Sildenafil reduces neuroinflammation and restores spatial learning in rats with hepatic encephalopathy: underlying mechanisms.
BACKGROUND
There are no specific treatments for the neurological alterations of cirrhotic patients with minimal hepatic encephalopathy (MHE). Rats with MHE due to portacaval shunt (PCS) show impaired spatial learning. The underlying mechanisms remain unknown. The aims of this work were to assess: (a) whether PCS rats show neuroinflammation in hippocampus, (b) whether treatment with sildenafil reduces neuroinflammation and restores spatial learning in PCS rats, and (c) analyze the underlying mechanisms.


METHODS
Neuroinflammation was assessed by determining inflammatory markers by Western blot. Phosphorylation of MAP-kinase p38 was assessed by immunohistochemistry. Membrane expression of GABA and glutamate receptors was analyzed using BS3 cross-linker. Spatial learning was analyzed using the radial and Morris water mazes. To assess if sildenafil reverses the alterations, rats were treated with sildenafil in the drinking water.


RESULTS
PCS rats show increased IL-1β and TNF-α levels and phosphorylation (activity) of p38 in hippocampus. Membrane expression of subunits α1 of GABAA receptor and GluR2 of AMPA receptor are increased in PCS rats, while subunits GluR1 of AMPA receptors and NR1 and NR2a of NMDA receptors are reduced. PCS rats show reduced spatial learning in the radial and Morris water mazes. Sildenafil treatment normalizes IL-1β and TNF-α levels, p38 phosphorylation, and membrane expression of GABAA, AMPA, and NMDA receptors and restores spatial learning.


CONCLUSIONS
Increased IL-1β alters GABAergic and glutamatergic neurotransmission in hippocampus and impairs spatial learning in rats with MHE. Sildenafil reduces neuroinflammation and restores learning. Phosphodiesterase-5 inhibitors may be useful to improve cognitive function in patients with MHE.
Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Calle Eduardo Primo Yufera, 3, 46012, Valencia, Spain.
Vicente
V
Hernandez-Rabaza
Fundación Investigación Hospital Clínico de Valencia. Instituto de Investigación Sanitaria-INCLIVA, Valencia, Spain.
Ana
A
Agusti
Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Calle Eduardo Primo Yufera, 3, 46012, Valencia, Spain.
Andrea
A
Cabrera-Pastor
Laboratorio de Moleculas Orgánicas, Centro de Investigación Príncipe Felipe, Valencia, Spain.|Departamento de Química Organica, Universidad de Valencia, Valencia, Spain.
Santos
S
Fustero
Laboratorio de Moleculas Orgánicas, Centro de Investigación Príncipe Felipe, Valencia, Spain.|Departamento de Química Organica, Universidad de Valencia, Valencia, Spain.
Oscar
O
Delgado
Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Calle Eduardo Primo Yufera, 3, 46012, Valencia, Spain.
Lucas
L
Taoro-Gonzalez
Fundación Investigación Hospital Clínico de Valencia. Instituto de Investigación Sanitaria-INCLIVA, Valencia, Spain.
Carmina
C
Montoliu
Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Calle Eduardo Primo Yufera, 3, 46012, Valencia, Spain.
Marta
M
Llansola
Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Calle Eduardo Primo Yufera, 3, 46012, Valencia, Spain. vfelipo@cipf.es.
Vicente
V
Felipo
D000818:Animals; D006501:Hepatic Encephalopathy / Q000188:drug therapy* / Q000473:pathology / Q000523:psychology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy* / Q000473:pathology; D053583:Interleukin-1beta / Q000378:metabolism; D008262:Macrophage Activation / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects*; D017628:Microglia / Q000187:drug effects; D011167:Portacaval Shunt, Surgical; D051381:Rats; D017208:Rats, Wistar; D018079:Receptors, GABA / Q000096:biosynthesis; D017470:Receptors, Glutamate / Q000096:biosynthesis; D000068677:Sildenafil Citrate / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014665:Vasodilator Agents / Q000627:therapeutic use*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D053583:Interleukin-1beta; D018079:Receptors, GABA; D017470:Receptors, Glutamate; D014409:Tumor Necrosis Factor-alpha; D014665:Vasodilator Agents; D000068677:Sildenafil Citrate; D048051:p38 Mitogen-Activated Protein Kinases