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Dendropanax morbifera Léveille extract ameliorates d-galactose-induced memory deficits by decreasing inflammatory responses in the hippocampus

Abstract

In the present study, we examined the effects of Dendropanax morbifera Léveille leaf extract (DML) on dgalactose-induced morphological changes in microglia and cytokines, including pro-inflammatory cytokines (interleukin [IL]-1β, IL-6, and tumor necrosis factor [TNF]-α) and anti-inflammatory cytokines (IL-4 and IL-10) in the hippocampus. Administration of DML to d-galactose-treated mice significantly improved d-galactose-induced reduction in escape latency, swimming speed, and spatial preference for the target quadrant. In addition, administration of DML to d-galactose-treated mice significantly ameliorated the microglial activation and increases of IL-1β, IL-6, and TNF-α levels in the hippocampus. Administration of d-galactose significantly reduced IL-4 levels in the hippocampus, while administration of DML to d-galactose-treated mice significantly increased IL-4 level. However, we did not observe any significant changes in IL-10 levels in hippocampal homogenates. These results suggest that DML reduces d-galactose-induced mouse senescence by reducing pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α, as well as increasing anti-inflammatory cytokine IL-4.

References

  1. 1.

    Golden TR, Hinerfeld DA, Melov S. Oxidative stress and aging: beyond correlation. Aging Cell 2002; 1(2): 117–123.

    CAS  Article  Google Scholar 

  2. 2.

    Joseph JA, Shukitt-Hale B, Casadesus G. Reversing the deleterious effects of aging on neuronal communication and behavior: beneficial properties of fruit polyphenolic compounds. Am J Clin Nutr 2005; 81(1 Suppl): 313S–316S.

    CAS  Article  Google Scholar 

  3. 3.

    Kigerl KA, Gensel JC, Ankeny DP, Alexander JK, Donnelly DJ, Popovich PG. Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord. J Neurosci 2009; 29(43): 13435–13444.

    CAS  Article  Google Scholar 

  4. 4.

    Kuzumaki N, Ikegami D, Imai S, Narita M, Tamura R, Yajima M, Suzuki A, Miyashita K, Niikura K, Takeshima H, Ando T, Ushijima T, Suzuki T, Narita M. Enhanced IL-1beta production in response to the activation of hippocampal glial cells impairs neurogenesis in aged mice. Synapse 2010; 64(9): 721–728.

    CAS  PubMed  Google Scholar 

  5. 5.

    Ershler WB, Keller ET. Age-associated increased interleukin-6 gene expression, late-life diseases, and frailty. Annu Rev Med 2000; 51: 245–270.

    CAS  Article  Google Scholar 

  6. 6.

    Bruunsgaard H, Andersen-Ranberg K, Jeune B, Pedersen AN, Skinhøj P, Pedersen BK. A high plasma concentration of TNF-alpha is associated with dementia in centenarians. J Gerontol A Biol Sci Med Sci 1999; 54(7): M357–M364.

    CAS  Article  Google Scholar 

  7. 7.

    Norden DM, Godbout JP. Review: microglia of the aged brain: primed to be activated and resistant to regulation. Neuropathol Appl Neurobiol 2013; 39(1): 19–34.

    CAS  Article  Google Scholar 

  8. 8.

    Lu J, Zheng YL, Wu DM, Luo L, Sun DX, Shan Q. Ursolic acid ameliorates cognition deficits and attenuates oxidative damage in the brain of senescent mice induced by d-galactose. Biochem Pharmacol 2007; 74(7): 1078–1090.

    CAS  Article  Google Scholar 

  9. 9.

    Kim W, Kim DW, Yoo DY, Jung HY, Nam SM, Kim JW, Hong SM, Kim DW, Choi JH, Moon SM, Yoon YS, Hwang IK. Dendropanax morbifera Léveille extract facilitates cadmium excretion and prevents oxidative damage in the hippocampus by increasing antioxidant levels in cadmium-exposed rats. BMC Complement Altern Med 2014; 14: 428.

    Article  Google Scholar 

  10. 10.

    Kim W, Kim DW, Yoo DY, Jung HY, Kim JW, Kim DW, Choi JH, Moon SM, Yoon YS, Hwang IK. Antioxidant effects of Dendropanax morbifera Léveille extract in the hippocampus of mercury-exposed rats. BMC Complement Altern Med 2015; 15: 247.

    Article  Google Scholar 

  11. 11.

    Kim ES, Lee JS, Akram M, Kim KA, Shin YJ, Yu JH, Bae ON. Protective activity of Dendropanax morbifera against cisplatininduced acute kidney injury. Kidney Blood Press Res 2015; 40(1): 1–12.

    CAS  Article  Google Scholar 

  12. 12.

    Akram M, Kim KA, Kim ES, Syed AS, Kim CY, Lee JS, Bae ON. Potent Anti-inflammatory and Analgesic Actions of the Chloroform Extract of Dendropanax morbifera Mediated by the Nrf2/HO-1 Pathway. Biol Pharm Bull 2016; 39(5): 728–736.

    CAS  Article  Google Scholar 

  13. 13.

    Jung HY, Chung TH, Hwang IK. Dendropanax morbifera Léveille extract ameliorates memory impairments and inflammatory responses in the hippocampus of streptozotocin-induced type 1 diabetic rats. Mol Cell Toxicol 2016; 12(4): 429–436.

    CAS  Article  Google Scholar 

  14. 14.

    Yoo DY, Kim W, Lee CH, Shin BN, Nam SM, Choi JH, Won MH, Yoon YS, Hwang IK. Melatonin improves D-galactose-induced aging effects on behavior, neurogenesis, and lipid peroxidation in the mouse dentate gyrus via increasing pCREB expression. J Pineal Res 2012; 52(1): 21–28.

    CAS  Article  Google Scholar 

  15. 15.

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

    CAS  Article  Google Scholar 

  16. 16.

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

    Article  Google Scholar 

  17. 17.

    Morris RGM. Spatial localization does not require the presence of local cues. Learn Motiv 1981; 12(2): 239–260.

    Article  Google Scholar 

  18. 18.

    Yu Y, Bai F, Wang W, Liu Y, Yuan Q, Qu S, Zhang T, Tian G, Li S, Li D, Ren G. Fibroblast growth factor 21 protects mouse brain against D-galactose induced aging via suppression of oxidative stress response and advanced glycation end products formation. Pharmacol Biochem Behav 2015; 133: 122–131.

    CAS  Article  Google Scholar 

  19. 19.

    Kim W, Yim HS, Yoo DY, Jung HY, Kim JW, Choi JH, Yoon YS, Kim DW, Hwang IK. Dendropanax morbifera Léveille extract ameliorates cadmium-induced impairment in memory and hippocampal neurogenesis in rats. BMC Complement Altern Med 2016; 16(1): 452.

    Article  Google Scholar 

  20. 20.

    Kim JM, Park SK, Guo TJ, Kang JY, Ha JS, Lee du S, Lee U, Heo HJ. Anti-amnesic effect of Dendropanax morbifera via JNK signaling pathway on cognitive dysfunction in high-fat dietinduced diabetic mice. Behav Brain Res 2016; 312: 39–54.

    CAS  Article  Google Scholar 

  21. 21.

    Kohman RA, Bhattacharya TK, Wojcik E, Rhodes JS. Exercise reduces activation of microglia isolated from hippocampus and brain of aged mice. J Neuroinflammation 2013; 10: 114.

    Article  Google Scholar 

  22. 22.

    Gordon S. Alternative activation of macrophages. Nat Rev Immunol 2003; 3(1): 23–35.

    CAS  Article  Google Scholar 

  23. 23.

    Li Y, Liu L, Barger SW, Griffin WS. Interleukin-1 mediates pathological effects of microglia on tau phosphorylation and on synaptophysin synthesis in cortical neurons through a p38-MAPK pathway. J Neurosci 2003; 23(5): 1605–1611.

    CAS  Article  Google Scholar 

  24. 24.

    Gemma C, Bachstetter AD, Bickford PC. Neuron-Microglia Dialogue and Hippocampal Neurogenesis in the Aged Brain. Aging Dis 2010; 1(3): 232–244.

    PubMed  PubMed Central  Google Scholar 

  25. 25.

    Ye SM, Johnson RW. Regulation of interleukin-6 gene expression in brain of aged mice by nuclear factor kappaB. J Neuroimmunol 2001; 117(1–2): 87–96.

    CAS  Article  Google Scholar 

  26. 26.

    Quintanilla RA, Orellana DI, González-Billault C, Maccioni RB. Interleukin-6 induces Alzheimer-type phosphorylation of tau protein by deregulating the cdk5/p35 pathway. Exp Cell Res 2004; 295(1): 245–257.

    CAS  Article  Google Scholar 

  27. 27.

    Bellinger FP, Madamba S, Siggins GR. Interleukin 1 beta inhibits synaptic strength and long-term potentiation in the rat CA1 hippocampus. Brain Res 1993; 628(1–2): 227–234.

    CAS  Article  Google Scholar 

  28. 28.

    Griffin R, Nally R, Nolan Y, McCartney Y, Linden J, Lynch MA. The age-related attenuation in long-term potentiation is associated with microglial activation. J Neurochem 2006; 99(4): 1263–1272.

    CAS  Article  Google Scholar 

  29. 29.

    Maher FO, Nolan Y, Lynch MA. Downregulation of IL-4-induced signalling in hippocampus contributes to deficits in LTP in the aged rat. Neurobiol Aging 2005; 26(5): 717–728.

    CAS  Article  Google Scholar 

  30. 30.

    Clarke RM, Lyons A, O’Connell F, Deighan BF, Barry CE, Anyakoha NG, Nicolaou A, Lynch MA. A pivotal role for interleukin-4 in atorvastatin-associated neuroprotection in rat brain. J Biol Chem 2008; 283(4): 1808–1817.

    CAS  Article  Google Scholar 

  31. 31.

    Lyons A, Griffin RJ, Costelloe CE, Clarke RM, Lynch MA. IL-4 attenuates the neuroinflammation induced by amyloid-beta in vivo and in vitro. J Neurochem 2007; 101(3): 771–781.

    CAS  Article  Google Scholar 

  32. 32.

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

    CAS  Article  Google Scholar 

  33. 33.

    Perez SD, Du K, Rendeiro C, Wang L, Wu Q, Rubakhin SS, Vazhappilly R, Baxter JH, Sweedler JV, Rhodes JS. A unique combination of micronutrients rejuvenates cognitive performance in aged mice. Behav Brain Res 2017; 320: 97–112.

    CAS  Article  Google Scholar 

  34. 34.

    Henry CJ, Huang Y, Wynne AM, Godbout JP. Peripheral lipopolysaccharide (LPS) challenge promotes microglial hyperactivity in aged mice that is associated with exaggerated induction of both pro-inflammatory IL-1beta and anti-inflammatory IL-10 cytokines. Brain Behav Immun 2009; 23(3): 309–317.

    CAS  Article  Google Scholar 

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Correspondence to Professor Jung Hoon Choi DVM, PhD.

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This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://doi.org/creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Lee, K.Y., Jung, H.Y., Yoo, D.Y. et al. Dendropanax morbifera Léveille extract ameliorates d-galactose-induced memory deficits by decreasing inflammatory responses in the hippocampus. Lab Anim Res 33, 283–290 (2017). https://doi.org/10.5625/lar.2017.33.4.283

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Keywords

  • Dendropanax morbifera extract
  • d-galactose
  • hippocampus
  • inflammation
  • memory
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