Fig. 12

Summary of the main effects of MSC-EVs in hippocampus of hyperammonemic rats: underlying mechanisms. Hyperammonemia induces neuroinflammation in hippocampus, with microglial activation, increasing pro-inflammatory factors (IL-1β, TNFα) and reducing anti-inflammatory factors (IL-4, Arg1). Increased IL-1β and activation of its receptor alters membrane expression of NR2B, GluA1 and GluA2 subunits of NMDA and AMPA receptors, leading to impairment of cognitive function, and to learning and memory deficits. Extracellular vesicles derived from mesenchymal stem cells (MSCs) injected to hyperammonemic rats reach the hippocampus, reduce the expression of pro-inflammatory factors and increase the expression of anti-inflammatory factors, reverse neuroinflammation in hippocampus and restore different forms of learning and memory. The results reported indicate that these beneficial effects are mediated by the TGFβ–TGFβR2–Smad7–IkBα–NF-κB pathway. The content of TGFβ, its receptor TGFβR2 and Smad7 are reduced in hyperammonemia, leading to reduced IkBα protein and increased NF-κB activation, which induces the expression of pro-inflammatory markers such as IL-1β and TNFα, leading to cognitive impairment. EVs from MSCs contain TGFβ, which normalizes the TGFβ–TGFβR2–Smad7–IkBα–NF-κB pathway in hyperammonemic rats. This normalizes IL-1β levels and, subsequently the membrane expression of NR2B, GluA1 and GluA2 subunits, restoring cognitive function. Created with Biorender