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

Saidan Ding,Weishan Zhuge,Qichuan Zhuge,Jianjing Yang,Yuanshao Lin,Xuebao Wang,Chengde Wang,Jiangnan Hu

doi:10.3389/fncel.2017.00258

Abstract

Insulin-like growth factor I (IGF-I) has been positively correlated with cognitive ability. Cognitive decline in minimal hepatic encephalopathy (MHE) was shown to be induced by elevated intracranial dopamine (DA). The beneficial effect of IGF-I signaling in MHE remains unknown. In this study, we found that IGF-I content was reduced in MHE rats and that IGF-I administration mitigated cognitive decline of MHE rats. A protective effect of IGF-I on the DA-induced interaction between postsynaptic density protein 95 (PSD95) and neuronal nitric oxide synthase (nNOS) was found in neurons. Ribosomal S6 protein kinase (RSK) phosphorylated nNOS in response to IGF-I by recruiting extracellular signal-regulated kinase (ERK1/2). In turn, DA inactivated the ERK1/2/RSK pathway and stimulated the PSD95–nNOS interaction by downregulating IGF-I. Inhibition of the interaction between PSD95 and nNOS ameliorated DA-induced memory impairment. As DA induced deficits in the ERK1/2/RSK pathway and the interaction between PSD95 and nNOS in MHE brains, IGF-I administration exerted a protective effect via interruption of the interaction between PSD95 and nNOS. These results suggest that IGF-I antagonizes DA-induced cognitive loss by disrupting PSD95–nNOS interactions in MHE.

Highlights

T by IC87201 treatment (F(2,37) = 4.318, p < 0.05). These results indicate that the PSD95–neuronal nitric oxide synthase (nNOS) interaction was associated with pathogenesis of minimal hepatic encephalopathy (MHE)
The liver cirrhosis in animal models and in patients was observed to be improved by the systemic administration of IGF-1 (Castilla-Cortazar et al, 1997; Conchillo et al, 2005; Sobrevals et al, 2010)
Our results demonstrate that IGF-1 has endogenous defense mechanisms against liver cirrhosis in MHE and provide support for use of IGF-1 against cognitive decline and MHE pathology via an antifibrotic effect (Blaas et al, 2010)

Summary

Introduction

Actions Implicated in Cognitive Function via Interaction of PSD95 and nNOS in Minimal Hepatic Encephalopathy.Front. Actions Implicated in Cognitive Function via Interaction of PSD95 and nNOS in Minimal Hepatic Encephalopathy. Minimal hepatic encephalopathy (MHE) is indicated by mild disruption in psychomotor skills, cognition, or bimanual and visuo-motor coordination, which can be demonstrated using psychometric tests (Wein et al, 2004; Montoliu et al, 2007). If the diagnosis is made early in the process of the disease, these characteristics are reversible (Blei et al, 2001). Patients in the early stages of cirrhosis disease often manifest MHE. MHE can eventually develop into clinical HE and this leads to more serious alterations in intellectual functions, consciousness and coordination, which, in the most severe cases, can progress to coma and even death (Romero-Gómez et al, 2001). The pathogenesis of MHE and therapeutic drugs remains to be investigated

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