A less severe approach to liver fibrosis research in rats has for the first time been developed that is both reversible and leads to minimal mortality compared with the common surgical method.
In the study led by PhD student Philip Probert, Newcastle University, male rats were orally dosed with 150mg of methapyrilene per kg body weight three times per week for up to six weeks and compared with rats who had undergone bile duct ligation, a common surgical procedure for causing liver injury which is classed as "severe" under the Animals (Scientific Procedures) Act 1986.
As well as being a severe procedure, bile duct ligation is irreversible in practice, the severity of the injury cannot be modulated and it leads to high mortality in rats.
Oral administration of methapyrilene, a type of antihistamine, was shown to be as effective as bile duct ligation in inducing liver injury and fibrosis. Injury, inflammation, fibrosis and ductular reaction which occurred as a result of treatment all reversed within three weeks after treatment withdrawal.
Studies with methapyrilene also resulted in no rat mortality. In their paper published in Toxicology Research, the authors conclude that the refined procedure is a more sensitive model to identify effective anti-fibrogenic drugs.
The NC3Rs-funded research is part of a £120,000 four-year studentship to apply the 3Rs to liver fibrosis research. Mr Probert aims to develop an animal model that reduces both suffering and the number of animals needed to better understand how drugs could treat this disease.
Fibrosis is a major complication in chronic liver disease, for which there is currently no cure, and remains a major cause of death worldwide.
Finding treatments requires the use of animals because several different cell types and several tissues combine to produce the main disease outcome fibrosis or tissue scarring.
Probert PME, Ebrahimkhani MR, Oakley F, Mann J, Burt AD, Mann DA, Wright MC (2013): A reversible model for periportal fibrosis and a refined alternative to bile duct ligation. Toxicology Research (In Press): DOI: 10.1039/c3tx50069a