Advertisement

Molecular Neurobiology

, Volume 53, Issue 8, pp 5324–5343 | Cite as

Dopamine Burden Triggers Neurodegeneration via Production and Release of TNF-α from Astrocytes in Minimal Hepatic Encephalopathy

  • Saidan Ding
  • Weikan Wang
  • Xuebao Wang
  • Yong Liang
  • Leping Liu
  • Yiru Ye
  • Jianjing Yang
  • Hongchang GaoEmail author
  • Qichuan ZhugeEmail author
Article

Abstract

Dopamine (DA)-induced learning and memory impairment is well documented in minimal hepatic encephalopathy (MHE), but the contribution of DA to neurodegeneration and the involved underlying mechanisms are not fully understood. In this study, the effect of DA on neuronal apoptosis was initially detected. The results showed that MHE/DA (10 μg)-treated rats displayed neuronal apoptosis. However, we found that DA (10 μM) treatment did not induce evident apoptosis in primary cultured neurons (PCNs) but did produce TNF-α in primary cultured astrocytes (PCAs). Furthermore, co-cultures between PCAs and PCNs exposed to DA exhibited increased astrocytic TNF-α levels and neuronal apoptosis compared with co-cultures exposed to the vehicle, indicating the attribution of the neuronal apoptosis to astrocytic TNF-α. We also demonstrated that DA enhanced TNF-α production from astrocytes by activation of the TLR4/MyD88/NF-κB pathway, and secreted astrocytic TNF-α-potentiated neuronal apoptosis through inactivation of the PI3K/Akt/mTOR pathway. Overall, the findings from this study suggest that DA stimulates substantial production and secretion of astrocytic TNF-α, consequently and indirectly triggering progressive neurodegeneration, resulting in cognitive decline and memory loss in MHE.

Keywords

Minimal hepatic encephalopathy (MHE) Dopamine (DA) Cognitive impairment Astrocytic TNF-α Neurodegeneration 

Notes

Acknowledgement

This study was funded by the Natural Science Foundation of China (81300308, 81171088, 81371396).

Supplementary material

12035_2015_9445_MOESM1_ESM.doc (152 kb)
ESM 1 (DOC 152 kb)

References

  1. 1.
    Amodio P, Montagnese S, Gatta A, Morgan MY (2004) Characteristics of minimal hepatic encephalopathy. Metab Brain Dis 19(3–4):253–267PubMedCrossRefGoogle Scholar
  2. 2.
    Ferenci P, Lockwood A, Mullen K, Tarter R, Weissenborn K, Blei AT (2002) Hepatic encephalopathy—definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998. Hepatology 35(3):716–721. doi: 10.1053/jhep.2002.31250 PubMedCrossRefGoogle Scholar
  3. 3.
    Montoliu C, Piedrafita B, Serra MA, del Olmo JA, Ferrandez A, Rodrigo JM, Felipo V (2007) Activation of soluble guanylate cyclase by nitric oxide in lymphocytes correlates with minimal hepatic encephalopathy in cirrhotic patients. J Mol Med 85(3):237–245. doi: 10.1007/s00109-006-0149-y PubMedCrossRefGoogle Scholar
  4. 4.
    Groeneweg M, Quero JC, De Bruijn I, Hartmann IJ, Essink-bot ML, Hop WC, Schalm SW (1998) Subclinical hepatic encephalopathy impairs daily functioning. Hepatology 28(1):45–49. doi: 10.1002/hep.510280108 PubMedCrossRefGoogle Scholar
  5. 5.
    Romero-Gomez M, Boza F, Garcia-Valdecasas MS, Garcia E, Aguilar-Reina J (2001) Subclinical hepatic encephalopathy predicts the development of overt hepatic encephalopathy. Am J Gastroenterol 96(9):2718–2723. doi: 10.1111/j.1572-0241.2001.04130.x PubMedCrossRefGoogle Scholar
  6. 6.
    Ding S, Hu J, Yang J, Liu L, Huang W, Gu X, Ye Y, Huang L et al (2014) The inactivation of JAK2/STAT3 signaling and desensitization of M1 mAChR in minimal hepatic encephalopathy (MHE) and the protection of naringin against MHE. Cell Physiol Biochem 34(6):1933–1950PubMedCrossRefGoogle Scholar
  7. 7.
    Ding S, Huang W, Ye Y, Yang J, Hu J, Wang X, Liu L, Lu Q et al (2014) Elevated intracranial dopamine impairs the glutamate-nitric oxide-cyclic guanosine monophosphate pathway in cortical astrocytes in rats with minimal hepatic encephalopathy. Mol Med Rep 10(3):1215–1224PubMedPubMedCentralGoogle Scholar
  8. 8.
    Ding S, Yang J, Liu L, Ye Y, Wang X, Hu J, Chen B, Zhuge Q (2014) Elevated dopamine induces minimal hepatic encephalopathy by activation of astrocytic NADPH oxidase and astrocytic protein tyrosine nitration. Int J Biochem Cell Biol 55:252–263PubMedCrossRefGoogle Scholar
  9. 9.
    Ding SD, Liu LP, Jing HJ, Xie JY, Wang XB, Mao JP, Chen BC, Zhuge QC (2013) Dopamine from cirrhotic liver contributes to the impaired learning and memory ability of hippocampus in minimal hepatic encephalopathy. Hepatol Int 7(3):923–936. doi: 10.1007/s12072-013-9431-6 PubMedCrossRefGoogle Scholar
  10. 10.
    Kar S, Slowikowski SP, Westaway D, Mount HT (2004) Interactions between beta-amyloid and central cholinergic neurons: implications for Alzheimer’s disease. J Psychiatry Neurosci 29(6):427–441PubMedPubMedCentralGoogle Scholar
  11. 11.
    McGuinness B, Barrett SL, Craig D, Lawson J, Passmore AP (2010) Executive functioning in Alzheimer’s disease and vascular dementia. Int J Geriatr Psychiatry 25(6):562–568. doi: 10.1002/gps.2375 PubMedGoogle Scholar
  12. 12.
    Millington C, Sonego S, Karunaweera N, Rangel A, Aldrich-Wright JR, Campbell IL, Gyengesi E, Munch G (2014) Chronic neuroinflammation in Alzheimer’s disease: new perspectives on animal models and promising candidate drugs. BioMed Res Int 2014:309129. doi: 10.1155/2014/309129 PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Montgomery SL, Bowers WJ (2012) Tumor necrosis factor-alpha and the roles it plays in homeostatic and degenerative processes within the central nervous system. J Neuroimmune Pharmacol 7(1):42–59. doi: 10.1007/s11481-011-9287-2 PubMedCrossRefGoogle Scholar
  14. 14.
    Kawasumi M, Chiba T, Yamada M, Miyamae-Kaneko M, Matsuoka M, Nakahara J, Tomita T, Iwatsubo T et al (2004) Targeted introduction of V642I mutation in amyloid precursor protein gene causes functional abnormality resembling early stage of Alzheimer’s disease in aged mice. Eur J Neurosci 19(10):2826–2838PubMedCrossRefGoogle Scholar
  15. 15.
    Yamada M, Chiba T, Sasabe J, Nawa M, Tajima H, Niikura T, Terashita K, Aiso S et al (2005) Implanted cannula-mediated repetitive administration of Abeta25-35 into the mouse cerebral ventricle effectively impairs spatial working memory. Behav Brain Res 164(2):139–146PubMedCrossRefGoogle Scholar
  16. 16.
    Mamiya T, Noda Y, Nishi M, Takeshima H, Nabeshima T (1998) Enhancement of spatial attention in nociceptin/orphanin FQ receptor-knockout mice. Brain Res 783(2):236–240PubMedCrossRefGoogle Scholar
  17. 17.
    Bernabeu R, Schmitz P, Faillace MP, Izquierdo I, Medina JH (1996) Hippocampal cGMP and cAMP are differentially involved in memory processing of inhibitory avoidance learning. Neuroreport 7(2):585–588PubMedCrossRefGoogle Scholar
  18. 18.
    Munoz-Fernandez MA, Fresno M (1998) The role of tumour necrosis factor, interleukin 6, interferon-gamma and inducible nitric oxide synthase in the development and pathology of the nervous system. Prog Neurobiol 56(3):307–340PubMedCrossRefGoogle Scholar
  19. 19.
    Saha RN, Liu X, Pahan K (2006) Up-regulation of BDNF in astrocytes by TNF-alpha: a case for the neuroprotective role of cytokine. J Neuroimmune Pharmacol 1(3):212–222. doi: 10.1007/s11481-006-9020-8 PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Viviani B, Bartesaghi S, Corsini E, Galli CL, Marinovich M (2004) Cytokines role in neurodegenerative events. Toxicol Lett 149(1–3):85–89. doi: 10.1016/j.toxlet.2003.12.022 PubMedCrossRefGoogle Scholar
  21. 21.
    Kuhn H, Petzold K, Hammerschmidt S, Wirtz H (2014) Interaction of cyclic mechanical stretch and toll-like receptor 4-mediated innate immunity in rat alveolar type II cells. Respirology 19(1):67–73. doi: 10.1111/resp.12149 PubMedCrossRefGoogle Scholar
  22. 22.
    Yang J, Yang J, Ding JW, Chen LH, Wang YL, Li S, Wu H (2008) Sequential expression of TLR4 and its effects on the myocardium of rats with myocardial ischemia-reperfusion injury. Inflammation 31(5):304–312. doi: 10.1007/s10753-008-9079-x PubMedCrossRefGoogle Scholar
  23. 23.
    Zhu W, Zhu N, Bai D, Miao J, Zou S (2014) The crosstalk between Dectin1 and TLR4 via NF-kappaB subunits p65/RelB in mammary epithelial cells. Int Immunopharmacol 23(2):417–425. doi: 10.1016/j.intimp.2014.09.004 PubMedCrossRefGoogle Scholar
  24. 24.
    Saini KS, Loi S, de Azambuja E, Metzger-Filho O, Saini ML, Ignatiadis M, Dancey JE, Piccart-Gebhart MJ (2013) Targeting the PI3K/AKT/mTOR and Raf/MEK/ERK pathways in the treatment of breast cancer. Cancer Treat Rev 39(8):935–946. doi: 10.1016/j.ctrv.2013.03.009 PubMedCrossRefGoogle Scholar
  25. 25.
    Coulthard EJ, Bogacz R, Javed S, Mooney LK, Murphy G, Keeley S, Whone AL (2012) Distinct roles of dopamine and subthalamic nucleus in learning and probabilistic decision making. Brain J Neurol 135(Pt 12):3721–3734CrossRefGoogle Scholar
  26. 26.
    Shiner T, Seymour B, Wunderlich K, Hill C, Bhatia KP, Dayan P, Dolan RJ (2012) Dopamine and performance in a reinforcement learning task: evidence from Parkinson’s disease. Brain J Neurol 135(Pt 6):1871–1883CrossRefGoogle Scholar
  27. 27.
    Kobza S, Ferrea S, Schnitzler A, Pollok B, Sudmeyer M, Bellebaum C (2012) Dissociation between active and observational learning from positive and negative feedback in Parkinsonism. PLoS One 7(11):e50250PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Moustafa AA, Herzallah MM, Gluck MA (2013) Dissociating the cognitive effects of levodopa versus dopamine agonists in a neurocomputational model of learning in Parkinson’s disease. Neurodegener Dis 11(2):102–111PubMedCrossRefGoogle Scholar
  29. 29.
    Bergeron M, Reader TA, Layrargues GP, Butterworth RF (1989) Monoamines and metabolites in autopsied brain tissue from cirrhotic patients with hepatic encephalopathy. Neurochem Res 14(9):853–859PubMedCrossRefGoogle Scholar
  30. 30.
    Knell AJ, Davidson AR, Williams R, Kantamaneni BD, Curzon G (1974) Dopamine and serotonin metabolism in hepatic encephalopathy. Br Med J 1(5907):549–551PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Fleminger S, Oliver DL, Lovestone S, Rabe-Hesketh S, Giora A (2003) Head injury as a risk factor for Alzheimer’s disease: the evidence 10 years on; a partial replication. J Neurol Neurosurg Psychiatry 74(7):857–862PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Johnson AA, Akman K, Calimport SR, Wuttke D, Stolzing A, de Magalhaes JP (2012) The role of DNA methylation in aging, rejuvenation, and age-related disease. Rejuvenation Res 15(5):483–494. doi: 10.1089/rej.2012.1324 PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Tashlykov V, Katz Y, Gazit V, Zohar O, Schreiber S, Pick CG (2007) Apoptotic changes in the cortex and hippocampus following minimal brain trauma in mice. Brain Res 1130(1):197–205. doi: 10.1016/j.brainres.2006.10.032 PubMedCrossRefGoogle Scholar
  34. 34.
    Abbott NJ, Ronnback L, Hansson E (2006) Astrocyte-endothelial interactions at the blood–brain barrier. Nat Rev Neurosci 7(1):41–53. doi: 10.1038/nrn1824 PubMedCrossRefGoogle Scholar
  35. 35.
    Kimelberg HK, Macvicar BA, Sontheimer H (2006) Anion channels in astrocytes: biophysics, pharmacology, and function. Glia 54(7):747–757. doi: 10.1002/glia.20423 PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Parpura V, Zorec R (2010) Gliotransmission: exocytotic release from astrocytes. Brain Res Rev 63(1–2):83–92. doi: 10.1016/j.brainresrev.2009.11.008 PubMedCrossRefGoogle Scholar
  37. 37.
    Qin H, Benveniste EN (2012) ELISA methodology to quantify astrocyte production of cytokines/chemokines in vitro. Methods Mol Biol 814:235–249. doi: 10.1007/978-1-61779-452-0_16 PubMedCrossRefGoogle Scholar
  38. 38.
    Carswell EA, Old LJ, Kassel RL, Green S, Fiore N, Williamson B (1975) An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci U S A 72(9):3666–3670PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Sharma V, Thakur V, Singh SN, Guleria R (2012) Tumor necrosis factor and Alzheimer’s disease: a cause and consequence relationship. Klin Psikofarmakol B 22(1):86–97. doi: 10.5455/bcp.20120112064639 Google Scholar
  40. 40.
    Frankola KA, Greig NH, Luo W, Tweedie D (2011) Targeting TNF-alpha to elucidate and ameliorate neuroinflammation in neurodegenerative diseases. CNS Neurol Disord Drug Targets 10(3):391–403PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    McCoy MK, Tansey MG (2008) TNF signaling inhibition in the CNS: implications for normal brain function and neurodegenerative disease. J Neuroinflammation 5:45. doi: 10.1186/1742-2094-5-45 PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Wyss-Coray T, Mucke L (2002) Inflammation in neurodegenerative disease—a double-edged sword. Neuron 35(3):419–432PubMedCrossRefGoogle Scholar
  43. 43.
    Medzhitov R, Preston-Hurlburt P, Janeway CA Jr (1997) A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388(6640):394–397. doi: 10.1038/41131 PubMedCrossRefGoogle Scholar
  44. 44.
    Hutchinson MR, Zhang Y, Brown K, Coats BD, Shridhar M, Sholar PW, Patel SJ, Crysdale NY et al (2008) Non-stereoselective reversal of neuropathic pain by naloxone and naltrexone: involvement of toll-like receptor 4 (TLR4). Eur J Neurosci 28(1):20–29. doi: 10.1111/j.1460-9568.2008.06321.x PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Kielian T (2006) Toll-like receptors in central nervous system glial inflammation and homeostasis. J Neurosci Res 83(5):711–730. doi: 10.1002/jnr.20767 PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Miyake K (2007) Innate immune sensing of pathogens and danger signals by cell surface Toll-like receptors. Semin Immunol 19(1):3–10. doi: 10.1016/j.smim.2006.12.002 PubMedCrossRefGoogle Scholar
  47. 47.
    Wang Y, Subramanian P, Shen D, Tuo J, Becerra SP, Chan CC (2013) Pigment epithelium-derived factor reduces apoptosis and pro-inflammatory cytokine gene expression in a murine model of focal retinal degeneration. ASN Neuro 5(5):e00126. doi: 10.1042/AN20130028 PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Chang L, Graham PH, Hao J, Bucci J, Cozzi PJ, Kearsley JH, Li Y (2014) Emerging roles of radioresistance in prostate cancer metastasis and radiation therapy. Cancer Metastasis Rev 33(2–3):469–496. doi: 10.1007/s10555-014-9493-5 PubMedCrossRefGoogle Scholar
  49. 49.
    Chang L, Graham PH, Hao J, Ni J, Bucci J, Cozzi PJ, Kearsley JH, Li Y (2013) Acquisition of epithelial-mesenchymal transition and cancer stem cell phenotypes is associated with activation of the PI3K/Akt/mTOR pathway in prostate cancer radioresistance. Cell Death Dis 4:e875. doi: 10.1038/cddis.2013.407 PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Ni J, Cozzi P, Hao J, Beretov J, Chang L, Duan W, Shigdar S, Delprado W et al (2013) Epithelial cell adhesion molecule (EpCAM) is associated with prostate cancer metastasis and chemo/radioresistance via the PI3K/Akt/mTOR signaling pathway. Int J Biochem Cell Biol 45(12):2736–2748. doi: 10.1016/j.biocel.2013.09.008 PubMedCrossRefGoogle Scholar
  51. 51.
    Vo BT, Morton D Jr, Komaragiri S, Millena AC, Leath C, Khan SA (2013) TGF-beta effects on prostate cancer cell migration and invasion are mediated by PGE2 through activation of PI3K/AKT/mTOR pathway. Endocrinology 154(5):1768–1779. doi: 10.1210/en.2012-2074 PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Kitamura Y, Shimohama S, Kamoshima W, Ota T, Matsuoka Y, Nomura Y, Smith MA, Perry G et al (1998) Alteration of proteins regulating apoptosis, Bcl-2, Bcl-x, Bax, Bak, Bad, ICH-1 and CPP32, in Alzheimer’s disease. Brain Res 780(2):260–269PubMedCrossRefGoogle Scholar
  53. 53.
    Woo RS, Lee JH, Yu HN, Song DY, Baik TK (2010) Expression of ErbB4 in the apoptotic neurons of Alzheimer’s disease brain. Anat Cell Biol 43(4):332–339. doi: 10.5115/acb.2010.43.4.332 PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Saidan Ding
    • 1
  • Weikan Wang
    • 2
  • Xuebao Wang
    • 1
  • Yong Liang
    • 1
  • Leping Liu
    • 4
  • Yiru Ye
    • 3
  • Jianjing Yang
    • 2
  • Hongchang Gao
    • 5
    Email author
  • Qichuan Zhuge
    • 2
    Email author
  1. 1.Zhejiang Provincial Key Laboratory of Aging and Neurological Disease Research, Department of Surgery Laboratorythe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouPeople’s Republic of China
  2. 2.Neurosurgery Departmentthe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouPeople’s Republic of China
  3. 3.School of Information and EngineeringWenzhou Medical UniversityWenzhouPeople’s Republic of China
  4. 4.Analytical and Testing CenterWenzhou Medical UniversityWenzhouPeople’s Republic of China
  5. 5.School of Pharmaceutical SciencesWenzhou Medical UniversityWenzhouPeople’s Republic of China

Personalised recommendations