Modified Levels of Renin Angiotensin Related Components in the Frontal Cortex and Hippocampus were Associated with Neuroinflammation and Lower Neuroprotective Effects of NGF During Acute Hepatic Encephalopathy in Mice

Abstract

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.

Nicorandil attenuates cognitive impairment after traumatic brain injury via inhibiting oxidative stress and inflammation: Involvement of BDNF and NGF

“…These results suggested that upregulation of BDNF and NGF levels may contribute to the protection of nicorandil against cognitive dysfunction after TBI. Previous studies also reveal that BDNF/NGF downregulates cellular oxidative stress and inflammation during brain injury (Oliveira et al, 2022;Scotton et al, 2020), implying the possible involvement of BDNF and NGF in the antioxidative stress and anti-inflammation of nicorandil.…”

Anti-inflammatory strategies for hepatic encephalopathy: preclinical studies

“… 50 51 52 In mice, Oliveira et al showed elevated levels of IFN-γ and CCL2 in the prefrontal cortex and of TNF, IL-6, IL-12, and CCL2 in the hippocampus of TAA-treated animals. 53 Alongside these data, TAA intoxication was associated with microglial and astroglial activation. 54 Briefly, acute injection of TAA leads to liver injury, impairing the elimination of blood toxins, such as ammonia and lipopolysaccharides.…”