TNFα induced up-regulation of Na+,K+,2Cl− cotransporter NKCC1 in hepatic ammonia clearance and cerebral ammonia toxicity

Abstract

The devastating consequences of hepatic failure include hepatic encephalopathy, a severe, life threatening impairment of neuronal function. Hepatic encephalopathy is caused by impaired hepatic clearance of NH4 +. Cellular NH4 + uptake is accomplished mainly by the Na+,K+,2Cl− cotransporter. Here we show that hepatic clearance of NH4 + is impaired in TNFα deficient as well as TNFR1&TNFR2 double knockout mice, which both develop hyperammonemia. Despite impaired hepatic clearance of NH4 +, TNFα deficient mice and TNFR1 deficient mice were protected against acute ammonia intoxication. While 54% of the wild-type mice and 60% of TNFR2 deficient mice survived an NH4 + load, virtually all TNFα deficient mice and TNFR1 deficient mice survived the treatment. Conversely, TNFα treatment of wild type mice sensitized the animals to the toxic effects of an NH4 + load. The protection of TNFα-deficient mice against an NH4 + load was paralleled by decreased cerebral expression of NKCC1. According to the present observations, inhibition of TNFα formation and/or NKCC1 may be strategies to favorably influence the clinical course of hepatic encephalopathy.

Repeated anodal trans‐spinal direct current stimulation results in long‐term reduction of spasticity in mice with spinal cord injury

“…; Pozdeev et al . ); therefore, we injected mice intrathecally with TNF‐α and MG‐132 30 min before a‐tsDCS application. The peak reflex stretch force was tested before a‐tsDCS and immediately after and 10, 30, 60 and 120 min after the cessation of stimulation.…”

“…To provide direct causal relationship between a-tsDCS-induced reduction in spasticity and NKCC1 expression, we performed experiments in which we used TNF-α or MG-132 to block the degradation. Both TNF-α and MG-132 were shown to prevent the degradation of NKCC1 (Ding et al 2014;Huang et al 2014;Pozdeev et al 2017); therefore, we injected mice intrathecally with TNF-α and MG-132 30 min before a-tsDCS application. The peak reflex stretch force was tested before a-tsDCS and immediately after and 10, 30, 60 and 120 min after the cessation of stimulation.…”

The Role of Intestinal Bacteria and Gut–Brain Axis in Hepatic Encephalopathy

“…Lactobacillus inhibits TNF production by converting the L-histidine in food into histamine, which improves anti-inflammatory or immunoregulatory functions through the H2 receptor ( Hemarajata et al, 2013 ). Furthermore, inhibition of TNFa formation may also protect against acute ammonia intoxication ( Pozdeev et al, 2017 ).…”

Application of tabu search-based Bayesian networks in exploring related factors of liver cirrhosis complicated with hepatic encephalopathy and disease identification

“…It is generally believed that when an organism becomes infected, catabolism increases; ammonia production increases; and liver, brain, kidney, and other solid organs are damaged. Hypoxia or hyperthermia increase the brain’s sensitivity to ammonia toxicity and induce or aggravate HE 38,41 . To a certain extent, increased total bilirubin and prolonged prothrombin time may reflect the deterioration of liver function, and severe cases of liver cirrhosis may be complicated by HE 34 .…”