Sustained Hyperammonemia Activates NF-κB in Purkinje Neurons Through Activation of the TrkB-PI3K-AKT Pathway by Microglia-Derived BDNF in a Rat Model of Minimal Hepatic Encephalopathy

Chronic hyperammonemia is a main contributor to the cognitive and motor impairment in patients with hepatic encephalopathy. Sustained hyperammonemia induces the TNF alpha expression in Purkinje neurons, mediated by NF-kappa B activation. The aims were the following: (1) to assess if enhanced TrkB activation by BDNF is responsible for enhanced NF-kappa B activation in Purkinje neurons in hyperammonemic rats, (2) to assess if this is associated with increased content of NF-kappa B modulated proteins such as TNF alpha, HMGB1, or glutaminase I, (3) to assess if these changes are due to enhanced activation of the TNFR1-S1PR2-CCR2-BDNF-TrkB pathway, (4) to analyze if increased activation of NF-kappa B is mediated by the PI3K-AKT pathway. It is shown that, in the cerebellum of hyperammonemic rats, increased BDNF levels enhance TrkB activation in Purkinje neurons leading to activation of PI3K, which enhances phosphorylation of AKT and of I kappa B, leading to increased nuclear translocation of NF-kappa B which enhances TNF alpha, HMGB1, and glutaminase I content. To assess if the changes are due to enhanced activation of the TNFR1-S1PR2-CCR2 pathway, we blocked TNFR1 with R7050, S1PR2 with JTE-013, and CCR2 with RS504393. These changes are reversed by blocking TrkB, PI3K, or the TNFR1-SP1PR2-CCL2-CCR2-BDNF-TrkB pathway at any step. In hyperammonemic rats, increased levels of BDNF enhance TrkB activation in Purkinje neurons, leading to activation of the PI3K-AKT-I kappa B-NF-kappa B pathway which increased the content of glutaminase I, HMGB1, and TNF alpha. Enhanced activation of this TrkB-PI3K-AKT-NF-kappa B pathway would contribute to impairing the function of Purkinje neurons and motor function in hyperammonemic rats and likely in cirrhotic patients with minimal or clinical hepatic encephalopathy.

Automated summary

Chronic hyperammonemia is a major cause of cognitive and motor impairment in hepatic encephalopathy patients. This study aimed to investigate the mechanism involving BDNF, TrkB, NF-kappa B, and various proteins in hyperammonemic rats. The results showed that increased BDNF levels enhanced TrkB activation, leading to PI3K-AKT-NF-kappa B pathway activation and increased content of glutaminase I, HMGB1, and TNF alpha. Blocking TrkB, PI3K, or components of the TNFR1-S1PR2-CCR2-BDNF-TrkB pathway reversed these changes. This TrkB-PI3K-AKT-NF-kappa B pathway activation may contribute to Purkinje neuron dysfunction and motor impairment in hyperammonemic rats and cirrhotic patients with hepatic encephalopathy.