EXTRACELLULAR VESICLES FROM PLASMA OF PATIENTS WITH MINIMAL HEPATIC ENCEPHALOPATHY INDUCE COGNITIVE IMPAIRMENT IN ANIMAL MODEL

Minimal hepatic encephalopathy (MHE) in cirrhotic patients is associated with a shift in peripheral inflammation. Reversal of this shift with rifaximin improves MHE. However, how peripheral alterations are transmitted to the brain to induce cognitive impairment remains unclear. In several pathologies and in rat models of MHE, extracellular vesicles (EV) from plasma are enough to induce cognitive impairment. Plasma EV could play a role in the induction of MHE in cirrhotic patients. The aims were to assess if injection to normal rats of plasmatic EV from MHE patients induce cognitive impairment and identify the underlying mechanisms.
We isolated EV from plasma of cirrhotic patients without and with MHE and from control subjects and injected them to normal rats. We analyzed cognitive function in the object location and recognition and radial maze tests, and glial activation, neuroinflammation and alterations in membrane expression of NMDA and AMPA receptors in hippocampus.
Results showed that EV from MHE patients, but not from patients without MHE, trigger cognitive impairment in normal rats. This is mediated by altered membrane expression of NMDA and AMPA receptor subunits in hippocampus, which is due to increased neuroinflammation, glial activation and TNFα and IL-1β levels.
In conclusion, in MHE patients, pathological blood EV would contribute to trigger neuroinflammation, alterations in neurotransmission and cognitive impairment. These EV could be a therapeutic target to improve MHE by modifying the EV content or by blocking the effects of the molecules that mediate their pathological effects such as TNFα.
Funding: ISCIII(PI23/00062) cofunded FEDER; GVA(CIACIF/2022/444)