Thalidomide ameliorates carbon tetrachloride induced cirrhosis in the rat.
OBJECTIVE
Thalidomide has anti-inflammatory, anti-tumour necrosis factor-alpha and anti-collagen activities. Cirrhosis is characterized by inflammation and fibrosis. Thus, thalidomide was evaluated in an experimental model of liver cirrhosis.


METHODS
Male Wistar rats were used. Group 1 (n = 8) received mineral oil i.p. (control); group 2 (n = 15) received CCl(4) i.p. for 8 weeks to induce cirrhosis; group 3 (n = 15) consisted of rats receiving CCl(4) plus thalidomide (200 mg/kg/12 h); animals in group 4 (n = 8) received thalidomide only. Alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (gamma-GTP) and alkaline phosphatase (ALP) were measured in serum, while collagen (hydroxyproline), glycogen and lipid peroxidation were determined in liver samples. A liver histopathological analysis was performed by using Gomori's trichromic staining.


RESULTS
Intoxication with CCl(4) induced 33.3% mortality, while thalidomide co-treatment reduced it to 13.3%. The serum activities of ALT, gamma-GTP and ALP increased 3, 2 and 4-fold by CCl(4) treatment; thalidomide completely prevented elevation of these enzymes. In the liver, lipid peroxidation increased about 20-fold and glycogen was abolished in CCl(4) cirrhotic rats; thalidomide completely prevented the former and partially (P < 0.05) the latter. CCl(4) treated rats revealed a loss of normal architecture and nodules of hepatocytes surrounded by thick bands of collagen. Thalidomide + CCl(4) treated rats showed minor histological alterations and thinner bands of collagen. The anti-fibrotic effect estimated by hydroxyproline was partial but significant (P < 0.05).


CONCLUSIONS
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.
Muriel
Pablo
P
Sección de Farmacología, CINVESTAV-I.P.N., México City, México. p.a.muriel@mail.cinvestav.mx
Fernández-Martínez
Eduardo
E
Pérez-Alvarez
Víctor
V
Lara-Ochoa
Francisco
F
Ponce
Susana
S
García
Julio
J
Shibayama
Mineko
M
Tsutsumi
Víctor
V
D000410:Alanine Transaminase / Q000097:blood; D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D002251:Carbon Tetrachloride; D004353:Drug Evaluation, Preclinical; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D016019:Survival Analysis; D013792:Thalidomide / Q000627:therapeutic use*; D005723:gamma-Glutamyltransferase / Q000097:blood
D007166:Immunosuppressive Agents; D013792:Thalidomide; D002251:Carbon Tetrachloride; D005723:gamma-Glutamyltransferase; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase