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Reactive Gliosis Contributes to Nrf2-Dependent Neuroprotection by Pretreatment with Dimethyl Fumarate or Korean Red Ginseng Against Hypoxic-Ischemia: Focus on Hippocampal Injury

  • Lei Liu
  • Mary K. Vollmer
  • Marie G. Kelly
  • Victoria M. Fernandez
  • Tyler G. Fernandez
  • Hocheol Kim
  • Sylvain DoréEmail author
Article

Abstract

Recently, dimethyl fumarate (DMF) and Korean red ginseng (ginseng), based on their purported antioxidative and anti-inflammatory properties, have exhibited protective potential in various neurological conditions. Their effects on cerebral ischemia and underlying mechanisms remain inconclusive; however, increasing evidence indicates the involvement of the transcriptional factor Nrf2. This study evaluated the preventive effects of DMF and ginseng on hippocampal neuronal damage following hypoxia-ischemia (HI) and assessed the contributions of reactive gliosis and the Nrf2 pathway. Adult wild type (WT) and Nrf2−/− mice were pretreated with DMF or ginseng for 7 days prior to HI. At 24 h after HI, DMF or ginseng significantly reduced infarct volume (52.5 ± 12.3% and 47.8 ± 10.7%), brain edema (61.5 ± 17.4% and 39.3 ± 12.8%), and hippocampal CA1 neuronal degeneration, and induced expressions of Nrf2 target proteins in WT, but not Nrf2−/−, mice. Such hippocampal neuroprotective benefits were also observed at 6 h and 7 days after HI. The dynamic attenuation of reactive gliosis in microglia and astrocytes correlated well with this sustained neuroprotection in an Nrf2-dependent manner. In both early and late stages of HI, astrocytic dysfunctions in extracellular glutamate clearance and water transport, as indicated by glutamine synthetase and aquaporin 4, were also attenuated after HI in WT, but not Nrf2−/−, mice treated with DMF or ginseng. Together, DMF and ginseng confer robust and prolonged Nrf2-dependent neuroprotection against ischemic hippocampal damage. The salutary Nrf2-dependent attenuation of reactive gliosis may contribute to this neuroprotection, offering new insight into the cellular basis of an Nrf2-targeting strategy for stroke prevention or treatment.

Keywords

Astrocyte Astrogliosis Microglia Oxidative stress Stroke Transcriptional factor 

Notes

Authors’ Contributions

L.L. and S.D. designed the project and experiments. L.L., M.K.V., M.G.K., V.F., and T.G.F. performed the experiments, the data collection, and the analysis. H.K. provided the Korean red ginseng and participated in the discussion. L.L. and S.D. wrote the manuscript. All authors discussed the manuscript and reviewed the final version.

Funding Information

This study was supported in part by the National Institutes of Health (R01AT007429 and R01NS046400, S.D.) and the American Heart Association (16POST31220032, L.L.).

Compliance with Ethical Standards

All procedures were approved by the University of Florida Institutional Animal Care and Use Committee. We conducted the experiments according to the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals.

Conflict of Interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Mozaffarian D, Benjamin EJ, Go AS et al (2016) Heart Disease and Stroke Statistics-2016 update: a report from the American Heart Association. Circulation 133:e38–e360.  https://doi.org/10.1161/CIR.0000000000000350 Google Scholar
  2. 2.
    Bosetti F, Koenig JI, Ayata C, Back SA, Becker K, Broderick JP, Carmichael ST, Cho S et al (2017) Translational stroke research: vision and opportunities. Stroke 48:2632–2637.  https://doi.org/10.1161/STROKEAHA.117.017112 CrossRefGoogle Scholar
  3. 3.
    Burda JE, Sofroniew MV (2014) Reactive gliosis and the multicellular response to CNS damage and disease. Neuron 81:229–248.  https://doi.org/10.1016/j.neuron.2013.12.034 CrossRefGoogle Scholar
  4. 4.
    Dirnagl U, Becker K, Meisel A (2009) Preconditioning and tolerance against cerebral ischaemia: from experimental strategies to clinical use. Lancet Neurol 8:398–412.  https://doi.org/10.1016/S1474-4422(09)70054-7 CrossRefGoogle Scholar
  5. 5.
    Palace J (2008) Neuroprotection and repair. J Neurol Sci 265:21–25.  https://doi.org/10.1016/j.jns.2007.08.039 CrossRefGoogle Scholar
  6. 6.
    Lakhan SE, Kirchgessner A, Hofer M (2009) Inflammatory mechanisms in ischemic stroke: therapeutic approaches. J Transl Med 7:97.  https://doi.org/10.1186/1479-5876-7-97 CrossRefGoogle Scholar
  7. 7.
    Calkins MJ, Johnson DA, Townsend JA, Vargas MR, Dowell JA, Williamson TP, Kraft AD, Lee JM et al (2009) The Nrf2/ARE pathway as a potential therapeutic target in neurodegenerative disease. Antioxid Redox Signal 11:497–508.  https://doi.org/10.1089/ars.2008.2242 CrossRefGoogle Scholar
  8. 8.
    Kumar H, Kim I-S, More SV, Kim BW, Choi DK (2014) Natural product-derived pharmacological modulators of Nrf2/ARE pathway for chronic diseases. Nat Prod Rep 31:109–139.  https://doi.org/10.1039/c3np70065h CrossRefGoogle Scholar
  9. 9.
    Leonardo CC, Doré S (2011) Dietary flavonoids are neuroprotective through Nrf2-coordinated induction of endogenous cytoprotective proteins. Nutr Neurosci 14:226–236.  https://doi.org/10.1179/1476830511Y.0000000013 CrossRefGoogle Scholar
  10. 10.
    Ma Q (2013) Role of nrf2 in oxidative stress and toxicity. Annu Rev Pharmacol Toxicol 53:401–426.  https://doi.org/10.1146/annurev-pharmtox-011112-140320 CrossRefGoogle Scholar
  11. 11.
    Tonelli C, Chio IIC, Tuveson DA (2018) Transcriptional regulation by nrf2. Antioxid Redox Signal 29:1727–1745.  https://doi.org/10.1089/ars.2017.7342 CrossRefGoogle Scholar
  12. 12.
    Wang B, Cao W, Biswal S, Doré S (2011) Carbon monoxide-activated Nrf2 pathway leads to protection against permanent focal cerebral ischemia. Stroke 42:2605–2610.  https://doi.org/10.1161/STROKEAHA.110.607101 CrossRefGoogle Scholar
  13. 13.
    Sofroniew MV (2015) Astrocyte barriers to neurotoxic inflammation. Nat Rev Neurosci 16:249–263.  https://doi.org/10.1038/nrn3898 CrossRefGoogle Scholar
  14. 14.
    Pekny M, Pekna M (2016) Reactive gliosis in the pathogenesis of CNS diseases. Biochim Biophys Acta 1862:483–491.  https://doi.org/10.1016/j.bbadis.2015.11.014 CrossRefGoogle Scholar
  15. 15.
    Gao Z, Zhu Q, Zhang Y, Zhao Y, Cai L, Shields CB, Cai J (2013) Reciprocal modulation between microglia and astrocyte in reactive gliosis following the CNS injury. Mol Neurobiol 48:690–701.  https://doi.org/10.1007/s12035-013-8460-4 CrossRefGoogle Scholar
  16. 16.
    Sims NR, Yew WP (2017) Reactive astrogliosis in stroke: contributions of astrocytes to recovery of neurological function. Neurochem Int 107:88–103.  https://doi.org/10.1016/j.neuint.2016.12.016 CrossRefGoogle Scholar
  17. 17.
    Brennan MS, Matos MF, Li B, Hronowski X, Gao B, Juhasz P, Rhodes KJ, Scannevin RH (2015) Dimethyl fumarate and monoethyl fumarate exhibit differential effects on KEAP1, NRF2 activation, and glutathione depletion in vitro. PLoS One 10:e0120254.  https://doi.org/10.1371/journal.pone.0120254 CrossRefGoogle Scholar
  18. 18.
    Brennan MS, Patel H, Allaire N, Thai A, Cullen P, Ryan S, Lukashev M, Bista P et al (2016) Pharmacodynamics of dimethyl fumarate are tissue specific and involve NRF2-dependent and -independent mechanisms. Antioxid Redox Signal 24:1058–1071.  https://doi.org/10.1089/ars.2015.6622 CrossRefGoogle Scholar
  19. 19.
    Lastres-Becker I, García-Yagüe AJ, Scannevin RH, Casarejos MJ, Kügler S, Rábano A, Cuadrado A (2016) Repurposing the NRF2 activator dimethyl fumarate as therapy against synucleinopathy in parkinson’s disease. Antioxid Redox Signal 25:61–77.  https://doi.org/10.1089/ars.2015.6549 CrossRefGoogle Scholar
  20. 20.
    Rastogi V, Santiago-Moreno J, Doré S (2014) Ginseng: a promising neuroprotective strategy in stroke. Front Cell Neurosci 8:457.  https://doi.org/10.3389/fncel.2014.00457 Google Scholar
  21. 21.
    Zhao X, Sun G, Zhang J, Ting SM, Gonzales N, Aronowski J (2015) Dimethyl fumarate protects brain from damage produced by intracerebral hemorrhage by mechanism involving nrf2. Stroke 46:1923–1928.  https://doi.org/10.1161/STROKEAHA.115.009398 CrossRefGoogle Scholar
  22. 22.
    Sheremata W, Brown AD, Rammohan KW (2015) Dimethyl fumarate for treating relapsing multiple sclerosis. Expert Opin Drug Saf 14:161–170.  https://doi.org/10.1517/14740338.2015.977251 CrossRefGoogle Scholar
  23. 23.
    Liu L, Vollmer MK, Fernandez VM, Dweik Y, Kim H, Doré S (2018) Korean red ginseng pretreatment protects against long-term sensorimotor deficits after ischemic stroke likely through Nrf2. Front Cell Neurosci 12:74.  https://doi.org/10.3389/fncel.2018.00074 CrossRefGoogle Scholar
  24. 24.
    Dai Y-L, Qiao M-D, Yu P, Zheng F, Yue H, Liu SY (2017) Comparing eight types of ginsenosides in ginseng of different plant ages and regions using RRLC-Q-TOF MS/MS. J Ginseng Res.  https://doi.org/10.1016/j.jgr.2017.11.001
  25. 25.
    Li TSC (1995) Asian and American ginseng: a review. Horttechnology 5:27–34CrossRefGoogle Scholar
  26. 26.
    Lee SM, Bae B-S, Park H-W, Ahn NG, Cho BG, Cho YL, Kwak YS (2015) Characterization of Korean red ginseng (Panax ginseng Meyer): history, preparation method, and chemical composition. J Ginseng Res 39:384–391.  https://doi.org/10.1016/j.jgr.2015.04.009 CrossRefGoogle Scholar
  27. 27.
    Kim YT, Yi Y-J, Kim M-Y, Bu Y, Jin ZH, Choi H, Doré S, Kim H (2008) Neuroprotection and enhancement of spatial memory by herbal mixture HT008-1 in rat global brain ischemia model. Am J Chin Med 36:287–299.  https://doi.org/10.1142/S0192415X08005771 CrossRefGoogle Scholar
  28. 28.
    Dirnagl U, Simon RP, Hallenbeck JM (2003) Ischemic tolerance and endogenous neuroprotection. Trends Neurosci 26:248–254.  https://doi.org/10.1016/S0166-2236(03)00071-7 CrossRefGoogle Scholar
  29. 29.
    Fan Y-Y, Hu W-W, Nan F, Chen Z (2017) Postconditioning-induced neuroprotection, mechanisms and applications in cerebral ischemia. Neurochem Int 107:43–56.  https://doi.org/10.1016/j.neuint.2017.01.006 CrossRefGoogle Scholar
  30. 30.
    Hausenloy DJ, Yellon DM (2016) Ischaemic conditioning and reperfusion injury. Nat Rev Cardiol 13:193–209.  https://doi.org/10.1038/nrcardio.2016.5 CrossRefGoogle Scholar
  31. 31.
    Li S, Hafeez A, Noorulla F, Geng X, Shao G, Ren C, Lu G, Zhao H et al (2017) Preconditioning in neuroprotection: from hypoxia to ischemia. Prog Neurobiol 157:79–91.  https://doi.org/10.1016/j.pneurobio.2017.01.001 CrossRefGoogle Scholar
  32. 32.
    Gidday JM (2006) Cerebral preconditioning and ischaemic tolerance. Nat Rev Neurosci 7:437–448.  https://doi.org/10.1038/nrn1927 CrossRefGoogle Scholar
  33. 33.
    Kuzuya T, Hoshida S, Yamashita N, Fuji H, Oe H, Hori M, Kamada T, Tada M (1993) Delayed effects of sublethal ischemia on the acquisition of tolerance to ischemia. Circ Res 72:1293–1299CrossRefGoogle Scholar
  34. 34.
    Koh HS, Chang CY, Jeon S-B, Yoon HJ, Ahn YH, Kim HS, Kim IH, Jeon SH et al (2015) The HIF-1/glial TIM-3 axis controls inflammation-associated brain damage under hypoxia. Nat Commun 6:6340.  https://doi.org/10.1038/ncomms7340 CrossRefGoogle Scholar
  35. 35.
    Huang J, Li Y, Tang Y, Tang G, Yang GY, Wang Y (2013) CXCR4 antagonist AMD3100 protects blood-brain barrier integrity and reduces inflammatory response after focal ischemia in mice. Stroke 44:190–197.  https://doi.org/10.1161/STROKEAHA.112.670299 CrossRefGoogle Scholar
  36. 36.
    Munakata M, Shirakawa H, Nagayasu K, Miyanohara J, Miyake T, Nakagawa T, Katsuki H, Kaneko S (2013) Transient receptor potential canonical 3 inhibitor Pyr3 improves outcomes and attenuates astrogliosis after intracerebral hemorrhage in mice. Stroke 44:1981–1987.  https://doi.org/10.1161/STROKEAHA.113.679332 CrossRefGoogle Scholar
  37. 37.
    Glushakov AV, Robbins SW, Bracy CL, Narumiya S, Doré S (2013) Prostaglandin F2α FP receptor antagonist improves outcomes after experimental traumatic brain injury. J Neuroinflammation 10:132.  https://doi.org/10.1186/1742-2094-10-132 CrossRefGoogle Scholar
  38. 38.
    Bandera E, Botteri M, Minelli C, Sutton A, Abrams KR, Latronico N (2006) Cerebral blood flow threshold of ischemic penumbra and infarct core in acute ischemic stroke: a systematic review. Stroke 37:1334–1339.  https://doi.org/10.1161/01.STR.0000217418.29609.22 CrossRefGoogle Scholar
  39. 39.
    Moskowitz MA, Lo EH, Iadecola C (2010) The science of stroke: mechanisms in search of treatments. Neuron 67:181–198.  https://doi.org/10.1016/j.neuron.2010.07.002 CrossRefGoogle Scholar
  40. 40.
    Ban JY, Kang SW, Lee JS et al (2012) Korean red ginseng protects against neuronal damage induced by transient focal ischemia in rats. Exp Ther Med 3:693–698.  https://doi.org/10.3892/etm.2012.449 CrossRefGoogle Scholar
  41. 41.
    Kunze R, Urrutia A, Hoffmann A, Liu H, Helluy X, Pham M, Reischl S, Korff T et al (2015) Dimethyl fumarate attenuates cerebral edema formation by protecting the blood-brain barrier integrity. Exp Neurol 266:99–111.  https://doi.org/10.1016/j.expneurol.2015.02.022 CrossRefGoogle Scholar
  42. 42.
    Lee JS, Choi HS, Kang SW, Chung JH, Park HK, Ban JY, Kwon OY, Hong HP et al (2011) Therapeutic effect of Korean red ginseng on inflammatory cytokines in rats with focal cerebral ischemia/reperfusion injury. Am J Chin Med 39:83–94.  https://doi.org/10.1142/S0192415X1100866X CrossRefGoogle Scholar
  43. 43.
    Yao Y, Miao W, Liu Z, Han W, Shi K, Shen Y, Li H, Liu Q et al (2016) Dimethyl fumarate and monomethyl fumarate promote post-ischemic recovery in mice. Transl Stroke Res 7:535–547.  https://doi.org/10.1007/s12975-016-0496-0 CrossRefGoogle Scholar
  44. 44.
    Caso JR, Moro MA, Lorenzo P, Lizasoain I, Leza JC (2007) Involvement of IL-1beta in acute stress-induced worsening of cerebral ischaemia in rats. Eur Neuropsychopharmacol 17:600–607.  https://doi.org/10.1016/j.euroneuro.2007.02.009 CrossRefGoogle Scholar
  45. 45.
    Vargas MR, Johnson JA (2009) The Nrf2-ARE cytoprotective pathway in astrocytes. Expert Rev Mol Med 11:e17.  https://doi.org/10.1017/S1462399409001094 CrossRefGoogle Scholar
  46. 46.
    Ajami B, Bennett JL, Krieger C, Tetzlaff W, Rossi FMV (2007) Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nat Neurosci 10:1538–1543.  https://doi.org/10.1038/nn2014 CrossRefGoogle Scholar
  47. 47.
    Hambardzumyan D, Gutmann DH, Kettenmann H (2016) The role of microglia and macrophages in glioma maintenance and progression. Nat Neurosci 19:20–27.  https://doi.org/10.1038/nn.4185 CrossRefGoogle Scholar
  48. 48.
    Hickey WF, Kimura H (1988) Perivascular microglial cells of the CNS are bone marrow-derived and present antigen in vivo. Science 239:290–292CrossRefGoogle Scholar
  49. 49.
    Priller J, Flügel A, Wehner T, Boentert M, Haas CA, Prinz M, Fernández-Klett F, Prass K et al (2001) Targeting gene-modified hematopoietic cells to the central nervous system: use of green fluorescent protein uncovers microglial engraftment. Nat Med 7:1356–1361.  https://doi.org/10.1038/nm1201-1356 CrossRefGoogle Scholar
  50. 50.
    Shin JA, Choi JH, Choi Y-H, Park E-M (2011) Conserved aquaporin 4 levels associated with reduction of brain edema are mediated by estrogen in the ischemic brain after experimental stroke. Biochim Biophys Acta 1812:1154–1163.  https://doi.org/10.1016/j.bbadis.2011.05.004 CrossRefGoogle Scholar
  51. 51.
    Vella J, Zammit C, Di Giovanni G et al (2015) The central role of aquaporins in the pathophysiology of ischemic stroke. Front Cell Neurosci 9:108.  https://doi.org/10.3389/fncel.2015.00108 CrossRefGoogle Scholar
  52. 52.
    Zador Z, Stiver S, Wang V, Manley GT (2009) Role of aquaporin-4 in cerebral edema and stroke. Handb Exp Pharmacol 159–170.  https://doi.org/10.1007/978-3-540-79885-9_7
  53. 53.
    Jeitner TM, Battaile K, Cooper AJL (2015) Critical evaluation of the changes in glutamine synthetase activity in models of cerebral stroke. Neurochem Res 40:2544–2556.  https://doi.org/10.1007/s11064-015-1667-1 CrossRefGoogle Scholar
  54. 54.
    Chen-Roetling J, Song W, Schipper HM, Regan CS, Regan RF (2015) Astrocyte overexpression of heme oxygenase-1 improves outcome after intracerebral hemorrhage. Stroke 46:1093–1098.  https://doi.org/10.1161/STROKEAHA.115.008686 CrossRefGoogle Scholar
  55. 55.
    Ko HM, Joo SH, Kim P, Park JH, Kim HJ, Bahn GH, Kim HY, Lee J et al (2013) Effects of Korean red ginseng extract on tissue plasminogen activator and plasminogen activator inhibitor-1 expression in cultured rat primary astrocytes. J Ginseng Res 37:401–412.  https://doi.org/10.5142/jgr.2013.37.401 CrossRefGoogle Scholar
  56. 56.
    Nagelhus EA, Ottersen OP (2013) Physiological roles of aquaporin-4 in brain. Physiol Rev 93:1543–1562.  https://doi.org/10.1152/physrev.00011.2013 CrossRefGoogle Scholar
  57. 57.
    Papadopoulos MC, Verkman AS (2013) Aquaporin water channels in the nervous system. Nat Rev Neurosci 14:265–277.  https://doi.org/10.1038/nrn3468 CrossRefGoogle Scholar
  58. 58.
    Verkman AS, Anderson MO, Papadopoulos MC (2014) Aquaporins: important but elusive drug targets. Nat Rev Drug Discov 13:259–277.  https://doi.org/10.1038/nrd4226 CrossRefGoogle Scholar
  59. 59.
    Liu L, Vollmer MK, Ahmad AS, Fernandez VM, Kim H, Doré S (2019) Pretreatment with Korean red ginseng or dimethyl fumarate attenuates reactive gliosis and confers sustained neuroprotection against cerebral hypoxic-ischemic damage by an Nrf2-dependent mechanism. Free Radic Biol Med 131:98–114.  https://doi.org/10.1016/j.freeradbiomed.2018.11.017 CrossRefGoogle Scholar
  60. 60.
    Kemmerer ZA, Ader NR, Mulroy SS, Eggler AL (2015) Comparison of human Nrf2 antibodies: A tale of two proteins. Toxicol Lett 238:83–89.  https://doi.org/10.1016/j.toxlet.2015.07.004 CrossRefGoogle Scholar
  61. 61.
    Lau A, Tian W, Whitman SA, Zhang DD (2013) The predicted molecular weight of Nrf2: it is what it is not. Antioxid Redox Signal 18:91–93.  https://doi.org/10.1089/ars.2012.4754 CrossRefGoogle Scholar

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Authors and Affiliations

  1. 1.Department of Anesthesiology, Center for Translational Research in Neurodegenerative Disease and McKnight Brain InstituteUniversity of FloridaGainesvilleUSA
  2. 2.Department of Herbal Pharmacology, College of Korean MedicineKyung Hee UniversitySeoulSouth Korea
  3. 3.Departments of Neurology, Psychiatry, Pharmaceutics, and NeuroscienceUniversity of FloridaGainesvilleUSA

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