Fig. 12

Proposed mechanisms by which chronic hyperammonemia increases TNF-a in neurons and glial cells. a Chronic hyperammonemia induces the activation of microglia and astrocytes in the white matter of the cerebellum. Activated glial cells increase the nuclear translocation of NF-kB, which induces the transcription of pro-inflammatory TNF-a. Glial TNF-a binds to the TNFR1 receptor in Purkinje cells, leading to the activation of the NF-kB pathway and TNF-a synthesis in these neurons. b Peripheral treatment with infliximab reduces glial cell activation and TNF-a synthesis, which prevents the activation of the NF-KB pathway and TNF-a synthesis in Purkinje neurons. Finally, ex vivo treatment of cerebellar slices from hyperammonemic rats with R7050 shows that TNF-a synthesis in glial cells and neurons is mediated by the activation of the TNFR1-TRAD/RIP1-NF-κB pathway