Late Protective Effect of Netrin-1 in the Murine Acetaminophen Hepatotoxicity Model.

08:00 EDT 24th March 2020 | BioPortfolio

Summary of "Late Protective Effect of Netrin-1 in the Murine Acetaminophen Hepatotoxicity Model."

Acetaminophen (APAP) overdose induced acute liver failure is an important clinical problem in the United States and the current antidote N-acetylcysteine, has a short early therapeutic window. Since most patients present late to the clinic, there is need for novel late acting therapeutic options. Though the neuronal guidance cue netrin-1, has been shown to promote hepatic repair and regeneration during liver ischemia/reperfusion injury, its effect in APAP - induced hepatotoxicity is unknown. In the quest for a late-acting therapeutic intervention in APAP-induced liver injury, we examined the role of netrin-1 in a mouse model of APAP overdose. Male C57BL/6J mice were co-treated with exogenous netrin-1 or vehicle control, along with 300mg/kg APAP and euthanized at 6, 12 and 24h. Significant elevations in ALT indicative of liver injury were seen in control mice at 6h and this was not affected by netrin-1 administration. Also, netrin-1 treatment did not influence mitochondrial translocation of phospho-JNK, or peroxynitrite formation indicating that there was no interference with APAP-induced injury processes. Interestingly however, netrin-1 administration attenuated liver injury at 24h, as seen by ALT levels and histology, at which time significant elevations in the netrin-1 receptor, adenosine A2B (A2BAR) as well as macrophage infiltration was evident. Removal of resident macrophages with clodronate liposomes or treatment with the A2BAR antagonist PSB1115 blocked the protective effects of netrin-1. Thus, our data indicate a previously unrecognized role for netrin-1 in attenuation of APAP hepatotoxicity by enhancing recovery and regeneration, which is mediated through the A2BAR and involves resident liver macrophages.


Journal Details

This article was published in the following journal.

Name: Toxicological sciences : an official journal of the Society of Toxicology
ISSN: 1096-0929


DeepDyve research library

PubMed Articles [23759 Associated PubMed Articles listed on BioPortfolio]

Early Acetaminophen-Protein Adducts Predict Hepatotoxicity Following Overdose.

Acetaminophen-protein adducts are a specific biomarker of toxic acetaminophen (paracetamol) metabolite exposure. In patients with hepatotoxicity (ALT>1000U/L), a concentration >1.0nmol/mL is sensitive...

Effect of Netrin-1 Anti-Inflammatory Factor on Acute Lung Injury in Sepsis Rats.

BACKGROUND Acute lung injury (ALI) often occurs early and seriously in the progress of sepsis. Netrin-1 is demonstrated to be an effective anti-inflammatory agent. However, whether netrin-1 can reliev...

Public awareness of acetaminophen and risks of drug induced liver injury: Results of a large outpatient clinic survey.

Acetaminophen is one of the most commonly consumed analgesics world wide. Generally perceived as a safe medication, it is the most common cause of acute liver failure in the United States with inadver...

Osthole ameliorates cartilage degradation by downregulation of NF-κB and HIF-2α pathways in an osteoarthritis murine model.

Osteoarthritis (OA) is a common and disabling joint disease mainly characterized by cartilage degradation, with the knees most commonly affected. No effective treatment for the cartilage degradation o...

Hesperetin attenuated acetaminophen-induced hepatotoxicity by inhibiting hepatocyte necrosis and apoptosis, oxidative stress and inflammatory response via upregulation of heme oxygenase-1 expression.

Acetaminophen (APAP) is a common antipyretic and analgesic drug, but its overdose can induce acute liver failure with lack of effective therapies. Hesperetin, a dihydrogen flavonoid compound, has been...

Clinical Trials [6931 Associated Clinical Trials listed on BioPortfolio]

Acetaminophen-Induced Hepatotoxicity in Chronic Alcohol Abusers

It is widely believed that people who abuse alcohol can sustain a liver injury after taking doses of acetaminophen just above the recommended maximum dose. This study is designed to look ...

Effect of Race/Ethnicity and Genes on Acetaminophen Pharmacokinetics

Although acetaminophen is the most commonly used nonprescription drug in the USA, little is known regarding the influence of genes and race/ethnicity on acetaminophen disposition. The inve...

The Role of Netrin -1 in Acute Coronary Syndrome

In our study, Netrin -1; We found that patients with ACS increased at the time of admission, decreased TIMI 3 flow after angiography, and higher risk groups in high risk groups such as TIM...

Effect of Use of Ureteral Access Sheath on Levels of Cystatin C & Netrin-1 in Patients Undergoing RIRS

In this study, it is aimed to evaluate whether use of a ureteral access sheath (UAS) during retrograde intrarenal surgery (RIRS) due to kidney stone has any effect on protecting the kidney...

A Study on Health - Related Quality of Life in Patients With Rheumatic Diseases Taking Tramadol 37.5mg/Acetaminophen 325mg Tablets

The objective of this observational study is to assess improvement of quality of life in the patients who are administered Tramadol 37.5mg/Acetaminophen 325mg tablets for 10~14 weeks accor...

Medical and Biotech [MESH] Definitions

A catatoxic steroid and microsomal enzyme inducer having significant effects on the induction of cytochrome P450. It has also demonstrated the potential for protective capability against acetaminophen-induced liver damage.

Specialized clothing or equipment worn for protection against health hazards. Personal Protective Equipment may include MASKS; RESPIRATORY PROTECTIVE DEVICES; HEAD PROTECTIVE DEVICES; EYE PROTECTIVE DEVICES; EAR PROTECTIVE DEVICES; PROTECTIVE CLOTHING; and protective footwear.

A replication-defective strain of Murine leukemia virus (LEUKEMIA VIRUS, MURINE) capable of transforming lymphoid cells and producing a rapidly progressing lymphoid leukemia after superinfection with FRIEND MURINE LEUKEMIA VIRUS; MOLONEY MURINE LEUKEMIA VIRUS; or RAUSCHER VIRUS.

A replication-defective murine sarcoma virus (SARCOMA VIRUSES, MURINE) capable of transforming mouse lymphoid cells and producing erythroid leukemia after superinfection with murine leukemia viruses (LEUKEMIA VIRUS, MURINE). It has also been found to transform cultured human fibroblasts, rat liver epithelial cells, and rat adrenocortical cells.

A dual inhibitor of both cyclooxygenase and lipoxygenase pathways. It exerts an anti-inflammatory effect by inhibiting the formation of prostaglandins and leukotrienes. The drug also enhances pulmonary hypoxic vasoconstriction and has a protective effect after myocardial ischemia.

Quick Search

DeepDyve research library

Relevant Topic

Hepatology is the study of liver, gallbladder, biliary tree, and pancreas, and diseases associated with them. This includes viral hepatitis, alcohol damage, cirrhosis and cancer. As modern lifestyles change, with alcoholism and cancer becoming more promi...

Searches Linking to this Article