Infliximab reduces peripheral inflammation, neuroinflammation, and extracellular GABA in the cerebellum and improves learning and motor coordination in rats with hepatic encephalopathy.
Peripheral inflammation contributes to the neurological alterations in hepatic encephalopathy (HE). Neuroinflammation and altered GABAergic neurotransmission mediate cognitive and motor alterations in rats with HE. It remains unclear (a) if neuroinflammation and neurological impairment in HE are a consequence of peripheral inflammation and (b) how neuroinflammation impairs GABAergic neurotransmission. The aims were to assess in rats with HE whether reducing peripheral inflammation with anti-TNF-α (1) prevents cognitive impairment and motor in-coordination, (2) normalizes neuroinflammation and extracellular GABA in the cerebellum and also (3) advances the understanding of mechanisms linking neuroinflammation and increased extracellular GABA.



Rats with HE due to portacaval shunt (PCS) were treated with infliximab. Astrocytes and microglia activation and TNF-α and IL-1β were analyzed by immunohistochemistry. Membrane expression of the GABA transporters GAT-3 and GAT-1 was analyzed by cross-linking with BS3. Extracellular GABA was analyzed by microdialysis. Motor coordination was tested using the beam walking and learning ability using the Y maze task.



PCS rats show peripheral inflammation, activated astrocytes, and microglia and increased levels of TNF-α and IL-1β. Membrane expression of GAT-3 and extracellular GABA are increased, leading to impaired motor coordination and learning ability. Infliximab reduces peripheral inflammation, microglia, and astrocyte activation and neuroinflammation and normalizes GABAergic neurotransmission, motor coordination, and learning ability.



Neuroinflammation is associated with altered GABAergic neurotransmission and increased GAT-3 membrane expression and extracellular GABA (a); peripheral inflammation is a main contributor to the impairment of motor coordination and of the ability to learn the Y maze task in PCS rats (b); and reducing peripheral inflammation using safe procedures could be a new therapeutic approach to improve cognitive and motor function in patients with HE
Laboratorio de Neurobiología, Centro Investigación Príncipe Felipe de Valencia, Eduardo Primo Yufera, 3, 46012, Valencia, Spain.
Sherry
S
Dadsetan
Laboratorio de Neurobiología, Centro Investigación Príncipe Felipe de Valencia, Eduardo Primo Yufera, 3, 46012, Valencia, Spain.
Tiziano
T
Balzano
Instituto Valenciano de Patología, Unidad Mixta de Patología Molecular, Centro de Investigación Príncipe Felipe/Universidad Católica de Valencia, Valencia, Spain.
Jerónimo
J
Forteza
Laboratorio de Neurobiología, Centro Investigación Príncipe Felipe de Valencia, Eduardo Primo Yufera, 3, 46012, Valencia, Spain.
Ana
A
Agusti
Laboratorio de Neurobiología, Centro Investigación Príncipe Felipe de Valencia, Eduardo Primo Yufera, 3, 46012, Valencia, Spain.
Andrea
A
Cabrera-Pastor
Laboratorio de Neurobiología, Centro Investigación Príncipe Felipe de Valencia, Eduardo Primo Yufera, 3, 46012, Valencia, Spain.
Lucas
L
Taoro-Gonzalez
Laboratorio de Neurobiología, Centro Investigación Príncipe Felipe de Valencia, Eduardo Primo Yufera, 3, 46012, Valencia, Spain.
Vicente
V
Hernandez-Rabaza
Laboratorio de Neurobiología, Centro Investigación Príncipe Felipe de Valencia, Eduardo Primo Yufera, 3, 46012, Valencia, Spain.
Belen
B
Gomez-Gimenez
Laboratorio de Neurobiología, Centro Investigación Príncipe Felipe de Valencia, Eduardo Primo Yufera, 3, 46012, Valencia, Spain.
Nisrin
N
ElMlili
Laboratorio de Neurobiología, Centro Investigación Príncipe Felipe de Valencia, Eduardo Primo Yufera, 3, 46012, Valencia, Spain.
Marta
M
Llansola
Laboratorio de Neurobiología, Centro Investigación Príncipe Felipe de Valencia, Eduardo Primo Yufera, 3, 46012, Valencia, Spain. vfelipo@cipf.es.
Vicente
0000-0003-3145-9538
V
Felipo
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D002531:Cerebellum / Q000378:metabolism*; D006152:Cyclic GMP / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D045604:Extracellular Fluid / Q000378:metabolism; D050485:GABA Plasma Membrane Transport Proteins / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006501:Hepatic Encephalopathy / Q000150:complications / Q000473:pathology*; D007249:Inflammation / Q000188:drug therapy* / Q000209:etiology; D000069285:Infliximab / Q000494:pharmacology / Q000627:therapeutic use*; D007859:Learning Disabilities / Q000188:drug therapy* / Q000209:etiology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D011596:Psychomotor Disorders / Q000188:drug therapy* / Q000209:etiology; D051381:Rats; D017208:Rats, Wistar; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D000893:Anti-Inflammatory Agents; D016207:Cytokines; D050485:GABA Plasma Membrane Transport Proteins; D005904:Glial Fibrillary Acidic Protein; D005680:gamma-Aminobutyric Acid; D000069285:Infliximab; D006152:Cyclic GMP; D015232:Dinoprostone
GABA; GAT-3; Hepatic encephalopathy; Infliximab; Microglial activation; Neuroinflammation; Neurological alterations