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

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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.

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Acknowledgement

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

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Authors and Affiliations

  1. Zhejiang Provincial Key Laboratory of Aging and Neurological Disease Research, Department of Surgery Laboratory, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, People’s Republic of China

    Saidan Ding, Xuebao Wang & Yong Liang

  2. Neurosurgery Department, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, People’s Republic of China

    Weikan Wang, Jianjing Yang & Qichuan Zhuge

  3. School of Information and Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, People’s Republic of China

    Yiru Ye

  4. Analytical and Testing Center, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, People’s Republic of China

    Leping Liu

  5. School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, People’s Republic of China

    Hongchang Gao

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  1. Saidan Ding
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Correspondence to Hongchang Gao or Qichuan Zhuge.

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Ding, S., Wang, W., Wang, X. et al. Dopamine Burden Triggers Neurodegeneration via Production and Release of TNF-α from Astrocytes in Minimal Hepatic Encephalopathy. Mol Neurobiol 53, 5324–5343 (2016). https://doi.org/10.1007/s12035-015-9445-2

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