Serotonin Deficiency Exacerbates Acetaminophen-Induced Liver Toxicity In Mice

Abstract

Acetaminophen (APAP) overdose is a major cause of acute liver failure. Peripheral 5-hydroxytryptamine (serotonin, 5-HT) is a cytoprotective neurotransmitter which is also involved in the hepatic physiological and pathological process. This study seeks to investigate the mechanisms involved in APAP-induced hepatotoxicity, as well as the role of 5-HT in the liver's response to APAP toxicity. We induced APAP hepatotoxicity in mice either sufficient of serotonin (wild-type mice and TPH1-/- plus 5- Hydroxytryptophan (5-HTP)) or lacking peripheral serotonin (Tph1-/- and wild-type mice plus p-chlorophenylalanine (PCPA)).Mice with sufficient 5-HT exposed to acetaminophen have a significantly lower mortality rate and a better outcome compared with mice deficient of 5-HT. This difference is at least partially attributable to a decreased level of inflammation, oxidative stress and endoplasmic reticulum (ER) stress, Glutathione (GSH) depletion, peroxynitrite formation, hepatocyte apoptosis, elevated hepatocyte proliferation, activation of 5-HT2B receptor, less activated c-Jun NH2-terminal kinase (JNK) and hypoxia-inducible factor (HIF)-1α in the mice sufficient of 5-HT versus mice deficient of 5-HT. We thus propose a physiological function of serotonin that serotonin could ameliorate APAP-induced liver injury mainly through inhibiting hepatocyte apoptosis ER stress and promoting liver regeneration.

Optical control of pain in vivo with a photoactive mGlu5 receptor negative allosteric modulator

“…single dose of 10 mg/kg, ip). Interestingly, while a 3-day acetaminophen treatment (300 mg/kg, ip) induced a significant increase in serum ALT and AST (Figure 6A), as described (Zhang et al, 2015), the 3-day raseglurant and JF-NP-26 treatment (50 mg/kg, ip) did not alter ALT and AST serum levels (Figure 6A). Thus, these results demonstrated that raseglurant and JF-NP-26 treatments used in our pain animal models were safe because no liver toxicity was observed.

10.7554/eLife.23545.009Figure 6.Effect of systemic administration and in vivo photoactivation of JF-NP-26 in liver toxicity and memory in mouse.( A ) Effect of Raseglurant and JF-NP-26 on serum transaminases.

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Protective effects of luteolin against acetaminophen-induced acute liver failure in mouse

“…injection [14]. Animals were divided into three groups as follows: (1) the normal control group: male C57BL/6 mice remained untreated; (2) the APAP group: male C57BL/6 mice were treated i.p with physiological saline for 3 days before APAP challenge; and (3) the APAP + luteolin group: male C57BL/6 mice were treated i.p with luteolin for 3 days before APAP challenge.…”

“…Activities of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were determined by an automated procedure in the Department of Inspection, The First Affiliated Hospital of Xi'an Jiaotong University [15].…”

“…The homogenates were then centrifuged at 4000 rpm (4°C) for 20 min to collect supernatants for determination of GSH, glutathione peroxidase (GSH-px), superoxide dismutase (SOD) and malondialdehyde (MDA) contents. They were measured using the activity assay kits from NanJing JianCheng Bioengineering Institute, using methods as described previously [15].…”

Modulation of the Tryptophan Hydroxylase 1/Monoamine Oxidase‐A/5‐Hydroxytryptamine/5‐Hydroxytryptamine Receptor 2A/2B/2C Axis Regulates Biliary Proliferation and Liver Fibrosis During Cholestasis

“…Although the role of 5HT in liver inflammation is more defined, the role of the 5HTR2A/2B/2C agonist/antagonists in liver inflammation is still unclear. Indeed, 5HT deficiency has been shown to worsen acetaminophen‐induced liver toxicity in mice . 5HTR7 agonists reduce CCl 4 ‐induced oxidative stress, liver inflammation, and fibrosis .…”