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


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.


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



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)


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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

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