Asymmetric Dimethylarginine and Hepatic Encephalopathy: Cause, Effect or Association?

Anna Czarnecka,Krzysztof Milewski,Magdalena Zielińska

doi:10.1007/s11064-016-2111-x

Anna Czarnecka, Krzysztof Milewski + Show 1 more

Open Access

https://doi.org/10.1007/s11064-016-2111-x

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Abstract

The methylated derivative of l-arginine, asymmetric dimethylarginine (ADMA) is synthesized in different mammalian tissues including the brain. ADMA acts as an endogenous, nonselective, competitive inhibitor of all three isoforms of nitric oxide synthase (NOS) and may limit l-arginine supply from the plasma to the enzyme via reducing its transport by cationic amino acid transporters. Hepatic encephalopathy (HE) is a relatively frequently diagnosed complex neuropsychiatric syndrome associated with acute or chronic liver failure, characterized by symptoms linked with impaired brain function leading to neurological disabilities. The l-arginine—nitric oxide (NO) pathway is crucially involved in the pathomechanism of HE via modulating important cerebral processes that are thought to contribute to the major HE symptoms. Specifically, activation of this pathway in acute HE leads to an increase in NO production and free radical formation, thus, contributing to astrocytic swelling and cerebral edema. Moreover, the NO-cGMP pathway seems to be involved in cerebral blood flow (CBF) regulation, altered in HE. For this reason, depressed NO-cGMP signaling accompanying chronic HE and ensuing cGMP deficit contributes to the cognitive and motor failure. However, it should be remembered that ADMA, a relatively little known element limiting NO synthesis in HE, may also influence the NO-cGMP pathway regulation. In this review, we will discuss the contribution of ADMA to the regulation of the NO-cGMP pathway in the brain, correlation of ADMA level with CBF and cognitive alterations observed during HE progression in patients and/or animal models of HE.

Highlights

ALF Acute liver failure asymmetric dimethylarginine (ADMA) Asymmetric dimethylarginine BH4 Tetrahydrobiopterin BDE Bile duct excision BDL Bile duct ligation CAT Cationic amino acid transporter cerebral blood flow (CBF) Cerebral blood flow CLF Chronic liver failure cyclic guanidine monophosphate (cGMP) Cyclic guanosine monophosphate DDAH Dimethylarginine dimethylaminohydrolase eNOS Endothelial nitric oxide synthase (NOS) HE Hepatic encephalopathy inducible NOS (iNOS) Inducible NOS neuronal NOS (nNOS) Neuronal NOS NO Nitric oxide NOS Nitric oxide synthase portacaval shunt (PCS) Portacaval shunt PPVL Partial portal vein ligation protein-methyl transferase (PRMT) Protein arginine methyltransferase SDMA Symmetric dimethylarginine TAA Thioacetamide transjugular intrahepatic portosystemic shunt (TIPS) Transjugular intrahepatic portosystemic shunt
The observations that elevated ADMA levels predict future outcomes in cohort studies associated with cardiovascular diseases demonstrated the potential for methylarginines to act as a marker in liver failure accompanying HE pathology
The exact mechanism, by which direct effects of ADMA in the brain are translated into CBF changes during HE has not been elucidated in detail

Summary

Introduction

ALF Acute liver failure ADMA Asymmetric dimethylarginine BH4 Tetrahydrobiopterin BDE Bile duct excision BDL Bile duct ligation CAT Cationic amino acid transporter CBF Cerebral blood flow CLF Chronic liver failure cGMP Cyclic guanosine monophosphate DDAH Dimethylarginine dimethylaminohydrolase eNOS Endothelial NOS HE Hepatic encephalopathy iNOS Inducible NOS nNOS Neuronal NOS NO Nitric oxide NOS Nitric oxide synthase PCS Portacaval shunt PPVL Partial portal vein ligation PRMT Protein arginine methyltransferase SDMA Symmetric dimethylarginine TAA Thioacetamide TIPS Transjugular intrahepatic portosystemic shunt. Inhibition of DDAH leads to an increase in ADMA levels and to a decrease in NO production. Elevated plasma concentrations of ADMA are observed in patients with severe acute alcoholic hepatitis [33] and acute liver failure [32].

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Conclusion