JKB-122 is effective, alone or in combination with prednisolone in Con A-induced hepatitis.

Con A-induced hepatitis in mice is an established model of autoimmune hepatitis (AIH). JKB-122, a toll-like receptor 4 (TLR4) antagonist, was tested for hepatotprotectant activity. Within several hours of Con A challenge (15mg/kg iv), increased production of proinflammatory cytokines with inflammatory infiltrate occurred in the liver. The severity of tissue necrosis and the amount of circulating liver enzymes peak at 24h post Con A challenge. JKB-122 was given 24 and 16h before, then concurrently, and 4 and 8h (× 5 doses) after challenge with Con A. Serum and liver were harvested at 3, 9 and 24h post Con A challenge. JKB-122 at 20 and 50mg/kg po prevented the increase of serum liver enzymes by 47% and 95% respectively vs vehicle control 24h post Con A. JKB-122 significantly inhibited Con A-induced pathological lesions in the liver and the amount of IFN-γ IL-1ß, IL-4, IL-5, IL-6, IL-17A and TNF-α starting as early as 3h post Con A. Moreover, JKB-122 given concurrently (× 3 doses) with Con A showed similar effect. Finally, JKB-122 enhanced the therapeutic effects of submaximal dose of prednisolone with improved lesion score. It is concluded that JKB-122 at 20 and 50mg/kg po caused dose-dependent inhibition of elevated liver enzymes in Con A-induced hepatitis in mice, indicating hepatoprotectant activity. The results suggest that JKB-122 as monotherapy or in combination with prednisolone may offer a viable approach to the treatment of AIH.

Opioid-like compound exerts anti-fibrotic activity via decreased hepatic stellate cell activation and inflammation.

Hepatic fibrosis is characterized by excess type I collagen deposition and exacerbated inflammatory response. Naltrexone, an opioid receptor antagonist used for treating alcohol abuse, attenuates hepatocellular injury in fibrotic animal models, which can be accompanied by deleterious side effects. Additionally, opioid neurotransmission is upregulated in patients with inflammatory liver disease. Several derivatives of Naltrexone, Nalmefene (Nal) and JKB-119, exert immunomodulatory activity; however, unlike Nal, JKB-119 does not show significant opioid receptor antagonism. To delineate the potential hepatoprotective effects of these compounds, we investigated if JKB-119 and Nal could modulate activation of hepatic stellate cells (HSCs), primary effector cells that secrete type I collagen and inflammatory mediators during liver injury. Our results demonstrated that Nal or JKB-119 treatment decreased smooth muscle α-actin, a marker of HSC activation, mRNA and protein expression. Despite decreased collagen mRNA expression, both compounds increased intracellular collagen protein expression; however, inhibition of collagen secretion was observed. To address a possible mechanism for suppressed collagen secretion or retention of intracellular collagen, endoplasmic (ER) protein expression and matrix metalloproteinase (MMP) activity were examined. While no change in ER protein expression (Grp78, PDI, Hsp47) was observed, MMP13 mRNA expression was dramatically increased. In an acute LPS inflammatory injury animal model, JKB-119 treatment decreased liver injury (ALT), plasma TNFα and PMN liver infiltration. Overall, these results suggest that JKB-119 can directly inhibit HSC activation attributed to anti-inflammatory activity and may, therefore, attenuate inflammation associated with HSC activation and liver disease.

Anti-inflammatory effects of LK-3, on LPS-induced sepsis in rats.

Dextromethorphan (DM), an antitussive agent, has been shown to have anti-inflammatory and immunomodulatory effects in vitro. Thus, the aim of this study was to evaluate the effects of LK-3, an analog of DM, on sepsis induced by intravenous (i.v.) administration of lipopolysaccharide (LPS; 10 mg/ kg) in anesthetized Wistar rats. Results demonstrated that post-treatment with LK-3 (4 mg/kg, i.v.) significantly attenuated the deleterious hemodynamic changes (e.g., hypotension and bradycardia) in rats treated with LPS. Meanwhile, LK-3 (4 mg/kg) significantly inhibited the elevation of plasma tumor necrosis factor-alpha, as well as values of glutamate-oxalacetate transaminase (GOT) and glutamate-pyruvate transaminase (GPT) caused by LPS. The induction of inducible NO synthase and the overproduction of NO and superoxide anions by LPS were also reduced by post-treatment of LK-3. Moreover, infiltration of neutrophils into the lungs and liver of rats 8 h after treatment with LPS was also reduced by post-treatment with LK-3. In conclusion, the beneficial effects of LK-3 on LPS-induced sepsis resulted from its anti-inflammatory and antioxidant effects.