title: Dopamine Burden Triggers Neurodegeneration via Production and Release of TNF-α from Astrocytes in Minimal Hepatic Encephalopathy.
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.
authors.affiliation: 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.
authors.forename: Saidan
authors.initials: S
authors.lastname: Ding
authors.affiliation: Neurosurgery Department, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, People's Republic of China.
authors.forename: Weikan
authors.initials: W
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Xuebao
authors.initials: X
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Yong
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Analytical and Testing Center, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, People's Republic of China.
authors.forename: Leping
authors.initials: L
authors.lastname: Liu
authors.affiliation: School of Information and Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, People's Republic of China.
authors.forename: Yiru
authors.initials: Y
authors.lastname: Ye
authors.affiliation: Neurosurgery Department, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, People's Republic of China.
authors.forename: Jianjing
authors.initials: J
authors.lastname: Yang
authors.affiliation: School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, People's Republic of China. gaohc27@wmu.edu.cn.
authors.forename: Hongchang
authors.initials: H
authors.lastname: Gao
authors.affiliation: Neurosurgery Department, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, People's Republic of China. firstdsdan@163.com.
authors.forename: Qichuan
authors.initials: Q
authors.lastname: Zhuge
mesh_terms: D000818:Animals; D017209:Apoptosis; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D018920:Coculture Techniques; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D006501:Hepatic Encephalopathy / Q000378:metabolism* / Q000473:pathology*; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000378:metabolism*
chemical_list: D004298:Dopamine; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha
keywords: Astrocytic TNF-α; Cognitive impairment; Dopamine (DA); Minimal hepatic encephalopathy (MHE); Neurodegeneration