Thalidomide ameliorates carbon tetrachloride induced cirrhosis in the rat

Muriel, Pablo; Fernández-Martínez, Eduardo; Pérez-Álvarez, Víctor; Lara‐Ochoa, Francisco; Ponce, Susana; García, J. Iglesias; Shibayama, Mineko; Tsutsumi, Vı́ctor

doi:10.1097/00042737-200309000-00003

Cited by 31 publications

(22 citation statements)

References 22 publications

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“…The doses of thalidomide administered in other studies 25,[56][57][58] were decided upon without explanation. In the present study, we considered that the maximum recommended oral dose for the treatment of TB, AIDS, and leprosy in adult humans is 200-1200 mg/day, and by assuming an average body weight of 60 kg, we decided on a dose of 3-20 mg/kg/day.…”

Section: Discussionmentioning

confidence: 99%

The effect of thalidomide on spinal cord ischemia/reperfusion injury in a rabbit model

et al. 2006

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Study design: Randomized study. Objectives: To evaluate the effects of thalidomide on spinal cord ischemia/reperfusion injury via reduced TNF-a production. Setting: Animal experimental laboratory, Clinical Research Institute of Seoul National University Hospital, Seoul, Korea. Methods: Spinal cord ischemia was induced in rabbits by occluding the infrarenal aorta. Rabbits in group N did not undergo ischemic insult, but rabbits in groups C (the untreated group), THA, and THB underwent ischemic insult for 15 min. The THA and THB groups received thalidomide (20 mg/kg) intraperitoneally (i.p.) before ischemia, but only the THB group received thalidomide (i.p., 20 mg/kg) after 24 and 48 h of reperfusion. After evaluating neurologic functions at 1.5 h, 3, and 5 days of reperfusion, rabbits were killed for histopathologic examination and Western blot analysis of TNF-a. Results: The THA and THB groups showed significantly less neurologic dysfunction than the C group at 1.5 h, 3, and 5 days of reperfusion. The number of normal spinal motor neurons in ventral gray matter was higher in THA and THB than in C, but no difference was observed between THA and THB. Western blot analysis showed a significantly higher level of TNF-a in C than in THA and THB at 1.5 h of reperfusion, but no difference was observed between C, THA, or THB at 3 or 5 days of reperfusion. Conclusion: Thalidomide treatment before ischemic insult reduces early phase ischemia/ reperfusion injury of the spinal cord in rabbits.

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Section: Discussionmentioning

confidence: 99%

The effect of thalidomide on spinal cord ischemia/reperfusion injury in a rabbit model

et al. 2006

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“…The effects of thalidomide on tumor necrosis factor-␣ (TNF-␣ ) release play an important role in these properties, which may depend on its selective degradation of TNF-␣ mRNA [4][5][6] . Recently, thalidomide has been found to be effective in experimental liver fibrosis, possibly via a mechanism which might be associated with the suppression of TNF-␣ production by thalidomide [7,8] . However, the definite pathway of this suppression has not been elucidated.…”

Section: Introductionmentioning

confidence: 99%

Thalidomide in Rat Liver Cirrhosis: Blockade of Tumor Necrosis Factor-α via Inhibition of Degradation of an Inhibitor of Nuclear Factor-κB

Paul

Xiao

et al. 2006

Pathobiology

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Background/Aims: Thalidomide inhibited tumor necrosis factor-α (TNF-α) effectively in many trials. The aim of this study was to investigate the effect of thalidomide on the expression of nuclear factor-ĸB (NF-ĸB), inhibitor of NF-ĸB (IĸB) and TNF-α in a rat model of liver cirrhosis. Methods: Liver cirrhosis was achieved by intraperitoneal injection of carbon tetrachloride thrice weekly, and thalidomide (10 or 100 mg/kg/day) was given daily by intragastric route for 8 weeks. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), prealbumin (PA), hyaluronic acid (HA) and laminin (LN), and hydroxyproline (HYP), NF-ĸBp65, α-smooth muscle actin (α-SMA) protein and TNF-α mRNA were studied in the liver, IĸBα and TNF-α protein in the cytoplasm and NF-ĸBp65 protein in the nucleus. Results: Compared with nontreated cirrhotic rats, the histopathology of rats given thalidomide (100 mg/kg) was significantly better. Serum ALT, AST, HA and LN and HYP content in the liver were significantly decreased and PA was elevated (p < 0.01) in this group; the expression of TNF-α mRNA and protein, NF-ĸBp65 and α-SMA were significantly decreased and IĸBα protein was also elevated (p < 0.01). Conclusion: Thalidomide downregulates NF-ĸB-induced TNF-α and activates hepatic stellate cells (HSC) via inhibition of IĸB degradation to prevent liver cirrhosis.

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“…This proposed mechanism may contribute to the anti-fibrogeneic actions of thalidomide in our in vitro and in vivo studies. In a previous study, Muriel et al observed that administration of thalidomide in carbontetrachloride-induced cirrhotic rats can reduce the hepatic hydroxyproline content, lipid peroxidation, ALT, c-GT and ALP levels [25]. In the present study using a different animal model, we additionally included a-SMA protein expression, and mRNA expression of fibrosis-related genes including TGF-b1, a-SMA and collagen 1a2 for therapeutic evaluation of thalidomide.…”

Section: Discussionmentioning

confidence: 95%

“…In alcohol-mediated toxicity, thalidomide prevents Kupffer cell sensitization and reduces liver injury [24]. Thalidomide has also been reported to ameliorate hepatic fibrosis in rat models induced by carbon tetrachloride, bile duct obstruction, and thioacetamide [25][26][27]. However, cellular mechanisms of action of thalidomide are yet unclear in these studies.…”

Section: Introductionmentioning

confidence: 99%

Anti-Fibrotic Effects of Thalidomide on Hepatic Stellate Cells and Dimethylnitrosamine-Intoxicated Rats

Chong¹,

Hsu²,

Chiu

et al. 2006

J Biomed Sci

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SummaryTumor necrosis factor-alpha (TNF-a) plays a central role in cellular necrosis, apoptosis, organ failure, tissue damage, inflammation and fibrosis. These processes, occurring in liver injury, may lead to cirrhosis. Thalidomide, a-N-phthalidoglutarimide, (C 13 H 10 N 2 ) 4 , has been shown to have immunomodulatory and anti-inflammatory properties, possibly mediated through its anti-TNF-a effect. In this study, we investigated the in vitro and in vivo effects of thalidomide on hepatic fibrosis. A cell line of rat hepatic stellate cells (HSC-T6) was stimulated with transforming growth factor-b1 (TGF-b1) or TNF-a. The inhibitory effects of thalidomide on the NFjB signaling cascade and fibrosis markers including a-smooth muscle actin (a-SMA) and collagen, were assessed. An in vivo therapeutic study was conducted in dimethylnitrosamine (DMN)-treated rats, which were randomly assigned to 1 of 4 groups: vehicle (0.7% carboxyl methyl cellulose, CMC), thalidomide (40 mg/kg), thalidomide (200 mg/kg), or silymarin (50 mg/kg), each given by gavage twice daily for 3 weeks starting after 1 week of DMN administration. Thalidomide (100-800 nM) concentration-dependently inhibited NFjB transcriptional activity induced by TNF-a, including IKKa expression and IjBa phosphorylation in HSC-T6 cells. In addition, thalidomide also suppressed TGF-b1-induced a-SMA expression and collagen deposition in HSC-T6 cells. Fibrosis scores of livers from DMNtreated rats receiving high dose of thalidomide (0.89±0.20) were significantly reduced in comparison with those of DMN-treated rats receiving vehicle (1.56±0.18). Hepatic collagen contents of DMN rats were also significantly reduced by either thalidomide or silymarin treatment. Immunohistochemical double staining results showed that a-SMA-and NFjB-positive cells were decreased in the livers from DMN rats receiving either thalidomide or silymarin treatment. In addition, real-time PCR analysis indicated that hepatic mRNA expressions of TGF-b1, a-SMA, collagen 1a2, TNF-a and iNOS genes were attenuated by thalidomide treatment. In conclusion, our results showed that thalidomide inhibited activation of HSC-T6 cells by TNF-a and ameliorated liver fibrosis in DMN-intoxicated rats.

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Thalidomide ameliorates carbon tetrachloride induced cirrhosis in the rat

Abstract: Thalidomide prevented necrosis, cholestasis and fibrosis induced by CCl(4). Its mechanism of action may be related to its anti-inflammatory, anti-tumour necrosis factor-alpha and anti-fibrotic activities reported previously.

Cited by 31 publications

References 22 publications

The effect of thalidomide on spinal cord ischemia/reperfusion injury in a rabbit model

The effect of thalidomide on spinal cord ischemia/reperfusion injury in a rabbit model

Thalidomide in Rat Liver Cirrhosis: Blockade of Tumor Necrosis Factor-α via Inhibition of Degradation of an Inhibitor of Nuclear Factor-κB

Anti-Fibrotic Effects of Thalidomide on Hepatic Stellate Cells and Dimethylnitrosamine-Intoxicated Rats

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