Valencia, 05/11/2023. The CIPF Neurobiology Laboratory investigates the molecular mechanisms responsible for cognitive and motor impairment in hepatic encephalopathy, a complex neuropsychiatric syndrome that reduces the quality and life span of patients with cirrhosis and other liver diseases. His research in animal models has allowed Dr Felipo group to identify some mechanisms responsible for the appearance of hepatic encephalopathy (HE). Based on these results, they have designed and tested new therapies and drugs in animal models that have allowed to reverse cognitive and motor impairments by acting on different therapeutic targets.
In this article, invited by the journal Expert Opinion on Investigational Drugs, the group reviews the different therapeutic possibilities for hepatic encephalopathy. Current treatments are lactulose or rifaximin, which act on the intestinal microbiota, but their efficacy is limited. Studies developed at the CIPF Neurobiology Laboratory have shown that the process by which liver failure induces cognitive and motor impairment involves a series of sequential steps that include the induction of hyperammonemia, microbiota alterations, and peripheral inflammation and changes in the immunophenotype and extracellular vesicles in blood. These peripheral alterations are transmitted to the brain to induce neuroinflammation, which alters neurotransmission leading to cognitive and motor impairment (Figure).
The group results show that hepatic encephalopathy can be improved by acting on any of these steps. Along these lines, HE can be reversed using drugs or treatments that act by modulating the microbiota such as rifaximin, probiotics or fecal transplant. The Neurobiology Laboratory has shown that HE may be also improved by reducing peripheral inflammation with anti-TNFα and other treatments, reducing neuroinflammation with sulforaphane, with p38 MAP kinase inhibitors or with sphingosine-1-phosphate receptor 2 antagonists or modulating cyclic GMP levels with phosphodiesterase 5 inhibitors. HE can also be improved by reducing GABAergic neurotransmission with GABAA receptor modulators such as preganolone sulfate or golexanolone. Another procedure that reverses cognitive and motor impairment in animal models of HE is treatment with extracellular vesicles from mesenchymal stem cells.
These results of the group have provided a wide range of possible treatments for HE in cirrhotic patients. However, progress in the treatment of HE is still very limited due to the lack of translation of advances from preclinical research to clinical trials.
This CIPF team points out that it is necessary to develop clinical trials to evaluate drugs that act on the immune system/peripheral inflammation, neuroinflammation or neurotransmission to improve HE and that have already shown their efficacy in animal models
Link to the article: https://doi.org/10.1080/13543784.2023.2277386
