Naltrexone Protects Against Lipopolysaccharide/D-Galactosamine–Induced Hepatitis in Mice

Wang, Chien-Chuan; Cheng, Pao-Yun; Peng, Yi‐Jen; Wu, E. S. C.; Wei, Hsiao-Ping; Yen, Mao‐Hsiung

doi:10.1254/jphs.08096fp

Cited by 17 publications

(10 citation statements)

References 44 publications

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“…In several documents, it has been shown that Naltrexone as an opioid receptor antagonist could attenuate some features of inflammation. For example, Wang et al (37) reported that Naltrexone decreased ALT, AST and TNF-α in lipopolysaccharide/D-galactosamine-induced hepatitis in mice. In another report Payabvash et al (32) revealed that blockade of opioid receptors with Naltrexone declined ALT, AST, ALP and TNF-α in a rat model of chronic cholestasis.…”

Section: Discussionmentioning

confidence: 99%

Naltrexone attenuates endoplasmic reticulum stress induced hepatic injury in mice

Moslehi

Nabavizadeh

Dehpou

et al. 2014

Acta Physiologica Hungarica

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Endoplasmic reticulum (ER) stress provides abnormalities in insulin action, inflammatory responses, lipoprotein B100 degradation and hepatic lipogenesis. Excess accumulation of triglyceride in hepatocytes may also lead to disorders such as non-alcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Opioid peptides are involved in triglyceride and cholesterol dysregulation, inflammation and cell death. In this study, we evaluated Naltrexone effects on ER stress induced liver injury. To do so, C57/BL6 mice received saline, DMSO and Naltrexone, as control groups. ER stress was induced by tunicamycin (TM) injection. Naltrexone was given before TM administration. Liver blood flow and biochemical serum analysis were measured. Histopathological evaluations, TNF-α measurement and Real-time RT-PCR were also performed. TM challenge provokes steatosis, cellular ballooning and lobular inflammation which significantly reduced in Naltrexone treated animals. ALT, AST and TNF-α increased in the TM group and improved in the Naltrexone plus TM group. Triglyceride and cholesterol levels decreased in TM treated mice with no increase in Naltrexone treated animals. In the Naltrexone plus TM group, gene expression of Bax/Bcl-2 ratio and caspase3 significantly lowered compared with the TM group. In this study, we found that Naltrexone had a notable alleviating role in ER stress induced steatosis and liver injury.

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Section: Discussionmentioning

confidence: 99%

Naltrexone attenuates endoplasmic reticulum stress induced hepatic injury in mice

Moslehi

Nabavizadeh

Dehpou

et al. 2014

Acta Physiologica Hungarica

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“…Therefore, examination of plasma lipid and lipoprotein levels will be helpful to evaluate the extent of the hepatic damage. It is well known that plasma levels of cytokines, lipid peroxides and anti-oxidant status could be changed under acute or chronic hepatitis [12-14], which may also interfere the lipid metabolism in vivo.…”

Section: Discussionmentioning

confidence: 99%

Impaired plasma lipid profiles in acute hepatitis

Luo

Wang

et al. 2010

Lipids Health Dis

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The present study examined plasma lipid profiles in thirty patients suffered from acute viral hepatitis. Patients' blood samples were collected at both the debut and recovery of diseases. Thirty sex and age matched normal subjects were included as controls. Plasma total triglycerides (TG), total cholesterol, high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), apolipoprotein AI (ApoAI), apolipoprotein B (ApoB), lipoprotein (a) (Lp(a)), blood coagulation status including prothrombin complex activity and activated partial tromboplastin time (APTT), and hepatic functions were determined by the automatic biochemical analytical instrument. It demonstrated that plasma levels of total cholesterol, HDL-C and apoAI were significantly lower in the patients at the acute phase of hepatitis than those in normal subjects, whereas plasma levels of TG and LDL-C were obviously higher in the patients than in normal subjects (P < 0.05). Moreover, we demonstrated that patients' plasma levels of total cholesterol, LDL-C, HDL-C and apoAI were lower at the active phase of the diseases than at the recovering phase, which indicating that acute liver damage could significant influence lipid metabolism in vivo. No pathological changes of blood coagulation status occurred in these patients during the study as all selected patients had moderate hepatitis. It may conclude that examinations of plasma lipid profile could be considered as a clinical index to reflect liver damage in the active phase of hepatitis.

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“…Hence a sizable literature on blockade of LPS effects by naloxone and naltrexone makes no mention of TLR4, as it had not yet been discovered. The evidence of naloxone/naltrexone blockade of LPS effects is now quite far-reaching including excitatory post-synaptic potentials [22], seizures [23, 24], microglial activation [25–27], proinflammatory cytokines [25, 28], nitric oxide and superoxide [29, 30], neurotoxicity and neurodegeneration [31–34], hepatitis [35], septic shock [36, 37], hormone release [38], fever [39], pain [40], reduction in morphine analgesia [41, 42], and so on. Even when (+)-isomers of naloxone and naltrexone are employed to prevent possible influence of opioid receptors, there is suppression of LPS-induced proinflammatory responses [34, 43], LPS-induced excitotoxic death of dopamine neurons [33, 34]; suppression of neuropathic pain [12, 44]; potentiation of opioid analgesia [10, 45]); and decreased opioid-induced withdrawal, tolerance, hyperalgesia and constipation [2, 7, 10, 40].…”

Section: How Did a Focus On Tlr4 Arise?mentioning

confidence: 99%

Targeting the Toll of Drug Abuse: The Translational Potential of Toll-Like Receptor 4

Bachtell

Hutchinson²,

Wang³

et al. 2015

CNSNDDT

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There is growing recognition that glial proinflammatory activation importantly contributes to the rewarding and reinforcing effects of a variety of drugs of abuse, including cocaine, methamphetamine, opioids, and alcohol. It has recently been proposed that glia are recognizing, and becoming activated by, such drugs as a CNS immunological response to these agents being xenobiotics; that is, substances foreign to the brain. Activation of glia, primarily microglia, by various drugs of abuse occurs via toll like receptor 4 (TLR4). The detection of such xenobiotics by TLR4 results in the release of glial neuroexcitatory and neurotoxic substances. These glial products of TLR4 activation enhance neuronal excitability within brain reward circuitry, thereby enhancing their rewarding and reinforcing effects. Indeed, selective pharmacological blockade of TLR4 activation, such as with the non-opioid TLR4 antagonist (+)-naltrexone, suppresses a number of indices of drug reward/reinforcement. These include: conditioned place preference, self-administration, drug-primed reinstatement, incubation of craving, and elevations of nucleus accumbens shell dopamine. Notably, TLR4 blockade fails to alter self-administration of food, indicative of a selective effect on drugs of abuse. Genetic disruption of TLR4 signaling recapitulates the effects of pharmacological TLR4 blockade, providing converging lines of evidence of a central importance of TLR4. Taken together, multiple lines of evidence converge to raise TLR4 as a promising therapeutic target for drug abuse.

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Naltrexone Protects Against Lipopolysaccharide/D-Galactosamine–Induced Hepatitis in Mice

Cited by 17 publications

References 44 publications

Naltrexone attenuates endoplasmic reticulum stress induced hepatic injury in mice

Naltrexone attenuates endoplasmic reticulum stress induced hepatic injury in mice

Impaired plasma lipid profiles in acute hepatitis

Targeting the Toll of Drug Abuse: The Translational Potential of Toll-Like Receptor 4

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