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.

DA Negatively Regulates IGF-I Actions Implicated in Cognitive Function via Interaction of PSD95 and nNOS in Minimal Hepatic Encephalopathy

“…Importantly, DA released by midbrain dopaminergic neurons in both the striatum and the substantia nigra (Cheramy et al, 1981 ) controls GABA release through activation of D1 receptors located at the somato-dendrites and terminals of striato-nigral medium spiny neurons (Acosta-García et al, 2009 ). In addition, we have reported that DA influenced astrocyte function (Ding et al, 2014b , c , 2016 ). Therefore, it is imperative to elucidate the underlying pathogenesis of MHE as well as the appropriate therapeutic drug.…”

Microinjection molding of polyamide 6

“…While the features of macroscopic parts and the correlations with processing conditions are well understood, less information is available about μ P. It was reported that the degree of crystallinity of the μ P and the fraction of oriented polymer layer were larger, and the average size of the crystallites was smaller for μ P compared with parts produced by conventional injection molding . For polypropylene, the crystallinity and molecular orientation was observed to vary with the shear stress induced during μ IM .…”

The Neurotrophic and Anti-Inflammatory Effect of β-asarone on the DA-Induced the Pathology of Minimal Hepatic Encephalopathy

“…Our previous studies have con rmed that the pathogenesis of MHE was caused by the abnormal elevation of intracranial DA [3,4,5,6,7,8]. It has been demonstrated as a novel regulatory mechanism that DA -induced astrocytic TNF-α release triggers progressive neurodegeneration, which leads to learning and memory decline in MHE [9]. Tumor necrosis factor-α (TNFα) signaling has been shown to regulate neuroin ammation, and plays roles in modulation of microglial activation [10], control of glutamatergic transmission and regulation of synaptic strength [11] in the central nervous system (CNS) [12].…”