS  PubMed  Google Scholar 

  21. Yellamma K (2014) Silk protein, sericin as a cognitive enhancer in Alzheimer’s disease. J Alzheimers Dis Parkinsonism 4(163):21610460.1000163. https://doi.org/10.4172/2161-0460.1000163

    Article  Google Scholar 

  22. Mohammadi AB, Torbati M, Farajdokht F, Sadigh-Eteghad S, Fazljou SMB, Vatandoust SM et al (2019) Sericin alleviates restraint stress induced depressive-and anxiety-like behaviors via modulation of oxidative stress, neuroinflammation and apoptosis in the prefrontal cortex and hippocampus. Brain Res 1715:47–56

    Google Scholar 

  23. Dong X, Zhao S-X, Yin X-L, Wang H-Y, Wei Z-G, Zhang Y-Q (2020) Silk sericin has significantly hypoglycaemic effect in type 2 diabetic mice via anti-oxidation and anti-inflammation. Int J Biol Macromol 150:1061–1071

    CAS  PubMed  Google Scholar 

  24. Kumar JP, Alam S, Jain AK, Ansari KM, Mandal BB (2018) Protective activity of silk sericin against UV radiation-induced skin damage by downregulating oxidative stress. ACS Appl Bio Mater 1(6):2120–2132

    CAS  PubMed  Google Scholar 

  25. Peera K, Yellamma K (2015) Sericin as a chlinergic modulator in alzaeimer’s disease induced rat. Int J Pharm Pharm Sci 7:108–112

    CAS  Google Scholar 

  26. Chen Z-H, Yang S-H, Chen C (2011) Effects of sericin on nitric oxide content and nitric oxide synthase expression in hippocampus of diabetes mellitus rats. Chin J Gerontol 9:034

    Google Scholar 

  27. Chen Z, He Y, Song C, Dong Z, Su Z, Xue J (2012) Sericin can reduce hippocampal neuronal apoptosis by activating the Akt signal transduction pathway in a rat model of diabetes mellitus. Neural Regen Res 7(3):197

    PubMed  PubMed Central  Google Scholar 

  28. Kitisin T, Maneekan P, Luplertlop N (2013) In-vitro characterization of silk sericin as an anti-aging agent. J Agric Sci 5(3):54

    Google Scholar 

  29. Haider S, Liaquat L, Shahzad S, Sadir S, Madiha S, Batool Z et al (2015) A high dose of short term exogenous D-galactose administration in young male rats produces symptoms simulating the natural aging process. Life Sci 124:110–119

    CAS  PubMed  Google Scholar 

  30. Nam SM, Choi JH, Yoo DY, Kim W, Jung HY, Kim JW et al (2013) Valeriana officinalis extract and its main component, valerenic acid, ameliorate D-galactose-induced reductions in memory, cell proliferation, and neuroblast differentiation by reducing corticosterone levels and lipid peroxidation. Exp Gerontol 48(11):1369–1377

    CAS  PubMed  Google Scholar 

  31. Bannerman DM, Sprengel R, Sanderson DJ, McHugh SB, Rawlins JNP, Monyer H et al (2014) Hippocampal synaptic plasticity, spatial memory and anxiety. Nat Rev Neurosci 15(3):181–192

    CAS  PubMed  Google Scholar 

  32. Felix-Ortiz AC, Tye KM (2014) Amygdala inputs to the ventral hippocampus bidirectionally modulate social behavior. J Neurosci 34(2):586–595

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Giovannini MG, Lana D, Pepeu G (2015) The integrated role of ACh, ERK and mTOR in the mechanisms of hippocampal inhibitory avoidance memory. Neurobiol Learn Mem 119:18–33

    CAS  PubMed  Google Scholar 

  34. Driscoll I, Hamilton DA, Petropoulos H, Yeo RA, Brooks WM, Baumgartner RN et al (2003) The aging hippocampus: cognitive, biochemical and structural findings. Cereb Cortex 13(12):1344–1351

    PubMed  Google Scholar 

  35. De Brabander J, Kramers R, Uylings H (1998) Layer-specific dendritic regression of pyramidal cells with ageing in the human prefrontal cortex. Eur J Neurosci 10:1261–1269

    PubMed  Google Scholar 

  36. Markham JA, Juraska JM (2002) Aging and sex influence the anatomy of the rat anterior cingulate cortex. Neurobiol Aging 23(4):579–588

    PubMed  Google Scholar 

  37. Dickstein DL, Kabaso D, Rocher AB, Luebke JI, Wearne SL, Hof PR (2007) Changes in the structural complexity of the aged brain. Aging Cell 6(3):275–284

    CAS  PubMed  Google Scholar 

  38. Buckner RL (2004) Memory and executive function in aging and AD: multiple factors that cause decline and reserve factors that compensate. Neuron 44(1):195–208

    CAS  PubMed  Google Scholar 

  39. Smith GD, Gao N, Lugo JN (2016) Kv4. 2 knockout mice display learning and memory deficits in the Lashley maze. F1000Res 5:2456

    PubMed  Google Scholar 

  40. Bressler A, Blizard D, Andrews A (2010) Low-stress route learning using the Lashley III maze in mice. JoVE 39:e1786

    Google Scholar 

  41. Shoji H, Mizoguchi K (2011) Aging-related changes in the effects of social isolation on social behavior in rats. Physiol Behav 102(1):58–62

    CAS  PubMed  Google Scholar 

  42. Bishop NA, Lu T, Yankner BA (2010) Neural mechanisms of ageing and cognitive decline. Nature 464(7288):529–535

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Pavlopoulos E, Jones S, Kosmidis S, Close M, Kim C, Kovalerchik O et al (2013) Molecular mechanism for age-related memory loss: the histone-binding protein RbAp48. Sci Transl Med 5(200):200ra115-200ra115

    PubMed  PubMed Central  Google Scholar 

  44. Wang T, Di G, Yang L, Dun Y, Sun Z, Wan J et al (2015) Saponins from P anax japonicus attenuate D-galactose-induced cognitive impairment through its anti-oxidative and anti-apoptotic effects in rats. J Pharm Pharmacol 67(9):1284–1296

    CAS  PubMed  Google Scholar 

  45. Logan S, Royce GH, Owen D, Farley J, Ranjo-Bishop M, Sonntag WE et al (2019) Accelerated decline in cognition in a mouse model of increased oxidative stress. Geroscience 41(5):591–607

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Huang T-T, Leu D, Zou Y (2015) Oxidative stress and redox regulation on hippocampal-dependent cognitive functions. Arch Biochem Biophys 576:2–7

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Ali SS, Xiong C, Lucero J, Behrens MM, Dugan LL, Quick KL (2006) Gender differences in free radical homeostasis during aging: shorter-lived female C57BL6 mice have increased oxidative stress. Aging Cell 5(6):565–574

    CAS  PubMed  Google Scholar 

  48. Hu D, Serrano F, Oury TD, Klann E (2006) Aging-dependent alterations in synaptic plasticity and memory in mice that overexpress extracellular superoxide dismutase. J Neurosci 26(15):3933–3941

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Raghavendra V, Kulkarni SK (2001) Possible antioxidant mechanism in melatonin reversal of aging and chronic ethanol-induced amnesia in plus-maze and passive avoidance memory tasks. Free Radic Biol Med 30(6):595–602

    CAS  PubMed  Google Scholar 

  50. Al-Amin MM, Hasan SN, Alam T, Hasan AT, Hossain I, Didar RR et al (2014) Tadalafil enhances working memory, and reduces hippocampal oxidative stress in both young and aged mice. Eur J Pharmacol 745:84–90

    CAS  PubMed  Google Scholar 

  51. Zhao H, Li Q, Li Y (2011) Long-term ginsenoside administration prevents memory loss in aged female C57BL/6J mice by modulating the redox status and up-regulating the plasticity-related proteins in hippocampus. Neuroscience 183:189–202

    CAS  PubMed  Google Scholar 

  52. Deori M, Devi D, Kumari S, Hazarika A, Kalita H, Sarma R et al (2016) Antioxidant effect of sericin in brain and peripheral tissues of oxidative stress induced hypercholesterolemic rats. Front Pharmacol 7:319

    PubMed  PubMed Central  Google Scholar 

  53. Devi R, Deori M, Devi D (2011) Evaluation of antioxidant activities of silk protein sericin secreted by silkworm Antheraea assamensis (Lepidoptera: Saturniidae). J Pharm Res 4(12):4688–4691

    Google Scholar 

  54. Kim TK, Park D, Yeon S, Lee SH, Choi YJ, Bae D-K et al (2011) Tyrosine-fortified silk amino acids improve physical function of Parkinson’s disease rats. Food Sci Biotechnol 20(1):79–84

    CAS  Google Scholar 

  55. Ryan SM, Nolan YM (2016) Neuroinflammation negatively affects adult hippocampal neurogenesis and cognition: can exercise compensate? Neurosci Biobehav Rev 61:121–131

    CAS  PubMed  Google Scholar 

  56. Sparkman NL, Johnson RW (2008) Neuroinflammation associated with aging sensitizes the brain to the effects of infection or stress. NeuroImmunoModulation 15(4–6):323–330

    CAS  PubMed  Google Scholar 

  57. Ye S-M, Johnson RW (2001) An age-related decline in interleukin-10 may contribute to the increased expression of interleukin-6 in brain of aged mice. NeuroImmunoModulation 9(4):183–192

    CAS  PubMed  Google Scholar 

  58. Frank MG, Barrientos RM, Biedenkapp JC, Rudy JW, Watkins LR, Maier SF (2006) mRNA up-regulation of MHC II and pivotal pro-inflammatory genes in normal brain aging. Neurobiol Aging 27(5):717–722

    CAS  PubMed  Google Scholar 

  59. Aramwit P, Towiwat P, Srichana T (2013) Anti-inflammatory potential of silk sericin. Nat Prod Commun 8(4):1934578X1300800424

    Google Scholar 

  60. Aramwit P, Kanokpanont S, De-Eknamkul W, Srichana T (2009) Monitoring of inflammatory mediators induced by silk sericin. J Biosci Bioeng 107(5):556–561

    CAS  PubMed  Google Scholar 

  61. Li Q, Yan Y, Qiao Z-y, Chen Z (2012) Changes of NO content in hippocampus of diabetes mellitus rats and protective effects of sericin. J Chengde Med Coll 3(004).

  62. Solleiro-Villavicencio H, Rivas-Arancibia S (2018) Effect of chronic oxidative stress on neuroinflammatory response mediated by CD4(+)T cells in neurodegenerative diseases. Front Cell Neurosci 12:114

    PubMed  PubMed Central  Google Scholar 

  63. Pollack M, Phaneuf S, Dirks A, Leeuwenburgh C (2002) The role of apoptosis in the normal aging brain, skeletal muscle, and heart. Ann N Y Acad Sci 959(1):93–107

    CAS  PubMed  Google Scholar 

  64. Sgonc R, Wick G (1994) Methods for the detection of apoptosis. Int Arch Allergy Immunol 105(4):327–332

    CAS  PubMed  Google Scholar 

Download references

Acknowledgement

The authors would like to thanks Dr. Farzin Kamari for the English language editing of the manuscript.

Funding

This research was supported by a grant from Neurosciences Research Center, Tabriz University of Medical Sciences (Grant Number: 64604), awarded to SS-E.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Saeed Sadigh-Eteghad.

Ethics declarations

Conflict of interest

All authors declare that they have no conflict of interest.

Ethical approval

All experiments in this study were approved by the Ethics Committee at Tabriz University of Medical Sciences (Approval No. IR.TBZMED.VCR.REC.1398.410) and followed the guidelines of the National Institute of Health (NIH; Publication No. 85–23, revised1985).

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Seyedaghamiri, F., Farajdokht, F., Vatandoust, S.M. et al. Sericin modulates learning and memory behaviors by tuning of antioxidant, inflammatory, and apoptotic markers in the hippocampus of aged mice. Mol Biol Rep 48, 1371–1382 (2021). https://doi.org/10.1007/s11033-021-06195-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-021-06195-2

Keywords

Navigation