Inhibition of Autotaxin Ameliorates LPA-Mediated Neuroinflammation and Alleviates Neurological Dysfunction in Acute Hepatic Encephalopathy

Growing evidence suggests an essential role of neuroinflammation in behavioral abnormalities associated with hepatic encephalopathy (HE). Here, we report the involvement of autotaxin-lysophosphatidic acid (LPA) signaling in HE's pathogenesis. We demonstrate that the autotaxin (ATX) inhibitor PF-8380 attenuates neuroinflammation and improves neurological dysfunction in the mouse model of HE. In the thioacetamide (TAA)-induced model of HE, we found a twofold increase in the levels of ammonia in the brain and in plasma along with a significant change in HE-related behavioral parameters. Mice with HE show an increased brain weight, increased levels of tumor necrosis factor-α (TNF-α), IL-1β (interleukin-1β), interleukin-6 (IL-6), and LPA 18:0 in the cerebral cortex and hippocampus, and increased levels of LPA 18:0 in plasma. Treatment with the autotaxin inhibitor (ATXi) did not affect liver injury, as we observed no change in liver function markers including aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin (TBIL) and no change in ammonia levels in the brain and plasma. However, ATXi treatment significantly ameliorated the neuroinflammation, reduced the levels of LPA 18:0 in the cerebral cortex and hippocampus in the brain and plasma, and reduced brain edema and the levels of IL1β, IL-6, and TNF-α. The neurobehavioral symptoms for HE such as the cognitive and motor function deficit and overall clinical grading score were significantly improved in ATXi-treated mice. Mouse astrocytes and microglia stimulated with NH4CL with or without ATXi showed significant attenuation of oxidative stress and the neuroinflammatory effect of NH4CL in ATXi-treated cells.

 

Comments:

The passage you provided describes a study conducted on a mouse model of hepatic encephalopathy (HE) to investigate the role of neuroinflammation and autotaxin-lysophosphatidic acid (LPA) signaling in the pathogenesis of HE. The researchers found that an autotaxin inhibitor called PF-8380 attenuated neuroinflammation and improved neurological dysfunction in mice with HE.

In the study, HE was induced in mice using thioacetamide (TAA), which led to increased levels of ammonia in the brain and plasma, along with changes in HE-related behavioral parameters. Mice with HE also exhibited increased brain weight and elevated levels of inflammatory markers such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and LPA 18:0 in the cerebral cortex and hippocampus. Increased levels of LPA 18:0 were also found in the plasma.

Treatment with the autotaxin inhibitor (ATXi) did not affect liver injury, as indicated by the levels of liver function markers. However, ATXi treatment had beneficial effects on neuroinflammation, reducing the levels of LPA 18:0 in the brain and plasma, as well as brain edema and the levels of IL-1β, IL-6, and TNF-α. Moreover, ATXi treatment significantly improved neurobehavioral symptoms associated with HE, such as cognitive and motor function deficits.

In cell studies using mouse astrocytes and microglia stimulated with NH4CL (ammonium chloride), ATXi treatment demonstrated a significant reduction in oxidative stress and the neuroinflammatory effects induced by NH4CL in these cells.

Overall, the study suggests that autotaxin-lysophosphatidic acid signaling plays a role in the pathogenesis of hepatic encephalopathy and that targeting autotaxin with an inhibitor could potentially be a therapeutic approach to alleviate neuroinflammation and improve neurological dysfunction associated with HE.