Hepatoprotective and Anti-fibrotic Agents: It's Time to Take the Next Step

Abstract

Hepatic fibrosis and cirrhosis cause strong human suffering and necessitate a monetary burden worldwide. Therefore, there is an urgent need for the development of therapies. Pre-clinical animal models are indispensable in the drug discovery and development of new anti-fibrotic compounds and are immensely valuable for understanding and proofing the mode of their proposed action. In fibrosis research, inbreed mice and rats are by far the most used species for testing drug efficacy. During the last decades, several hundred or even a thousand different drugs that reproducibly evolve beneficial effects on liver health in respective disease models were identified. However, there are only a few compounds (e.g., GR-MD-02, GM-CT-01) that were translated from bench to bedside. In contrast, the large number of drugs successfully tested in animal studies is repeatedly tested over and over engender findings with similar or identical outcome. This circumstance undermines the 3R (Replacement, Refinement, Reduction) principle of Russell and Burch that was introduced to minimize the suffering of laboratory animals. This ethical framework, however, represents the basis of the new animal welfare regulations in the member states of the European Union. Consequently, the legal authorities in the different countries are halted to foreclose testing of drugs in animals that were successfully tested before. This review provides a synopsis on anti-fibrotic compounds that were tested in classical rodent models. Their mode of action, potential sources and the observed beneficial effects on liver health are discussed. This review attempts to provide a reference compilation for all those involved in the testing of drugs or in the design of new clinical trials targeting hepatic fibrosis.

Ursolic acid ameliorates CCl4‐induced liver fibrosis through the NOXs/ROS pathway

“…This occurs because NOXs deliver electrons to O 2 molecules, and generate reactive oxygen species (ROS). The agglutination of intracellular ROS can lead to cell structure damage, oxidative stress, and inflammatory injury (Nisimoto, Diebold, Cosentino‐Gomes, & Lambeth, ; Weiskirchen, ). We observed the effect of UA intervention on ROS in HCs, HSCs, and KCs.…”

Consensus on the diagnosis and treatment of hepatic fibrosis (2019)

“…Chronic inflammatory response is the premise of fibrogenesis and the driving force of fibrosis progression. The inhibition of hepatic inflammation, the protection of hepatocytes and anti‐oxidation are important measures for anti‐fibrosis treatment …”

Therapeutic targeting of the mitochondrial reactive oxygen species engine prevents portal hypertension and hepatic fibrogenesis

“…Of course, there is already an extensive list of hepatoprotective compounds targeting ROS formation. 8 Beneficial effects were reported for several sulphur-containing antioxidants (eg glutathione, N-acetyl-L-cysteine, S-Nitroso-N-acetylcysteine, S-adenosyl-L-methionine, S-allylcysteine), non-sulphur-containing substances (α-tocopherol, trolox), naturally occurring phenols, isoflavones (caffeic acids, rosmarinic acid, genistein, luteolin, quercitin, apigenin), nicotinic acid derivatives and lots of other drugs. However, all these substances do not specifically target mitochondria that in normal, non-ischaemic cells are the motor of ROS formation producing up to 95% of all cellular ROS.…”