Hepatoprotective effects of melatonin and celecoxib against ethanol-induced hepatotoxicity in rats

Abstract

Objectives: Several studies demonstrated the antioxidant and anti-inflammatory role of melatonin and celecoxib. This study is designed to explore the underlying mechanism of hepatoprotective effects of melatonin and celecoxib against ethanol-induced hepatotoxicity by morphological, and biochemical approaches.

Materials and methods: Adult male rats were divided into five groups: saline, ethanol, melatonin, and celecoxib were administered for 11 consecutive days after ethanol injection. Biochemical analyses were performed for the determination of glutathione (GSH), glutathione S-transferase (GST), and inducible nitric oxide (iNOS). Immunohistochemistry was performed to determine the level of different inflammatory markers.

Results: Histopathological results showed that ethanol-induced marked hepatic injury leads to cloudy swelling, hydropic degeneration, apoptosis, and focal necrosis in all hepatic zones. Biochemical analysis revealed significant increases in serum transaminases and alkaline phosphatase in the ethanol group. Oxidative stress associated with attenuated antioxidant enzymes was also spotted in the ethanol group, as ethanol down-regulated GSH, GST, and upregulated NO. Additionally, ethanol increased the activation and the expression of tumor necrotic factor (TNF-α), p-NF_KB, and COX2. Finally, hepatic cellular apoptosis was clearly obvious in ethanol intoxicated animals using activated JNK staining.

Conclusion: These results provided pieces of evidence that the hepatoprotective effect of melatonin and celecoxib is possibly mediated through the modulation of JNK and TNF-α signaling pathways with subsequent suppression of inflammatory and apoptotic processes.     

塞来考昔对女性卵巢功能的影响

目的 :观察塞来考昔 (celecoxib)对女性卵巢功能的影响。方法 :5 6例痛经病人分为 2组 ,A组给予塞来考昔治疗 1wk ,B组给予山莨菪碱治疗1wk ,采用对照的方法进行临床试验。结果 :塞来考昔对治疗前后病人性激素 (PRL ,E2 ,LH ,FSH)水平无明显影响 (P >0 .0 5 ) ,与山莨菪碱治疗组比较无显著差异 (P >0 .0 5 ) ,其对滤泡直径的影响与山莨菪碱治疗组比较亦无显著差异 [(2 0 .1±s 1.3)mmvs(19.4± 1.1)mm ,P >0 .0 5 ]。结论 :短期使用塞来考昔对女性卵巢功能可能无明显影响。     

Etoricoxib and celecoxib sensitive indomethacin-responsive headache disorders

Indomethacin-responsive headaches encompass a group of disorders which include a subset of the trigeminal autonomic cephalalgias and other paroxysmal, often precipitated primary headaches. Many patients show a rapid therapeutic response to indomethacin, which is limited by intolerability. Etoricoxib and celecoxib, selective inhibitors of cyclo-oxygenase-2 (COX-2), spare gastroduodenal COX-1 activity and are less likely to cause gastrointestinal adverse effects than indomethacin. We report a case series of eight patients, seven who responded to etoricoxib and one patient who responded to celecoxib.     

Experimental study of the safety of the selective COX‐2 inhibitor,celecoxib, for gastric mucosa

OBJECTIVE: To compare the gastric mucosal damage induced by a COX‐2 inhibitor, celecoxib, and a conventional NSAID, indomethacin. METHODS: A rat model of NSAID‐induced gastric mucosal damage was prepared for indomethacin and celecoxib separately (n = 8). After gastric damage was induced by 100% ethanol, celecoxib was administered by gastric gavage (n = 8). Gastric mucosal concentrations of 6‐keto‐PGF_1α and TXB₂ and the lesion index (LI) were measured. Morphological changes of the gastric mucosa were assessed under light and scanning electron microscopy. RESULTS: Indomethacin caused marked gastric damage (LI: 13.38 ± 2.06) and significant reduction of the concentrations of 6‐keto‐PGF_1α and TXB₂ (P < 0.01), Celecoxib did not produce necrotic injuries on healthy gastric mucosa (LI: 0), but the mucosal injuries previously induced by ethanol worsened after its administration (LI: 37.19 ± 3.34 vs 19.90 ± 2.28, P < 0.01). CONCLUSIONS: Inhibition of COX‐1 is the major mechanism of NSAIDs in producing gastric mucosal damage. As a selective COX‐2 inhibitor, celecoxib does not produce toxic injuries of the healthy gastric mucosa, and is thus safer than conventional NSAID. However, when administered in the presence of an altered gastric mucosa, gastric injuries were worsened.