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Regulatory Effects of Neuroinflammatory Responses Through Brain-Derived Neurotrophic Factor Signaling in Microglial Cells

  • Sheng-Wei Lai
  • Jia-Hong Chen
  • Hsiao-Yun Lin
  • Yu-Shu Liu
  • Cheng-Fang Tsai
  • Pei-Chun Chang
  • Dah-Yuu Lu
  • Chingju Lin
Article

Abstract

Inhibition of microglial over-activation is an important strategy to counter balance neurodegenerative progression. We previously demonstrated that the adenosine monophosphate-activated protein kinase (AMPK) may be a therapeutic target in mediating anti-neuroinflammatory responses in microglia. Brain-derived neurotrophic factor (BDNF) is one of the major neurotrophic factors produced by astrocytes to maintain the development and survival of neurons in the brain, and have recently been shown to modulate homeostasis of neuroinflammation. Therefore, the present study focused on BDNF-mediated neuroinflammatory responses and may provide an endogenous regulation of neuroinflammation. Among the tested neuroinflammation, epigallocatechin gallate (EGCG) and minocycline exerted BDNF upregulation to inhibit COX-2 and proinflammatory mediator expressions. Furthermore, both EGCG and minocycline upregulated BDNF expression in microglia through AMPK signaling. In addition, minocycline and EGCG also increased expressions of erythropoietin (EPO) and sonic hedgehog (Shh). In the endogenous modulation of neuroinflammation, astrocyte-conditioned medium (AgCM) also decreased the expression of COX-2 and upregulated BDNF expression in microglia. The anti-inflammatory effects of BDNF were mediated through EPO/Shh in microglia. Our results indicated that the BDNF-EPO-Shh novel-signaling pathway underlies the regulation of inflammatory responses and may be regarded as a potential therapeutic target in neurodegenerative diseases. This study also reveals a better understanding of an endogenous crosstalk between astrocytes and microglia to regulate anti-inflammatory actions, which could provide a novel strategy for the treatment of neuroinflammation and neurodegenerative diseases.

Keywords

BDNF Cox-2 Microglia Astrocytes Neuroinflammation 

Notes

Funding Information

This work is supported in part by grants from the Ministry of Science and Technology (102-2320-B-039-026-MY3 and 105-2320-B-039-058-), China Medical University (CMU102-ASIA-24 and CMU103-ASIA-02), Taichung Tzu Chi Hospital (TTCRD104-13 and TTCRD102-11), and Taiwan Ministry of Health and Welfare Clinical Trial and Research Center of Excellence (MOHW106-TDU-B-212-113004).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Czeh M, Gressens P, Kaindl AM (2011) The yin and yang of microglia. Dev Neurosci 33(3–4):199–209.  https://doi.org/10.1159/000328989 PubMedCrossRefGoogle Scholar
  2. 2.
    Lin HY, Huang BR, Yeh WL, Lee CH, Huang SS, Lai CH, Lin H, Lu DY (2014) Antineuroinflammatory effects of lycopene via activation of adenosine monophosphate-activated protein kinase-alpha1/heme oxygenase-1 pathways. Neurobiol Aging 35(1):191–202.  https://doi.org/10.1016/j.neurobiolaging.2013.06.020 PubMedCrossRefGoogle Scholar
  3. 3.
    Olson JK, Miller SD (2004) Microglia initiate central nervous system innate and adaptive immune responses through multiple TLRs. J Immunol 173(6):3916–3924.  https://doi.org/10.4049/jimmunol.173.6.3916 PubMedCrossRefGoogle Scholar
  4. 4.
    Wee Yong V (2010) Inflammation in neurological disorders: a help or a hindrance? Neuroscientist 16(4):408–420.  https://doi.org/10.1177/1073858410371379 PubMedCrossRefGoogle Scholar
  5. 5.
    Saijo K, Glass CK (2011) Microglial cell origin and phenotypes in health and disease. Nat Rev Immunol 11(11):775–787.  https://doi.org/10.1038/nri3086 PubMedCrossRefGoogle Scholar
  6. 6.
    Cartier N, Lewis CA, Zhang R, Rossi FM (2014) The role of microglia in human disease: therapeutic tool or target? Acta Neuropathol 128(3):363–380.  https://doi.org/10.1007/s00401-014-1330-y PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Hudson CC, Liu M, Chiang GG, Otterness DM, Loomis DC, Kaper F, Giaccia AJ, Abraham RT (2002) Regulation of hypoxia-inducible factor 1alpha expression and function by the mammalian target of rapamycin. Mol Cell Biol 22(20):7004–7014.  https://doi.org/10.1128/MCB.22.20.7004-7014.2002 PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Amor S, Peferoen LA, Vogel DY, Breur M, van der Valk P, Baker D, van Noort JM (2014) Inflammation in neurodegenerative diseases—an update. Immunology 142(2):151–166.  https://doi.org/10.1111/imm.12233 PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Dinarello CA (2009) Immunological and inflammatory functions of the interleukin-1 family. Annu Rev Immunol 27(1):519–550.  https://doi.org/10.1146/annurev.immunol.021908.132612 PubMedCrossRefGoogle Scholar
  10. 10.
    Kreutzberg GW (1996) Microglia: a sensor for pathological events in the CNS. Trends Neurosci 19(8):312–318.  https://doi.org/10.1016/0166-2236(96)10049-7 PubMedCrossRefGoogle Scholar
  11. 11.
    Block ML, Zecca L, Hong JS (2007) Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci 8(1):57–69.  https://doi.org/10.1038/nrn2038 PubMedCrossRefGoogle Scholar
  12. 12.
    Qian L, Flood PM, Hong JS (2010) Neuroinflammation is a key player in Parkinson’s disease and a prime target for therapy. J Neural Transm 117(8):971–979.  https://doi.org/10.1007/s00702-010-0428-1 PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Guillot-Sestier MV, Town T (2013) Innate immunity in Alzheimer’s disease: a complex affair. CNS Neurol Disord Drug Targets 12(5):593–607.  https://doi.org/10.2174/1871527311312050008 PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Patel AR, Ritzel R, McCullough LD, Liu F (2013) Microglia and ischemic stroke: a double-edged sword. Int J Physiol Pathophysiol Pharmacol 5(2):73–90PubMedPubMedCentralGoogle Scholar
  15. 15.
    Tonelli LH, Stiller J, Rujescu D, Giegling I, Schneider B, Maurer K, Schnabel A, Moller HJ et al (2008) Elevated cytokine expression in the orbitofrontal cortex of victims of suicide. Acta Psychiatr Scand 117(3):198–206.  https://doi.org/10.1111/j.1600-0447.2007.01128.x PubMedCrossRefGoogle Scholar
  16. 16.
    Samad TA, Moore KA, Sapirstein A, Billet S, Allchorne A, Poole S, Bonventre JV, Woolf CJ (2001) Interleukin-1beta-mediated induction of Cox-2 in the CNS contributes to inflammatory pain hypersensitivity. Nature 410(6827):471–475.  https://doi.org/10.1038/35068566 PubMedCrossRefGoogle Scholar
  17. 17.
    Samantaray S, Knaryan VH, Shields DC, Banik NL (2013) Critical role of calpain in spinal cord degeneration in Parkinson’s disease. J Neurochem 127(6):880–890.  https://doi.org/10.1111/jnc.12374 PubMedCrossRefGoogle Scholar
  18. 18.
    Bartels AL, Leenders KL (2010) Cyclooxygenase and neuroinflammation in Parkinson’s disease neurodegeneration. Curr Neuropharmacol 8(1):62–68.  https://doi.org/10.2174/157015910790909485 PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Granado N, Ares-Santos S, Moratalla R (2013) Methamphetamine and Parkinson’s disease. Parkinsons Dis 2013:308052.  https://doi.org/10.1155/2013/308052 PubMedPubMedCentralGoogle Scholar
  20. 20.
    Poo MM (2001) Neurotrophins as synaptic modulators. Nat Rev Neurosci 2(1):24–32.  https://doi.org/10.1038/35049004 PubMedCrossRefGoogle Scholar
  21. 21.
    Blesch A (2006) Neurotrophic factors in neurodegeneration. Brain Pathol 16(4):295–303.  https://doi.org/10.1111/j.1750-3639.2006.00036.x PubMedCrossRefGoogle Scholar
  22. 22.
    Alfa RW, Tuszynski MH, Blesch A (2009) A novel inducible tyrosine kinase receptor to regulate signal transduction and neurite outgrowth. J Neurosci Res 87(12):2624–2631.  https://doi.org/10.1002/jnr.22101 PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Autry AE, Monteggia LM (2012) Brain-derived neurotrophic factor and neuropsychiatric disorders. Pharmacol Rev 64(2):238–258.  https://doi.org/10.1124/pr.111.005108 PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Fumagalli F, Molteni R, Calabrese F, Maj PF, Racagni G, Riva MA (2008) Neurotrophic factors in neurodegenerative disorders: potential for therapy. CNS Drugs 22(12):1005–1019.  https://doi.org/10.2165/0023210-200822120-00004 PubMedCrossRefGoogle Scholar
  25. 25.
    Howells DW, Porritt MJ, Wong JY, Batchelor PE, Kalnins R, Hughes AJ, Donnan GA (2000) Reduced BDNF mRNA expression in the Parkinson’s disease substantia nigra. Exp Neurol 166(1):127–135.  https://doi.org/10.1006/exnr.2000.7483 PubMedCrossRefGoogle Scholar
  26. 26.
    Tapia-Arancibia L, Rage F, Givalois L, Arancibia S (2004) Physiology of BDNF: focus on hypothalamic function. Front Neuroendocrinol 25(2):77–107.  https://doi.org/10.1016/j.yfrne.2004.04.001 PubMedCrossRefGoogle Scholar
  27. 27.
    Zuccato C, Ciammola A, Rigamonti D, Leavitt BR, Goffredo D, Conti L, MacDonald ME, Friedlander RM et al (2001) Loss of huntingtin-mediated BDNF gene transcription in Huntington’s disease. Science 293(5529):493–498.  https://doi.org/10.1126/science.1059581 PubMedCrossRefGoogle Scholar
  28. 28.
    Miwa T, Furukawa S, Nakajima K, Furukawa Y, Kohsaka S (1997) Lipopolysaccharide enhances synthesis of brain-derived neurotrophic factor in cultured rat microglia. J Neurosci Res 50(6):1023–1029PubMedCrossRefGoogle Scholar
  29. 29.
    Simard AR, Rivest S (2007) Neuroprotective effects of resident microglia following acute brain injury. J Comp Neurol 504(6):716–729.  https://doi.org/10.1002/cne.21469 PubMedCrossRefGoogle Scholar
  30. 30.
    Ziv Y, Ron N, Butovsky O, Landa G, Sudai E, Greenberg N, Cohen H, Kipnis J et al (2006) Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood. Nat Neurosci 9(2):268–275.  https://doi.org/10.1038/nn1629 PubMedCrossRefGoogle Scholar
  31. 31.
    Fujita R, Ma Y, Ueda H (2008) Lysophosphatidic acid-induced membrane ruffling and brain-derived neurotrophic factor gene expression are mediated by ATP release in primary microglia. J Neurochem 107(1):152–160.  https://doi.org/10.1111/j.1471-4159.2008.05599.x PubMedCrossRefGoogle Scholar
  32. 32.
    Trang T, Beggs S, Wan X, Salter MW (2009) P2X4-receptor-mediated synthesis and release of brain-derived neurotrophic factor in microglia is dependent on calcium and p38-mitogen-activated protein kinase activation. J Neurosci 29(11):3518–3528.  https://doi.org/10.1523/JNEUROSCI.5714-08.2009 PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Ferrini F, De Koninck Y (2013, 2013) Microglia control neuronal network excitability via BDNF signalling. Neural plasticity:429815, 1–429811.  https://doi.org/10.1155/2013/429815
  34. 34.
    Song X, Zhou B, Zhang P, Lei D, Wang Y, Yao G, Hayashi T, Xia M et al (2016) Protective effect of Silibinin on learning and memory impairment in LPS-treated rats via ROS-BDNF-TrkB pathway. Neurochem Res 41(7):1662–1672.  https://doi.org/10.1007/s11064-016-1881-5 PubMedCrossRefGoogle Scholar
  35. 35.
    Asami T, Ito T, Fukumitsu H, Nomoto H, Furukawa Y, Furukawa S (2006) Autocrine activation of cultured macrophages by brain-derived neurotrophic factor. Biochem Biophys Res Commun 344(3):941–947.  https://doi.org/10.1016/j.bbrc.2006.03.228 PubMedCrossRefGoogle Scholar
  36. 36.
    Hooper JE, Scott MP (2005) Communicating with hedgehogs. Nat Rev Mol Cell Biol 6(4):306–317.  https://doi.org/10.1038/nrm1612 PubMedCrossRefGoogle Scholar
  37. 37.
    Ingham PW, Placzek M (2006) Orchestrating ontogenesis: variations on a theme by sonic hedgehog. Nat Rev Genet 7(11):841–850.  https://doi.org/10.1038/nrg1969 PubMedCrossRefGoogle Scholar
  38. 38.
    Ingham PW, McMahon AP (2001) Hedgehog signaling in animal development: paradigms and principles. Genes Dev 15(23):3059–3087.  https://doi.org/10.1101/gad.938601 PubMedCrossRefGoogle Scholar
  39. 39.
    Gilbert-Barness E, Debich-Spicer D, Cohen MM Jr, Opitz JM (2001) Evidence for the “midline” hypothesis in associated defects of laterality formation and multiple midline anomalies. Am J Med Genet 101(4):382–387.  https://doi.org/10.1002/ajmg.1224 PubMedCrossRefGoogle Scholar
  40. 40.
    Porter JA, Ekker SC, Park WJ, von Kessler DP, Young KE, Chen CH, Ma Y, Woods AS et al (1996) Hedgehog patterning activity: role of a lipophilic modification mediated by the carboxy-terminal autoprocessing domain. Cell 86(1):21–34.  https://doi.org/10.1016/S0092-8674(00)80074-4 PubMedCrossRefGoogle Scholar
  41. 41.
    McMahon AP, Ingham PW, Tabin CJ (2003) Developmental roles and clinical significance of hedgehog signaling. Curr Top Dev Biol 53:1–114.  https://doi.org/10.1016/S0070-2153(03)53002-2 PubMedCrossRefGoogle Scholar
  42. 42.
    Ahn S, Joyner AL (2005) In vivo analysis of quiescent adult neural stem cells responding to Sonic hedgehog. Nature 437(7060):894–897.  https://doi.org/10.1038/nature03994 PubMedCrossRefGoogle Scholar
  43. 43.
    Chari NS, McDonnell TJ (2007) The sonic hedgehog signaling network in development and neoplasia. Adv Anat Pathol 14(5):344–352.  https://doi.org/10.1097/PAP.0b013e3180ca8a1d PubMedCrossRefGoogle Scholar
  44. 44.
    Galvin KE, Ye H, Wetmore C (2007) Differential gene induction by genetic and ligand-mediated activation of the Sonic hedgehog pathway in neural stem cells. Dev Biol 308(2):331–342.  https://doi.org/10.1016/j.ydbio.2007.05.031 PubMedCrossRefGoogle Scholar
  45. 45.
    Amankulor NM, Hambardzumyan D, Pyonteck SM, Becher OJ, Joyce JA, Holland EC (2009) Sonic hedgehog pathway activation is induced by acute brain injury and regulated by injury-related inflammation. J Neurosci 29(33):10299–10308.  https://doi.org/10.1523/JNEUROSCI.2500-09.2009 PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Heine VM, Rowitch DH (2009) Hedgehog signaling has a protective effect in glucocorticoid-induced mouse neonatal brain injury through an 11betaHSD2-dependent mechanism. J Clin Invest 119(2):267–277.  https://doi.org/10.1172/JCI36376 PubMedPubMedCentralGoogle Scholar
  47. 47.
    Paganelli AR, Ocana OH, Prat MI, Franco PG, Lopez SL, Morelli L, Adamo AM, Riccomagno MM et al (2001) The Alzheimer-related gene presenilin-1 facilitates sonic hedgehog expression in Xenopus primary neurogenesis. Mech Dev 107(1–2):119–131.  https://doi.org/10.1016/S0925-4773(01)00458-0 PubMedCrossRefGoogle Scholar
  48. 48.
    Tsuboi K, Shults CW (2002) Intrastriatal injection of sonic hedgehog reduces behavioral impairment in a rat model of Parkinson’s disease. Exp Neurol 173(1):95–104.  https://doi.org/10.1006/exnr.2001.7825 PubMedCrossRefGoogle Scholar
  49. 49.
    Torres EM, Monville C, Lowenstein PR, Castro MG, Dunnett SB (2005) Delivery of sonic hedgehog or glial derived neurotrophic factor to dopamine-rich grafts in a rat model of Parkinson’s disease using adenoviral vectors Increased yield of dopamine cells is dependent on embryonic donor age. Brain Res Bull 68(1–2):31–41.  https://doi.org/10.1016/j.brainresbull.2005.08.021 PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Yang H, Feng GD, Olivera C, Jiao XY, Vitale A, Gong J, You SW (2012) Sonic hedgehog released from scratch-injured astrocytes is a key signal necessary but not sufficient for the astrocyte de-differentiation. Stem Cell Res 9(2):156–166.  https://doi.org/10.1016/j.scr.2012.06.002 PubMedCrossRefGoogle Scholar
  51. 51.
    Pitter KL, Tamagno I, Feng X, Ghosal K, Amankulor N, Holland EC, Hambardzumyan D (2014) The SHH/Gli pathway is reactivated in reactive glia and drives proliferation in response to neurodegeneration-induced lesions. Glia 62(10):1595–1607.  https://doi.org/10.1002/glia.22702 PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Liu Z, Chopp M (2016) Astrocytes, therapeutic targets for neuroprotection and neurorestoration in ischemic stroke. Prog Neurobiol 144:103–120.  https://doi.org/10.1016/j.pneurobio.2015.09.008
  53. 53.
    Marti HH (2004) Erythropoietin and the hypoxic brain. J Exp Biol 207(Pt 18):3233–3242.  https://doi.org/10.1242/jeb.01049 PubMedCrossRefGoogle Scholar
  54. 54.
    Jelkmann W (1992) Erythropoietin: structure, control of production, and function. Physiol Rev 72(2):449–489.  https://doi.org/10.1152/physrev.1992.72.2.449 PubMedCrossRefGoogle Scholar
  55. 55.
    Brines ML, Ghezzi P, Keenan S, Agnello D, de Lanerolle NC, Cerami C, Itri LM, Cerami A (2000) Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury. Proc Natl Acad Sci U S A 97(19):10526–10531.  https://doi.org/10.1073/pnas.97.19.10526 PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Siren AL, Fratelli M, Brines M, Goemans C, Casagrande S, Lewczuk P, Keenan S, Gleiter C et al (2001) Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress. Proc Natl Acad Sci U S A 98(7):4044–4049.  https://doi.org/10.1073/pnas.051606598 PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Viviani B, Bartesaghi S, Corsini E, Villa P, Ghezzi P, Garau A, Galli CL, Marinovich M (2005) Erythropoietin protects primary hippocampal neurons increasing the expression of brain-derived neurotrophic factor. J Neurochem 93(2):412–421.  https://doi.org/10.1111/j.1471-4159.2005.03033.x PubMedCrossRefGoogle Scholar
  58. 58.
    Wang L, Zhang ZG, Gregg SR, Zhang RL, Jiao Z, LeTourneau Y, Liu X, Feng Y et al (2007) The Sonic hedgehog pathway mediates carbamylated erythropoietin-enhanced proliferation and differentiation of adult neural progenitor cells. J Biol Chem 282(44):32462–32470.  https://doi.org/10.1074/jbc.M706880200 PubMedCrossRefGoogle Scholar
  59. 59.
    Jou TC, Jou MJ, Chen JY, Lee SY (1985) Properties of rat brain astrocytes in long-term culture. Taiwan Yi Xue Hui Za Zhi 84(8):865–881PubMedGoogle Scholar
  60. 60.
    Lin HY, Yeh WL, Huang BR, Lin C, Lai CH, Lin H, Lu DY (2012) Desipramine protects neuronal cell death and induces heme oxygenase-1 expression in Mes23.5 dopaminergic neurons. PLoS One 7(11):e50138.  https://doi.org/10.1371/journal.pone.0050138 PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Lu DY, Tang CH, Chen YH, Wei IH (2010) Berberine suppresses neuroinflammatory responses through AMP-activated protein kinase activation in BV-2 microglia. J Cell Biochem 110(3):697–705.  https://doi.org/10.1002/jcb.22580 PubMedCrossRefGoogle Scholar
  62. 62.
    Lin C, Lin HY, Chen JH, Tseng WP, Ko PY, Liu YS, Yeh WL, Lu DY (2015) Effects of paeonol on anti-neuroinflammatory responses in microglial cells. Int J Mol Sci 16(4):8844–8860.  https://doi.org/10.3390/ijms16048844 PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Lu DY, Huang BR, Yeh WL, Lin HY, Huang SS, Liu YS, Kuo YH (2013) Anti-neuroinflammatory effect of a novel caffeamide derivative, KS370G, in microglial cells. Mol Neurobiol 48(3):863–874.  https://doi.org/10.1007/s12035-013-8474-y PubMedCrossRefGoogle Scholar
  64. 64.
    Tsai CF, Kuo YH, Yeh WL, Wu CY, Lin HY, Lai SW, Liu YS, Wu LH et al (2015) Regulatory effects of caffeic acid phenethyl ester on neuroinflammation in microglial cells. Int J Mol Sci 16(3):5572–5589.  https://doi.org/10.3390/ijms16035572 PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Chen JH, Huang SM, Chen CC, Tsai CF, Yeh WL, Chou SJ, Hsieh WT, Lu DY (2011) Ghrelin induces cell migration through GHS-R, CaMKII, AMPK, and NF-kappaB signaling pathway in glioma cells. J Cell Biochem 112(10):2931–2941.  https://doi.org/10.1002/jcb.23209 PubMedCrossRefGoogle Scholar
  66. 66.
    Choi IY, Ju C, Anthony Jalin AM, Lee DI, Prather PL, Kim WK (2013) Activation of cannabinoid CB2 receptor-mediated AMPK/CREB pathway reduces cerebral ischemic injury. Am J Pathol 182(3):928–939.  https://doi.org/10.1016/j.ajpath.2012.11.024 PubMedCrossRefGoogle Scholar
  67. 67.
    Thornton CC, Al-Rashed F, Calay D, Birdsey GM, Bauer A, Mylroie H, Morley BJ, Randi AM et al (2016) Methotrexate-mediated activation of an AMPK-CREB-dependent pathway: a novel mechanism for vascular protection in chronic systemic inflammation. Ann Rheum Dis 75(2):439–448.  https://doi.org/10.1136/annrheumdis-2014-206305 PubMedCrossRefGoogle Scholar
  68. 68.
    Gao HM, Hong JS (2008) Why neurodegenerative diseases are progressive: uncontrolled inflammation drives disease progression. Trends Immunol 29(8):357–365.  https://doi.org/10.1016/j.it.2008.05.002 PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Krause DL, Muller N (2010) Neuroinflammation, microglia and implications for anti-inflammatory treatment in Alzheimer’s disease. Int J Alzheimers Dis 2010:1–9.  https://doi.org/10.4061/2010/732806 CrossRefGoogle Scholar
  70. 70.
    Hanisch UK, Kettenmann H (2007) Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 10(11):1387–1394.  https://doi.org/10.1038/nn1997 PubMedCrossRefGoogle Scholar
  71. 71.
    Perry VH, Nicoll JA, Holmes C (2010) Microglia in neurodegenerative disease. Nat Rev Neurol 6(4):193–201.  https://doi.org/10.1038/nrneurol.2010.17 PubMedCrossRefGoogle Scholar
  72. 72.
    Lehnardt S (2010) Innate immunity and neuroinflammation in the CNS: the role of microglia in toll-like receptor-mediated neuronal injury. Glia 58(3):253–263.  https://doi.org/10.1002/glia.20928 PubMedGoogle Scholar
  73. 73.
    Kim BW, Koppula S, Park SY, Hwang JW, Park PJ, Lim JH, Choi DK (2014) Attenuation of inflammatory-mediated neurotoxicity by Saururus chinensis extract in LPS-induced BV-2 microglia cells via regulation of NF-kappaB signaling and anti-oxidant properties. BMC Complement Altern Med 14(1):502.  https://doi.org/10.1186/1472-6882-14-502 PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Lin HY, Tsai CH, Lin C, Yeh WL, Tsai CF, Chang PC, Wu LH, Lu DY (2016) Cobalt protoporphyrin upregulates cyclooxygenase-2 expression through a heme oxygenase-independent mechanism. Mol Neurobiol 53(7):4497–4508.  https://doi.org/10.1007/s12035-015-9376-y PubMedCrossRefGoogle Scholar
  75. 75.
    Sofroniew MV, Vinters HV (2010) Astrocytes: biology and pathology. Acta Neuropathol 119(1):7–35.  https://doi.org/10.1007/s00401-009-0619-8 PubMedCrossRefGoogle Scholar
  76. 76.
    Gordon S (2003) Alternative activation of macrophages. Nat Rev Immunol 3(1):23–35.  https://doi.org/10.1038/nri978 PubMedCrossRefGoogle Scholar
  77. 77.
    Lovren F, Pan Y, Quan A, Szmitko PE, Singh KK, Shukla PC, Gupta M, Chan L et al (2010) Adiponectin primes human monocytes into alternative anti-inflammatory M2 macrophages. Am J Physiol Heart Circ Physiol 299(3):H656–H663.  https://doi.org/10.1152/ajpheart.00115.2010 PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Kido K, Yokokawa T, Ato S, Sato K, Fujita S (2017) Effect of resistance exercise under conditions of reduced blood insulin on AMPKalpha Ser485/491 inhibitory phosphorylation and AMPK pathway activation. Am J Physiol Regul Integr Comp Physiol:ajpregu 00063 02017. doi: https://doi.org/10.1152/ajpregu.00063.2017, 2, R110, R119
  79. 79.
    Thomson DM, Herway ST, Fillmore N, Kim H, Brown JD, Barrow JR, Winder WW (2008) AMP-activated protein kinase phosphorylates transcription factors of the CREB family. J Appl Physiol (1985) 104(2):429–438.  https://doi.org/10.1152/japplphysiol.00900.2007 CrossRefGoogle Scholar
  80. 80.
    Martinez-Levy GA, Rocha L, Rodriguez-Pineda F, Alonso-Vanegas MA, Nani A, Buentello-Garcia RM, Briones-Velasco M, San-Juan D et al (2017) Increased expression of brain-derived neurotrophic factor transcripts I and VI, cAMP response element binding, and glucocorticoid receptor in the cortex of patients with temporal lobe epilepsy. Mol Neurobiol.  https://doi.org/10.1007/s12035-017-0597-0
  81. 81.
    Hossain MS, Oomura Y, Katafuchi T (2017) Glucose can epigenetically alter the gene expression of neurotrophic factors in the murine brain cells. Mol Neurobiol.  https://doi.org/10.1007/s12035-017-0578-3
  82. 82.
    Jang S, Kim H, Jeong J, Lee SK, Kim EW, Park M, Kim CH, Lee JE et al (2016) Blunted response of hippocampal AMPK associated with reduced neurogenesis in older versus younger mice. Prog Neuro-Psychopharmacol Biol Psychiatry 71:57–65.  https://doi.org/10.1016/j.pnpbp.2016.06.011 CrossRefGoogle Scholar
  83. 83.
    Mattson MP, Maudsley S, Martin B (2004) A neural signaling triumvirate that influences ageing and age-related disease: insulin/IGF-1, BDNF and serotonin. Ageing Res Rev 3(4):445–464.  https://doi.org/10.1016/j.arr.2004.08.001 PubMedCrossRefGoogle Scholar
  84. 84.
    Lin CS, Lim SK, D'Agati V, Costantini F (1996) Differential effects of an erythropoietin receptor gene disruption on primitive and definitive erythropoiesis. Genes Dev 10(2):154–164.  https://doi.org/10.1101/gad.10.2.154 PubMedCrossRefGoogle Scholar
  85. 85.
    Wu H, Liu X, Jaenisch R, Lodish HF (1995) Generation of committed erythroid BFU-E and CFU-E progenitors does not require erythropoietin or the erythropoietin receptor. Cell 83(1):59–67.  https://doi.org/10.1016/0092-8674(95)90234-1 PubMedCrossRefGoogle Scholar
  86. 86.
    Khairallah MI, Kassem LA, Yassin NA, Din MA, Zekri M, Attia M (2016) Activation of migration of endogenous stem cells by erythropoietin as potential rescue for neurodegenerative diseases. Brain Res Bull 121:148–157.  https://doi.org/10.1016/j.brainresbull.2016.01.007 PubMedCrossRefGoogle Scholar
  87. 87.
    Morishita E, Masuda S, Nagao M, Yasuda Y, Sasaki R (1997) Erythropoietin receptor is expressed in rat hippocampal and cerebral cortical neurons, and erythropoietin prevents in vitro glutamate-induced neuronal death. Neuroscience 76(1):105–116PubMedCrossRefGoogle Scholar
  88. 88.
    Sakanaka M, Wen TC, Matsuda S, Masuda S, Morishita E, Nagao M, Sasaki R (1998) In vivo evidence that erythropoietin protects neurons from ischemic damage. Proc Natl Acad Sci U S A 95(8):4635–4640.  https://doi.org/10.1073/pnas.95.8.4635 PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Ueda K, Takano H, Niitsuma Y, Hasegawa H, Uchiyama R, Oka T, Miyazaki M, Nakaya H et al (2010) Sonic hedgehog is a critical mediator of erythropoietin-induced cardiac protection in mice. J Clin Invest 120(6):2016–2029.  https://doi.org/10.1172/JCI39896 PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Lee JH, Chung YC, Bok E, Lee H, Huh SH, Lee JE, Jin BK, Ko HW (2017) Injury-stimulated Sonic hedgehog expression in microglia contributes to neuroinflammatory response in the MPTP model of Parkinson’s disease. Biochem Biophys Res Commun 482(4):980–986.  https://doi.org/10.1016/j.bbrc.2016.11.144 PubMedCrossRefGoogle Scholar
  91. 91.
    Bak M, Hansen C, Henriksen KF, Hansen L, Pakkenberg H, Eiberg H, Tommerup N (2004) Mutation analysis of the sonic hedgehog promoter and putative enhancer elements in Parkinson’s disease patients. Brain Res Mol Brain Res 126(2):207–211.  https://doi.org/10.1016/j.molbrainres.2004.04.005 PubMedCrossRefGoogle Scholar
  92. 92.
    Park S, Lee KS, Lee YJ, Shin HA, Cho HY, Wang KC, Kim YS, Lee HT et al (2004) Generation of dopaminergic neurons in vitro from human embryonic stem cells treated with neurotrophic factors. Neurosci Lett 359(1–2):99–103.  https://doi.org/10.1016/j.neulet.2004.01.073 PubMedCrossRefGoogle Scholar
  93. 93.
    Hashimoto M, Ishii K, Nakamura Y, Watabe K, Kohsaka S, Akazawa C (2008) Neuroprotective effect of sonic hedgehog up-regulated in Schwann cells following sciatic nerve injury. J Neurochem 107(4):918–927.  https://doi.org/10.1111/j.1471-4159.2008.05666.x PubMedGoogle Scholar
  94. 94.
    Wu CL, Chen SD, Yin JH, Hwang CS, Yang DI (2010) Erythropoietin and sonic hedgehog mediate the neuroprotective effects of brain-derived neurotrophic factor against mitochondrial inhibition. Neurobiol Dis 40(1):146–154.  https://doi.org/10.1016/j.nbd.2010.05.019 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Graduate Institute of Basic Medical ScienceChina Medical UniversityTaichungTaiwan
  2. 2.Department of General Surgery, Taichung Tzu Chi HospitalBuddhist Tzu Chi Medical FoundationTaichungTaiwan
  3. 3.School of MedicineTzu Chi UniversityHualienTaiwan
  4. 4.Department of Pharmacology, School of MedicineChina Medical UniversityTaichungTaiwan
  5. 5.Department of BiotechnologyAsia UniversityTaichungTaiwan
  6. 6.Department of BioinformaticsAsia UniversityTaichungTaiwan
  7. 7.Department of Photonics and Communication EngineeringAsia UniversityTaichungTaiwan
  8. 8.Department of Physiology, School of MedicineChina Medical UniversityTaichungTaiwan

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