Peripheral inflammation induces neuroinflammation that alters neurotransmission and cognitive and motor function in hepatic encephalopathy: Underlying mechanisms and therapeutic implications

Abstract

Several million patients with liver cirrhosis suffer minimal hepatic encephalopathy (MHE), with mild cognitive and coordination impairments that reduce their quality of life and life span. Hyperammonaemia and peripheral inflammation act synergistically to induce these neurological alterations. We propose that MHE appearance is because of the changes in peripheral immune system, which are transmitted to brain, leading to neuroinflammation that alters neurotransmission leading to cognitive and motor alterations. We summarize studies showing that MHE in cirrhotic patients is associated with alterations in the immune system and that patients died with HE show neuroinflammation in cerebellum, with microglial and astrocytic activation and Purkinje cell loss. We also summarize studies in animal models of MHE on the role of peripheral inflammation in neuroinflammation induction, how neuroinflammation alters neurotransmission and how this leads to cognitive and motor alterations. These studies identify therapeutic targets and treatments that improve cognitive and motor function. Rats with MHE show neuroinflammation in hippocampus and altered NMDA and AMPA receptor membrane expression, which impairs spatial learning and memory. Neuroinflammation in cerebellum is associated with altered GABA transporters and extracellular GABA, which impair motor coordination and learning in a Y maze. These alterations are reversed by treatments that reduce peripheral inflammation (anti‐TNFα, ibuprofen), neuroinflammation (sulphoraphane, p38 inhibitors), GABAergic tone (bicuculline, pregnenolone sulphate) or increase extracellular cGMP (sildenafil or cGMP). The mechanisms identified would also occur in other chronic diseases associated with inflammation, aging and some mental and neurodegenerative diseases. Treatments that improve MHE may also be beneficial to treat these pathologies.

COVID-19, Mast Cells, Cytokine Storm, Psychological Stress, and Neuroinflammation

“…Though the research on COVID-19 is very active globally, the pathogenesis is not yet clearly understood. Previous studies have shown that peripheral immune response and inflammation can cause and exacerbate acute and chronic neuroinflammatory response (Cabrera-Pastor and others 2019; Kempuraj and others 2017; Kempuraj and others 2019a; Kempuraj and others 2019b; Kustrimovic and others 2019; Magrone and others 2020; Skaper and others 2017; Stuve and Zettl 2014). Mast cells are implicated in psychological stress, inflammatory and neuroinflammatory response (Theoharides 2020b).…”

Extracellular Vesicles from Hyperammonemic Rats Induce Neuroinflammation and Motor Incoordination in Control Rats

“…Studies in patients and in animal models show that MHE appearance is associated with changes in the peripheral immune system that are transferred to the brain, inducing neuroinflammation, which in turn leads to cognitive and motor impairment [6][7][8][9][10][11].…”

“…We have shown that induction of motor incoordination by hyperammonemia is mainly mediated by induction of microglia and astrocytes activation in cerebellum, which is associated to increased TNFα, which activates its receptor TNFR1, leading to increased NF-κB in microglia and expression of glutaminase, which increases glutamate, leading to reversal of the GABA transporter GAT3 function in activated astrocytes and increased GABAergic neurotransmission, finally inducing motor incoordination [9][10][11]. We have therefore analyzed the effects of injecting EVs from hyperammonemic rats to control rats on these mechanisms in cerebellum.…”

Cognition-tracking-based strategies for diagnosis and treatment of minimal hepatic encephalopathy

“…Neuroinflammation in cerebellum impairs learning in a Y maze and motor co-ordination. Hyperaminemia triggers neuroinflammation by activating microglia and increasing markers associated with impaired cognitive function (Cabrera-Pastor et al 2019 ; Malaguarnera et al 2019 ). Cabrera-Pastor demonstrated that hyperammonemia induced neuroinflammation was related to impaired memory and spatial learning in hyperammonemic rats.…”