Toll-like receptor 4 blocker as potential therapy for acetaminophen-induced organ failure in mice

Abstract

Acetaminophen (APAP, 4-hydroxyacetanilide) is the most common cause of acute liver failure in the United States. In addition to exhibiting hepatotoxicity, APAP exerts a nephrotoxic effect may be independent of the induced liver damage. Toll-like receptors (TLRs) have been suggested as a potential class of novel therapeutic targets. The aim of the present study was to investigate the potential of the TLR-4 blocker TAK-242 in the prevention of APAP-induced hepato-renal failure. Four groups of C57BL mice were studied: Vehicle-treated/control (VEH), APAP-treated (APAP), N-acetyl cysteine (NAC)-pretreated plus APAP (APAP + NAC) and TAK-242-pretreated plus APAP (APAP + TAK) groups. Mice were clinically assessed then perfused 4 h later. Liver and kidney tissues were collected and examined histologically using basic hematoxylin and eosin staining to detect signs of necrosis and inflammation. Plasma samples were collected to measure the levels of alanine transaminase, aspartate transaminase and serum creatinine. In addition, liver and kidney tissues were assayed to determine the levels of reduced glutathione. The results of the present study indicate the potential role of TLR-4 in APAP-induced organ toxicity. In the APAP + TAK and APAP + NAC groups, histopathological examination indicated that pretreatment with TAK-242 or NAC afforded protection against APAP-induced injury. However, this protective effect was more clinically evident in the APAP + TAK group compared with the APAP + NAC group. The various biochemical parameters (serum enzymes and reduced glutathione) revealed no significant protection in either of the pretreated groups. Therefore, the present study indicated that the TLR-4 blocker had protective effects against acute APAP toxicity in liver and kidney tissues. These effects were identified clinically, histologically and biochemically. Furthermore, the TLR-4 blocker TAK-242 exhibited antioxidant properties in addition to anti-inflammatory effects.

Acetaminophen from liver to brain: New insights into drug pharmacological action and toxicity

“…Additionally, blockers of TLR-4 are also capable of attenuating APAP-induced liver injury (102). Interestingly, activation of TLR-4 promotes activation of X-box Binding Protein-1 (XBP1) (103), which is a well known XBP1 transcription factor associated with endoplasmic reticulum (ER) stress.…”

“…ER-stress promotes post-transcriptional maturation of XBP1 mRNA resulting in the production of an active form of this transcription factor. Sodium 4-phenylbutyrate (4-PBA) is a low molecular weight fatty acid, that has been used in the treatment of several diseases, including liver injury by ischemia/reperfusion (102) and carbon tetrachloride toxicity (104). Among its known pharmacological effects, 4-PBA modulates the function of transcription factors associated with ER-stress, including JNK and XBP1 (105).…”

Alleviative effects from boswellic acid on acetaminophen-induced hepatic injury

“…Toll-like receptors (TLRs) are pattern recognition receptors mainly responsible for immuno modulation. The activation of TLR-3 and TLR-4 has been implicated in APAP-induced hepatic damage because both TLRs could stimulate the production of adaptor proteins including MYD88 and nuclear factor kappa B (NF-κB), which in turn promote the generation of oxidants and inflammatory cytokines and chemokines [ 7 , 8 ]. Furthermore, Cavassani et al .…”

The Effect of Pretreatment With Toll-Like Receptor 4 Antagonist Resatorvid on Methotrexate-Induced Liver Injury in Rats: Histopathological Study

“…It may indicate the requirement of longer treatment courses or coadministration courses. Still, it could be explained by resatorvid antagonism of TLR4 activation and upregulation caused by intracellular and extracellular damage-associated molecular patterns released during oxidative stress [45]. As a selective antagonist of TLR4, resatorvid inhibits both TLR4-Myeloid differential88 (MyD88)-dependent and MyD88-independent signaling pathways which induce inflammatory immune response and release of CK as TNF-α and interleukin-6 [46][47][48].…”