Protein Pept Lett. 2022 Aug 25. doi: 10.2174/0929866529666220825150025. Online ahead of print.
BACKGROUND: Hepatic encephalopathy (HE) is a neuropsychiatric syndrome that involves cognitive and motor dysfunctions due to hepatic failure. Clinical and experimental studies suggest that the angiotensin (Ang) converting enzyme (ACE), Ang II, and angiotensin type 1 receptor (AT1R), that compose the classical pathway of the renin-angiotensin system (RAS), exacerbate neuroinflammation in different neurologic diseases. Conversely, Ang-(1-7), ACE2, and Mas receptor, which integrate the alternative RAS axis, have been shown as a promise therapeutic targets in neuropsychiatric disorders, leading to neuroprotection.
OBJECTIVE: This study aimed to investigate the potential participation of the RAS components in thioacetamide (TAA)-induced HE in mice.
METHODS: We also evaluated the levels of neurotrophic factors, pro-inflammatory cytokines, and chemokine in the central nervous system of TAA-induced HE in mice. Mice were submitted to acute liver failure induced by TAA administration by intraperitoneal route. Measurements of RAS components (ACE, Ang II, ACE2 and Ang1-7) and neurotrophic factors (BDNF, GDNF and NGF) were obtained by ELISA assay. Pro-inflammatory cytokines (TNF, IFN-γ, IL-6, IL-12p70) and the chemokine (CCL2) were quantified by cytometric bead array. Student’s t test was applied for statistical analysis.
RESULTS: Mice presented increased cortical levels of ACE, while Ang-(1-7) levels were decreased in cortical and hippocampal samples compared to controls. Moreover, HE mice had an increase in the Ang II/Ang-(1-7) ratio along with reduced levels of neural growth factor (NGF) in the prefrontal cortex. They also showed elevated levels of IFN-γ and CCL2 in the prefrontal cortex and of TNF, IL-6, IL-12, and CCL2 in the hippocampus, compared with controls.
CONCLUSION: This study suggested that the reduction of components of the alternative RAS axis was associated with the deleterious effects of neuroinflammation and lower neuroprotective effects of NGF during TAA-induced HE.