Specific type IV phosphodiesterase inhibitor ameliorates thioacetamide-induced liver injury in rats.
OBJECTIVE
Rolipram is a specific type IV phosphodiesterase inhibitor that suppresses the activity of immune cells and the production of pro-inflammatory cytokines. In this study, we assessed the effect of rolipram on acute liver injury using thioacetamide (TAA)-induced liver injury in rats as a model.


METHODS
Rats were treated with rolipram (0.5-5 mg/kg, intraperitoneally) or vehicle and injected 30 min later with TAA (100 mg/kg, subcutaneously). Serum transaminase concentrations and tumor necrosis factor-alpha (TNF-alpha), interleukin 1beta (IL-1beta) and growth related oncogene/cytokine-induced neutrophil chemoattractant-1 (GRO/CINC-1) levels were measured and livers were examined for microscopic changes. Dose-dependent protection against TAA liver injury was based on transaminase levels and inflammatory cytokine production, and was measured 9 h after TAA when the peak release of cytokines occurred.


RESULTS
Rolipram suppressed liver injury based on serum aspartate transaminase (AST), alanine transaminase (ALT) and histology and reduced TNF-alpha, IL-1beta and GRO/CINC-1 levels. Rolipram, at doses of 0.5-5 mg/kg, suppressed serum transaminase and TNF-alpha production in a dose-dependent manner, and these effects were significant at doses of 2.5 and 5 mg/kg.


CONCLUSIONS
In our rodent model of acute liver injury, rolipram clearly reduced liver damage and inhibited pro-inflammatory cytokine production. These results suggest that specific type IV phosphodiesterase inhibitors, such as rolipram, have potent hepatoprotective effects that are associated with suppressing inflammatory cytokine production.
Matsuhashi
Tamotsu
T
Department of Gastroenterology, Akita University School of Medicine, Akita City, Akita, Japan.
Otaka
Michiro
M
Odashima
Masaru
M
Jin
Mario
M
Komatsu
Koga
K
Konishi
Noriaki
N
Wada
Isao
I
Sato
Toshihiro
T
Horikawa
Youhei
Y
Ohba
Reina
R
Oyake
Jinko
J
Hatakeyama
Natsumi
N
Watanabe
Sumio
S
D000818:Animals; D056486:Chemical and Drug Induced Liver Injury; D008107:Liver Diseases / Q000188:drug therapy*; D008297:Male; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020889:Rolipram / Q000627:therapeutic use*; D013853:Thioacetamide / Q000009:adverse effects*
D010726:Phosphodiesterase Inhibitors; D013853:Thioacetamide; D020889:Rolipram